1 1475 85 DISTRIBUTION OF H3K27ME3, H3K9ME3, AND H3K4ME3 ALONG AUTOPHAGY-RELATED GENES HIGHLY EXPRESSED IN STARVED ZEBRAFISH MYOTUBES. THE ZEBRAFISH (DANIO RERIO) REMAINS THE TELEOST FISH OF CHOICE FOR BIOLOGICAL INVESTIGATIONS DUE TO THE VAST ARRAY OF MOLECULAR TOOLS AND RESOURCES AVAILABLE. TO BETTER UNDERSTAND THE EPIGENETIC REGULATION OF AUTOPHAGY, WE UTILIZED A PRIMARY MYOTUBE CULTURE SYSTEM GENERATED FROM ISOLATED MYOGENIC PRECURSOR CELLS (MPCS) FROM ZEBRAFISH GROWN UNDER STARVATION CONDITIONS USING A MEDIA DEVOID OF SERUM AND AMINO ACIDS. HERE, WE REPORT STARVATION-INDUCED REGULATION OF SEVERAL AUTOPHAGY-RELATED GENES (ATG) EXPRESSION AND PROFILE THE DISTRIBUTION OF H3K27ME3, H3K9ME3, AND H3K4ME3 MARKS ALONG LC3B, ATG4B AND P62/SQSTM1 LOCI. THESE DATA SUPPORT EPIGENETIC REGULATION OF AUTOPHAGY IN RESPONSE TO STARVATION THAT SUGGESTS A LEVEL OF REGULATION THAT CAN BE SUSTAINED FOR CHRONIC CONDITIONS VIA CHROMATIN MODIFICATION. 2017 2 3160 15 GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: PATHOPHYSIOLOGY-BASED REVIEW ON CURRENT APPROACHES AND FUTURE DIRECTIONS. GRAFT-VERSUS-HOST DISEASE (GVHD) WAS FIRST DESCRIBED IN 1959, SINCE THEN MAJOR EFFORTS HAVE BEEN MADE IN ORDER TO UNDERSTAND ITS PHYSIOPATHOLOGY AND ANIMAL MODELS HAVE PLAYED A KEY ROLE. THREE STEPS, INVOLVING DIFFERENT PATHWAYS, HAVE BEEN RECOGNISED IN EITHER ACUTE AND CHRONIC GVHD, IDENTIFYING THEM AS TWO DISTINCT ENTITIES. IN ORDER TO REDUCE GVHD INCIDENCE AND SEVERITY, PROPHYLACTIC MEASURES WERE ADDED TO TRANSPLANT PROTOCOLS. THE COMBINATION OF A CALCINEURIN INHIBITOR (CNI) PLUS AN ANTIMETABOLITE REMAINS THE STANDARD OF CARE. BETTER KNOWLEDGE OF GVHD PATHOPHYSIOLOGY HAS MOVED THIS FIELD FORWARD AND NOWADAYS DIFFERENT DRUGS ARE BEING USED ON A DAILY BASIS. IMPROVING GVHD PROPHYLAXIS IS A MAJOR GOAL AS IT WOULD TRANSLATE INTO LESS NON-RELAPSE MORTALITY AND BETTER OVERALL SURVIVAL. AS COMPARED TO CNI PLUS METHOTREXATE THE COMBINATION OF CNI PLUS MYCOPHENOLATE MOPHETIL (MMF) ALLOWS US TO OBTAIN SIMILAR RESULTS IN TERMS OF GVHD INCIDENCE BUT A LOWER TOXICITY RATE IN TERMS OF NEUTROPENIA OR MUCOSITIS. THE USE OF ATG HAS BEEN RELATED TO A LOWER RISK OF ACUTE AND CHRONIC GVHD IN PROSPECTIVE RANDOMIZED TRIALS AS WELL AS THE USE OF POSTTRANSPLANT CYCLOPHOSPHAMIDE, WITH NO OR MARGINAL IMPACT ON OVERALL SURVIVAL BUT WITH AN IMPROVEMENT IN GVHD-RELAPSE FREE SURVIVAL (GRFS). THE USE OF SIROLIMUS HAS BEEN RELATED TO A LOWER RISK OF ACUTE GVHD AND SIGNIFICANTLY INFLUENCED OVERALL SURVIVAL IN ONE PROSPECTIVE RANDOMIZED TRIAL. OTHER PROSPECTIVE TRIALS HAVE EVALUATED THE USE OF RECEPTORS SUCH AS CCR5 OR ALPHA4BETA7 TO AVOID T-CELLS TRAFFICKING INTO GVHD TARGET ORGANS, CYTOKINE BLOCKERS OR IMMUNE CHECK POINT AGONISTS. ALSO, EPIGENETIC MODIFIERS HAVE SHOWN PROMISING RESULTS IN PHASE II TRIALS. ATTENTION SHOULD BE PAID TO GRAFT-VERSUS-LEUKEMIA, INFECTIONS AND IMMUNE RECOVERY BEFORE BRINGING NEW PROPHYLACTIC STRATEGIES TO CLINICAL PRACTICE. ALTHOUGH THE LIST OF NOVEL AGENTS FOR GVHD PROPHYLAXIS IS GROWING, RANDOMIZED TRIALS ARE STILL LACKING FOR MANY OF THEM. 2021 3 2821 19 FINE-TUNING AUTOPHAGY: FROM TRANSCRIPTIONAL TO POSTTRANSLATIONAL REGULATION. MACROAUTOPHAGY (HEREAFTER CALLED AUTOPHAGY) IS A VACUOLAR LYSOSOMAL PATHWAY FOR DEGRADATION OF INTRACELLULAR MATERIAL IN EUKARYOTIC CELLS. AUTOPHAGY PLAYS CRUCIAL ROLES IN TISSUE HOMEOSTASIS, IN ADAPTATION TO STRESS SITUATIONS, AND IN IMMUNE AND INFLAMMATORY RESPONSES. ALTERATION OF AUTOPHAGY IS ASSOCIATED WITH CANCER, DIABETES AND OBESITY, CARDIOVASCULAR DISEASE, NEURODEGENERATIVE DISEASE, AUTOIMMUNE DISEASE, INFECTION, AND CHRONIC INFLAMMATORY DISEASE. AUTOPHAGY IS CONTROLLED BY AUTOPHAGY-RELATED (ATG) PROTEINS THAT ACT IN A COORDINATED MANNER TO BUILD UP THE INITIAL AUTOPHAGIC VACUOLE NAMED THE AUTOPHAGOSOME. IT IS NOW KNOWN THAT THE ACTIVITIES OF ATG PROTEINS ARE MODULATED BY POSTTRANSLATIONAL MODIFICATIONS SUCH AS PHOSPHORYLATION, UBIQUITINATION, AND ACETYLATION. MOREOVER, TRANSCRIPTIONAL AND EPIGENETIC CONTROLS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY IN STRESS SITUATIONS. HERE WE SUMMARIZE AND DISCUSS HOW POSTTRANSLATIONAL MODIFICATIONS AND TRANSCRIPTIONAL AND EPIGENETIC CONTROLS REGULATE THE INVOLVEMENT OF AUTOPHAGY IN THE PROTEOSTASIS NETWORK. 2016 4 3716 17 INHIBITING INFLAMMATION WITH MYELOID CELL-SPECIFIC NANOBIOLOGICS PROMOTES ORGAN TRANSPLANT ACCEPTANCE. INDUCING GRAFT ACCEPTANCE WITHOUT CHRONIC IMMUNOSUPPRESSION REMAINS AN ELUSIVE GOAL IN ORGAN TRANSPLANTATION. USING AN EXPERIMENTAL TRANSPLANTATION MOUSE MODEL, WE DEMONSTRATE THAT LOCAL MACROPHAGE ACTIVATION THROUGH DECTIN-1 AND TOLL-LIKE RECEPTOR 4 (TLR4) DRIVES TRAINED IMMUNITY-ASSOCIATED CYTOKINE PRODUCTION DURING ALLOGRAFT REJECTION. WE CONDUCTED NANOIMMUNOTHERAPEUTIC STUDIES AND FOUND THAT A SHORT-TERM MTOR-SPECIFIC HIGH-DENSITY LIPOPROTEIN (HDL) NANOBIOLOGIC TREATMENT (MTORI-HDL) AVERTED MACROPHAGE AEROBIC GLYCOLYSIS AND THE EPIGENETIC MODIFICATIONS UNDERLYING INFLAMMATORY CYTOKINE PRODUCTION. THE RESULTING REGULATORY MACROPHAGES PREVENTED ALLOREACTIVE CD8(+) T CELL-MEDIATED IMMUNITY AND PROMOTED TOLEROGENIC CD4(+) REGULATORY T (TREG) CELL EXPANSION. TO ENHANCE THERAPEUTIC EFFICACY, WE COMPLEMENTED THE MTORI-HDL TREATMENT WITH A CD40-TRAF6-SPECIFIC NANOBIOLOGIC (TRAF6I-HDL) THAT INHIBITS CO-STIMULATION. THIS SYNERGISTIC NANOIMMUNOTHERAPY RESULTED IN INDEFINITE ALLOGRAFT SURVIVAL. TOGETHER, WE SHOW THAT HDL-BASED NANOIMMUNOTHERAPY CAN BE EMPLOYED TO CONTROL MACROPHAGE FUNCTION IN VIVO. OUR STRATEGY, FOCUSED ON PREVENTING INFLAMMATORY INNATE IMMUNE RESPONSES, PROVIDES A FRAMEWORK FOR DEVELOPING TARGETED THERAPIES THAT PROMOTE IMMUNOLOGICAL TOLERANCE. 2018 5 4039 16 MACROPHAGE NOX2 NADPH OXIDASE MAINTAINS ALVEOLAR HOMEOSTASIS IN MICE. THE LEUKOCYTE NADPH OXIDASE 2 (NOX2) PLAYS A KEY ROLE IN PATHOGEN KILLING AND IMMUNOREGULATION. GENETIC DEFECTS IN NOX2 RESULT IN CHRONIC GRANULOMATOUS DISEASE (CGD), ASSOCIATED WITH MICROBIAL INFECTIONS AND INFLAMMATORY DISORDERS, OFTEN INVOLVING THE LUNG. ALVEOLAR MACROPHAGES (AMS) ARE THE PREDOMINANT IMMUNE CELL IN THE AIRWAYS AT STEADY STATE, AND LIMITING THEIR ACTIVATION IS IMPORTANT, GIVEN THE CONSTANT EXPOSURE TO INHALED MATERIALS, YET THE IMPORTANCE OF NOX2 IN THIS PROCESS IS NOT WELL UNDERSTOOD. IN THIS STUDY, WE SHOWED A PREVIOUSLY UNDESCRIBED ROLE FOR NOX2 IN MAINTAINING LUNG HOMEOSTASIS BY SUPPRESSING AM ACTIVATION, IN CGD MICE OR MICE WITH SELECTIVE LOSS OF NOX2 PREFERENTIALLY IN MACROPHAGES. AMS LACKING NOX2 HAD INCREASED CYTOKINE RESPONSES TO TOLL-LIKE RECEPTOR-2 (TLR2) AND TLR4 STIMULATION EX VIVO. MOREOVER, BETWEEN 4 AND 12 WEEK OF AGE, MICE WITH GLOBAL NOX2 DELETION DEVELOPED AN ACTIVATED CD11BHIGH SUBSET OF AMS WITH EPIGENETIC AND TRANSCRIPTIONAL PROFILES REFLECTING IMMUNE ACTIVATION COMPARED WITH WT AMS. THE PRESENCE OF CD11BHIGH AMS IN CGD MICE CORRELATED WITH AN INCREASED NUMBER OF ALVEOLAR NEUTROPHILS AND PROINFLAMMATORY CYTOKINES AT STEADY STATE AND INCREASED LUNG INFLAMMATION AFTER INSULTS. MOREOVER, DELETION OF NOX2 PREFERENTIALLY IN MACROPHAGES WAS SUFFICIENT FOR MICE TO DEVELOP AN ACTIVATED CD11BHIGH AM SUBSET AND ACCOMPANYING PROINFLAMMATORY SEQUELAE. IN ADDITION, WE SHOWED THAT THE ALTERED RESIDENT MACROPHAGE TRANSCRIPTIONAL PROFILE IN THE ABSENCE OF NOX2 IS TISSUE SPECIFIC, AS THOSE CHANGES WERE NOT SEEN IN RESIDENT PERITONEAL MACROPHAGES. THUS, THESE DATA DEMONSTRATE THAT THE ABSENCE OF NOX2 IN ALVEOLAR MACROPHAGES LEADS TO THEIR PROINFLAMMATORY REMODELING AND DYSREGULATES ALVEOLAR HOMEOSTASIS. 2022 6 1807 15 EFFECTIVE MODULATION OF INFLAMMATION AND OXIDATIVE STRESS FOR ENHANCED REGENERATION OF INTERVERTEBRAL DISCS USING 3D POROUS HYBRID PROTEIN NANOSCAFFOLD. DEGENERATION OF FIBROCARTILAGINOUS TISSUES IS OFTEN ASSOCIATED WITH COMPLEX PRO-INFLAMMATORY FACTORS. THESE INCLUDE REACTIVE OXYGEN SPECIES (ROS), CELL-FREE NUCLEIC ACIDS (CF-NAS), AND EPIGENETIC CHANGES IN IMMUNE CELLS. TO EFFECTIVELY CONTROL THIS COMPLEX INFLAMMATORY SIGNALING, IT DEVELOPED AN ALL-IN-ONE NANOSCAFFOLD-BASED 3D POROUS HYBRID PROTEIN (3D-PHP) SELF-THERAPEUTIC STRATEGY FOR TREATING INTERVERTEBRAL DISC (IVD) DEGENERATION. THE 3D-PHP NANOSCAFFOLD IS SYNTHESIZED BY INTRODUCING A NOVEL NANOMATERIAL-TEMPLATED PROTEIN ASSEMBLY (NTPA) STRATEGY. 3D-PHP NANOSCAFFOLDS THAT AVOID COVALENT MODIFICATION OF PROTEINS DEMONSTRATE INFLAMMATORY STIMULI-RESPONSIVE DRUG RELEASE, DISC-MIMETIC STIFFNESS, AND EXCELLENT BIODEGRADABILITY. ENZYME-LIKE 2D NANOSHEETS INCORPORATED INTO NANOSCAFFOLDS FURTHER ENABLED ROBUST SCAVENGING OF ROS AND CF-NAS, REDUCING INFLAMMATION AND ENHANCING THE SURVIVAL OF DISC CELLS UNDER INFLAMMATORY STRESS IN VITRO. IMPLANTATION OF 3D-PHP NANOSCAFFOLDS LOADED WITH BROMODOMAIN EXTRATERMINAL INHIBITOR (BETI) INTO A RAT NUCLEOTOMY DISC INJURY MODEL EFFECTIVELY SUPPRESSED INFLAMMATION IN VIVO, THUS PROMOTING RESTORATION OF THE EXTRACELLULAR MATRIX (ECM). THE RESULTING REGENERATION OF DISC TISSUE FACILITATED LONG-TERM PAIN REDUCTION. THEREFORE, SELF-THERAPEUTIC AND EPIGENETIC MODULATOR-ENCAPSULATED HYBRID PROTEIN NANOSCAFFOLD SHOWS GREAT PROMISE AS A NOVEL APPROACH TO RESTORE DYSREGULATED INFLAMMATORY SIGNALING AND TREAT DEGENERATIVE FIBROCARTILAGINOUS DISEASES, INCLUDING DISC INJURIES, PROVIDING HOPE AND RELIEF TO PATIENTS WORLDWIDE. 2023 7 5009 16 PERK IS A CRITICAL METABOLIC HUB FOR IMMUNOSUPPRESSIVE FUNCTION IN MACROPHAGES. CHRONIC INFLAMMATION TRIGGERS COMPENSATORY IMMUNOSUPPRESSION TO STOP INFLAMMATION AND MINIMIZE TISSUE DAMAGE. STUDIES HAVE DEMONSTRATED THAT ENDOPLASMIC RETICULUM (ER) STRESS AUGMENTS THE SUPPRESSIVE PHENOTYPES OF IMMUNE CELLS; HOWEVER, THE MOLECULAR MECHANISMS UNDERPINNING THIS PROCESS AND HOW IT LINKS TO THE METABOLIC REPROGRAMMING OF IMMUNOSUPPRESSIVE MACROPHAGES REMAIN ELUSIVE. IN THE PRESENT STUDY, WE REPORT THAT THE HELPER T CELL 2 CYTOKINE INTERLEUKIN-4 AND THE TUMOR MICROENVIRONMENT INCREASE THE ACTIVITY OF A PROTEIN KINASE RNA-LIKE ER KINASE (PERK)-SIGNALING CASCADE IN MACROPHAGES AND PROMOTE IMMUNOSUPPRESSIVE M2 ACTIVATION AND PROLIFERATION. LOSS OF PERK SIGNALING IMPEDED MITOCHONDRIAL RESPIRATION AND LIPID OXIDATION CRITICAL FOR M2 MACROPHAGES. PERK ACTIVATION MEDIATED THE UPREGULATION OF PHOSPHOSERINE AMINOTRANSFERASE 1 (PSAT1) AND SERINE BIOSYNTHESIS VIA THE DOWNSTREAM TRANSCRIPTION FACTOR ATF-4. INCREASED SERINE BIOSYNTHESIS RESULTED IN ENHANCED MITOCHONDRIAL FUNCTION AND ALPHA-KETOGLUTARATE PRODUCTION REQUIRED FOR JMJD3-DEPENDENT EPIGENETIC MODIFICATION. INHIBITION OF PERK SUPPRESSED MACROPHAGE IMMUNOSUPPRESSIVE ACTIVITY AND COULD ENHANCE THE EFFICACY OF IMMUNE CHECKPOINT PROGRAMMED CELL DEATH PROTEIN 1 INHIBITION IN MELANOMA. OUR FINDINGS DELINEATE A PREVIOUSLY UNDESCRIBED CONNECTION BETWEEN PERK SIGNALING AND PSAT1-MEDIATED SERINE METABOLISM CRITICAL FOR PROMOTING IMMUNOSUPPRESSIVE FUNCTION IN M2 MACROPHAGES. 2022 8 3875 17 KDM2A DEFICIENCY IN MACROPHAGES ENHANCES THERMOGENESIS TO PROTECT MICE AGAINST HFD-INDUCED OBESITY BY ENHANCING H3K36ME2 AT THE PPARG LOCUS. KDM2A CATALYZES H3K36ME2 DEMETHYLATION TO PLAY AN INTRIGUING EPIGENETIC REGULATORY ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HEREIN WE FOUND THAT MYELOID-SPECIFIC KNOCKOUT OF KDM2A (LYSM-CRE-KDM2A(F/F), KDM2A(-/-)) PROMOTED MACROPHAGE M2 PROGRAM BY REPROGRAMING METABOLIC HOMEOSTASIS THROUGH ENHANCING FATTY ACID UPTAKE AND LIPOLYSIS. KDM2A(-/-) INCREASED H3K36ME2 LEVELS AT THE PPARG LOCUS ALONG WITH AUGMENTED CHROMATIN ACCESSIBILITY AND STAT6 RECRUITMENT, WHICH RENDERED MACROPHAGES WITH PREFERENTIAL M2 POLARIZATION. THEREFORE, THE KDM2A(-/-) MICE WERE HIGHLY PROTECTED FROM HIGH-FAT DIET (HFD)-INDUCED OBESITY, INSULIN RESISTANCE, AND HEPATIC STEATOSIS, AND FEATURED BY THE REDUCED ACCUMULATION OF ADIPOSE TISSUE MACROPHAGES AND REPRESSED CHRONIC INFLAMMATION FOLLOWING HFD CHALLENGE. PARTICULARLY, KDM2A(-/-) MACROPHAGES PROVIDED A MICROENVIRONMENT IN FAVOR OF THERMOGENESIS. UPON HFD OR COLD CHALLENGE, THE KDM2A(-/-) MICE MANIFESTED HIGHER CAPACITY FOR INDUCING ADIPOSE BROWNING AND BEIGING TO PROMOTE ENERGY EXPENDITURE. COLLECTIVELY, OUR FINDINGS DEMONSTRATE THE IMPORTANCE OF KDM2A-MEDIATED H3K36 DEMETHYLATION IN ORCHESTRATING MACROPHAGE POLARIZATION, PROVIDING NOVEL INSIGHT THAT TARGETING KDM2A IN MACROPHAGES COULD BE A VIABLE THERAPEUTIC APPROACH AGAINST OBESITY AND INSULIN RESISTANCE. 2021 9 4967 19 PATHOLOGICAL CONDITIONS RE-SHAPE PHYSIOLOGICAL TREGS INTO PATHOLOGICAL TREGS. CD4(+)FOXP3(+) REGULATORY T CELLS (TREGS) ARE A SUBSET OF CD4 T CELLS THAT PLAY AN ESSENTIAL ROLE IN MAINTAINING PERIPHERAL IMMUNE TOLERANCE, CONTROLLING ACUTE AND CHRONIC INFLAMMATION, ALLERGY, AUTOIMMUNE DISEASES, AND ANTI-CANCER IMMUNE RESPONSES. OVER THE PAST 20 YEARS, SIGNIFICANT PROGRESS HAS BEEN MADE SINCE TREGS WERE FIRST CHARACTERIZED IN 1995. MANY CONCEPTS AND PRINCIPLES REGARDING TREGS GENERATION, PHENOTYPIC FEATURES, SUBSETS (TTREGS, PTREGS, ITREGS, AND ITREG35), TISSUE SPECIFICITY (CENTRAL TREGS, EFFECTOR TREGS, AND TISSUE RESIDENT TREGS), HOMEOSTASIS (HIGHLY DYNAMIC AND APOPTOTIC), REGULATION OF TREGS BY RECEPTORS FOR PAMPS AND DAMPS, TREG PLASTICITY (RE-DIFFERENTIATION TO OTHER CD4 T HELPER CELL SUBSETS, TH1, TH2, TFH AND TH17), AND EPIGENETIC REGULATION OF TREGS PHENOTYPES AND FUNCTIONS HAVE BEEN INNOVATED. IN THIS CONCISE REVIEW, WE WANT TO BRIEFLY ANALYZE THESE EIGHT NEW PROGRESSES IN THE STUDY OF TREGS. WE HAVE ALSO PROPOSED FOR THE FIRST TIME A NOVEL CONCEPT THAT "PHYSIOLOGICAL TREGS" HAVE BEEN RE-SHAPED INTO "PATHOLOGICAL TREGS" IN VARIOUS PATHOLOGICAL ENVIRONMENTS. CONTINUING OF THE IMPROVEMENT IN OUR UNDERSTANDING ON THIS IMPORTANT CELLULAR COMPONENT ABOUT THE IMMUNE TOLERANCE AND IMMUNE SUPPRESSION, WOULD LEAD TO THE FUTURE DEVELOPMENT OF NOVEL THERAPEUTICS APPROACHES FOR ACUTE AND CHRONIC INFLAMMATORY DISEASES, ALLERGY, ALLOGENEIC TRANSPLANTATION-RELATED IMMUNITY, SEPSIS, AUTOIMMUNE DISEASES, AND CANCERS. 2015 10 4894 21 OXIDATIVE STRESS CAUSED BY ACUTE AND CHRONIC EXPOSITION TO ALTITUDE. IN THIS ARTICLE, CURRENT VIEWS ON CELLULAR AND MOLECULAR BIOLOGY (BIOCHEMICAL) MECHANISMS ARE DISCUSSED UNDER THE ASPECT OF ALTITUDE EXPOSITION. THE ANDEAN, TIBETAN, AND ETHIOPIAN PATTERNS OF ADAPTATION TO HIGH-ALTITUDE HYPOXIA ARE KNOWN [BEAL ET AL. (2002) PROC NATL ACAD SCI USA 99: 17215-17218]. THE PHYLOGENETIC TREE OF THE HUMAN SPECIES SUGGESTS THAT THERE ARE GENETIC DIFFERENCES IN ADAPTATION PATTERNS TO CHRONIC HYPOXIC HYPOXIA. FIVE DEFENSE MECHANISMS ARE WELL ESTABLISHED FOR LOWLANDERS WHO ARE EXPOSED TO ACUTE HYPOXIC HYPOXIA. CONSEQUENCES OF THE CELLULAR DECREASE IN ATP ARE THE FORMATION OF HYPOXANTHINE AND XANTHINE, WHICH ARE THE SUBSTRATES FOR THE MASSIVE FORMATION OF SUPEROXIDE ANION RADICALS AND HYDROGEN PEROXIDE VIA THE OXIDASE ACTIVITY OF THE XANTHINE OXIDOREDUCTASE REACTION. UNDER SEVERE HYPOXIA, ABOUT 51 % OF THE TOTAL INHALED OXYGEN IS USED TO FORM SUPEROXIDE ANION RADICALS IN RAT LIVER [GERBER ET AL. (1989) ADV EXP MED BIOL 253B, PLENUM PRESS, NEW YORK, 497-504]. THE REACTIVITY AND SELECTIVITY OF THE SUPEROXIDE ANION RADICAL ARE MODIFIED BY SPECIFIC INTERACTIONS AND ELECTRON EXCHANGE. IT IS COMMONLY ACCEPTED THAT THE SUPEROXIDE ANION RADICAL IN AQUEOUS SOLUTIONS HAS A LIFETIME IN THE MILLISECOND RANGE. HOWEVER, ELECTRON SPIN RESONANCE SPECTROSCOPY STUDIES IN A KO2/H2O/IRON ION SYSTEM REVEALED FOR THE FIRST TIME A STABILIZATION OF A PART OF THE INITIALLY ADDED SUPEROXIDE ANION RADICALS LASTING UP TO HOURS AT ROOM TEMPERATURE [FOLDES-PAPP (1992) GEN PHYSIOL BIOPHYS 11: 3-38]. SUPEROXIDE ANION RADICALS ADSORBED ON AN OXIDIC IRON HYDRATE PHASE IN AQUEOUS SYSTEMS MIGHT FUNCTION AS A STRONG OXIDANT SIMILAR TO THAT SPECIES WHICH HAS BEEN SUGGESTED TO BE A COMPLEX BETWEEN OXYGEN AND DIFFERENT VALENCE STATES OF IRON IN THE INITIATION OF LIPID PEROXIDATION BY FERROUS IRON. THERE WERE SERIOUS DOUBTS ABOUT THE IDENTITY OF ALKOXY RADICALS. FOR THE FIRST TIME, ALKOXY RADICALS WERE DIRECTLY DEMONSTRATED IN SOLUTION BY ELECTRON SPIN RESONANCE SPECTROSCOPY [FOLDES-PAPP ET AL. (1991) ADV SYNTH CATAL 333: 293-301]. THE REDOX STATUS IN MAMMALIAN CELLS IS MAINLY DETERMINED BY THE ANTIOXIDANT GLUTATHIONE, WHICH IS A KEY PLAYER IN MAINTAINING THE INTRACELLULAR REDOX EQUILIBRIUM AND IN THE METABOLIC REGULATION OF THE CELLULAR DEFENSE AGAINST OXIDATIVE STRESS. AS REACTIVE OXYGEN SPECIES OCCUPY AN ESSENTIAL ROLE IN MEMBRANE DAMAGE, THE IDEA OF MEMBRANE-BOUND ENZYMATIC DEFENSE MECHANISMS GETS A NEW DIMENSION [FOLDES-PAPP ET AL. (1981) ACTA BIOL MED GER 40: 1129-1132; FOLDES-PAPP AND MARETZKI (1982) ACTA BIOL MED GER 41: 1003-1008]. THE STEADY-STATE BETWEEN ANTIOXIDANTS AND PRO-OXIDANTS AFFECTS THE GENE EXPRESSION VIA HYPOXIA-INDUCED TRANSCRIPTION ACTIVITIES. THE TRANSCRIPTION FACTOR HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1) IS A GLOBAL REGULATOR OF OXYGEN HOMEOSTASIS. AS DISCUSSED IN THIS ARTICLE, HYPOXIA OR 'OXIDATIVE STRESS' IS ACCOMPANIED BY APPROPRIATE MOLECULAR ADAPTATION MECHANISMS AT THE ENZYMATIC OR EPIGENETIC LEVEL (ENZYMATIC AND NON-ENZYMATIC RADICAL INHIBITORS, POSTTRANSLATIONAL MODIFICATIONS) AND AT THE GENETIC LEVEL (TRANSCRIPTION, TRANSLATION). 2005 11 6888 9 [ROLE OF VASCULAR AGING IN THE PATHOGENESIS OF ABDOMINAL AORTIC ANEURYSM AND POTENTIAL THERAPEUTIC TARGETS]. ABDOMINAL AORTIC ANEURYSM(AAA)IS A COMMON AORTIC DEGENERATIVE DISEASE IN THE ELDERLY,AND ITS INCIDENCE IS GRADUALLY INCREASING WITH THE AGING OF THE POPULATION.THERE ARE NO SPECIFIC DRUGS AVAILABLE TO DELAY THE EXPANSION OF AAA.ONCE THE ANEURYSM RUPTURES,THE MORTALITY WILL EXCEED 90%,WHICH SERIOUSLY THREATENS THE LIFE OF PATIENTS.GIVEN THE HIGH INCIDENCE OF AAA IN THE ELDERLY,THIS REVIEW DISCUSSES THE ROLE OF VASCULAR AGING IN THE PATHOGENESIS OF AAA,INVOLVING CHRONIC INFLAMMATION,OXIDATIVE STRESS,MITOCHONDRIAL DYSFUNCTION,PROTEIN HOMEOSTASIS IMBALANCE,INCREASED APOPTOSIS AND NECROSIS,EXTRACELLULAR MATRIX REMODELING,NUTRITIONAL SENSING DISORDERS,EPIGENETIC CHANGES,AND INCREASED PRO-AGING FACTORS.MEANWHILE,SEVERAL POTENTIAL AGING-RELATED DRUG TARGETS OF AAA ARE LISTED.THIS REVIEW PROVIDES NEW IDEAS FOR BASIC AND TRANSLATIONAL MEDICAL RESEARCH OF AAA. 2021 12 4210 20 METFORMIN AND VITAMIN D MODULATE INFLAMMATION AND AUTOPHAGY DURING ADIPOSE-DERIVED STEM CELL DIFFERENTIATION. ADIPOSE-DERIVED STEM CELLS (ADSCS) CAME OUT FROM THE REGENERATIVE MEDICINE LANDSCAPE FOR THEIR ABILITY TO DIFFERENTIATE INTO SEVERAL PHENOTYPES, CONTRIBUTING TO TISSUE REGENERATION BOTH IN VITRO AND IN VIVO. DYSREGULATION IN STEM CELL RECRUITMENT AND DIFFERENTIATION DURING ADIPOGENESIS IS LINKED TO A CHRONIC LOW-GRADE INFLAMMATION AND MACROPHAGE INFILTRATION INSIDE THE ADIPOSE TISSUE, INSULIN RESISTANCE, CARDIOVASCULAR DISEASE AND OBESITY. IN THE PRESENT PAPER WE AIMED TO EVALUATE THE ROLE OF METFORMIN AND VITAMIN D, ALONE OR IN COMBINATION, IN MODULATING INFLAMMATION AND AUTOPHAGY IN ADSCS DURING ADIPOGENIC COMMITMENT. ADSCS WERE CULTURED FOR 21 DAYS IN THE PRESENCE OF A SPECIFIC ADIPOGENIC DIFFERENTIATION MEDIUM, TOGETHER WITH METFORMIN, OR VITAMIN D, OR BOTH. WE THEN ANALYZED THE EXPRESSION OF FOXO1 AND HEAT SHOCK PROTEINS (HSP) AND THE SECRETION OF PROINFLAMMATORY CYTOKINES IL-6 AND TNF-ALPHA BY ELISA. AUTOPHAGY WAS ALSO ASSESSED BY SPECIFIC WESTERN BLOT ANALYSIS OF ATG12, LC3B I, AND LC3B II EXPRESSION. OUR RESULTS SHOWED THE ABILITY OF THE CONDITIONED MEDIA TO MODULATE ADIPOGENIC DIFFERENTIATION, FINELY TUNING THE INFLAMMATORY RESPONSE AND AUTOPHAGY. WE OBSERVED A MODULATION IN HSP MRNA LEVELS, AND A SIGNIFICANT DOWNREGULATION IN CYTOKINE SECRETION. TAKEN TOGETHER, OUR FINDINGS SUGGEST THE POSSIBLE APPLICATION OF THESE MOLECULES IN CLINICAL PRACTICE TO COUNTERACT UNCONTROLLED LIPOGENESIS AND PREVENT OBESITY AND OBESITY-RELATED METABOLIC DISORDERS. 2021 13 5231 14 PROBIOTICS AND AMELIORATION OF RHEUMATOID ARTHRITIS: SIGNIFICANT ROLES OF LACTOBACILLUS CASEI AND LACTOBACILLUS ACIDOPHILUS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE DISORDER THAT CAN LEAD TO DISABILITY CONDITIONS WITH SWOLLEN JOINTS, PAIN, STIFFNESS, CARTILAGE DEGRADATION, AND OSTEOPOROSIS. GENETIC, EPIGENETIC, SEX-SPECIFIC FACTORS, SMOKING, AIR POLLUTION, FOOD, ORAL HYGIENE, PERIODONTITIS, PREVOTELLA, AND IMBALANCE IN THE GASTROINTESTINAL MICROBIOTA ARE POSSIBLE SOURCES OF THE INITIATION OR PROGRESSION OF RHEUMATOID ARTHRITIS, ALTHOUGH THE DETAILED MECHANISMS STILL NEED TO BE ELUCIDATED. PROBIOTICS CONTAINING LACTOBACILLUS SPP. ARE COMMONLY USED AS ALLEVIATING AGENTS OR FOOD SUPPLEMENTS TO MANAGE DIARRHEA, DYSENTERY, DEVELOP IMMUNITY, AND MAINTAIN GENERAL HEALTH. THE MECHANISM OF ACTION OF LACTOBACILLUS SPP. AGAINST RHEUMATOID ARTHRITIS IS STILL NOT CLEARLY KNOWN TO DATE. IN THIS NARRATIVE REVIEW, WE RECAPITULATE THE FINDINGS OF RECENT STUDIES TO UNDERSTAND THE OVERALL PATHOGENESIS OF RHEUMATOID ARTHRITIS AND THE ROLES OF PROBIOTICS, PARTICULARLY L. CASEI OR L. ACIDOPHILUS, IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS IN CLINICAL AND PRECLINICAL STUDIES. 2021 14 4032 19 M344 PROMOTES NONAMYLOIDOGENIC AMYLOID PRECURSOR PROTEIN PROCESSING WHILE NORMALIZING ALZHEIMER'S DISEASE GENES AND IMPROVING MEMORY. ALZHEIMER'S DISEASE (AD) COMPRISES MULTIFACTORIAL AILMENTS FOR WHICH CURRENT THERAPEUTIC STRATEGIES REMAIN INSUFFICIENT TO BROADLY ADDRESS THE UNDERLYING PATHOPHYSIOLOGY. EPIGENETIC GENE REGULATION RELIES UPON MULTIFACTORIAL PROCESSES THAT REGULATE MULTIPLE GENE AND PROTEIN PATHWAYS, INCLUDING THOSE INVOLVED IN AD. WE THEREFORE TOOK AN EPIGENETIC APPROACH WHERE A SINGLE DRUG WOULD SIMULTANEOUSLY AFFECT THE EXPRESSION OF A NUMBER OF DEFINED AD-RELATED TARGETS. WE SHOW THAT THE SMALL-MOLECULE HISTONE DEACETYLASE INHIBITOR M344 REDUCES BETA-AMYLOID (ABETA), REDUCES TAU SER(396) PHOSPHORYLATION, AND DECREASES BOTH BETA-SECRETASE (BACE) AND APOEEPSILON4 GENE EXPRESSION. M344 INCREASES THE EXPRESSION OF AD-RELEVANT GENES: BDNF, ALPHA-SECRETASE (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, AND ABCA7, AMONG OTHERS. M344 INCREASES SAPPALPHA AND CTFALPHA APP METABOLITE PRODUCTION, BOTH CLEAVAGE PRODUCTS OF ADAM10, CONCORDANT WITH INCREASED ADAM10 GENE EXPRESSION. M344 ALSO INCREASES LEVELS OF IMMATURE APP, SUPPORTING AN EFFECT ON APP TRAFFICKING, CONCURRENT WITH THE OBSERVED INCREASE IN MINT2 AND FE65, BOTH SHOWN TO INCREASE IMMATURE APP IN THE EARLY SECRETORY PATHWAY. CHRONIC I.P. TREATMENT OF THE TRIPLE TRANSGENIC (APP(SW)/PS1(M146V)/TAU(P301L)) MICE WITH M344, AT DOSES AS LOW AS 3 MG/KG, SIGNIFICANTLY PREVENTED COGNITIVE DECLINE EVALUATED BY Y-MAZE SPONTANEOUS ALTERNATION, NOVEL OBJECT RECOGNITION, AND BARNES MAZE SPATIAL MEMORY TESTS. M344 DISPLAYS SHORT BRAIN EXPOSURE, INDICATING THAT BRIEF PULSES OF DAILY DRUG TREATMENT MAY BE SUFFICIENT FOR LONG-TERM EFFICACY. TOGETHER, THESE DATA SHOW THAT M344 NORMALIZES SEVERAL DISPARATE PATHOGENIC PATHWAYS RELATED TO AD. M344 THEREFORE SERVES AS AN EXAMPLE OF HOW A MULTITARGETING COMPOUND COULD BE USED TO ADDRESS THE POLYGENIC NATURE OF MULTIFACTORIAL DISEASES. 2017 15 3249 20 HEPATITIS B VIRUS HIJACKS CTHRC1 TO EVADE HOST IMMUNITY AND MAINTAIN REPLICATION. HEPATITIS B VIRUS (HBV) INFECTION CAUSES ACUTE AND CHRONIC LIVER DISEASES, BUT IS NOT DIRECTLY CYTOPATHIC. LIVER INJURY RESULTS FROM REPEATED ATTEMPTS OF THE CELLULAR IMMUNE RESPONSE SYSTEM TO CONTROL THE VIRAL INFECTION. HERE, WE INVESTIGATE THE ROLES OF CELLULAR FACTORS AND SIGNALING PATHWAYS INVOLVED IN THE REGULATION OF HBV REPLICATION TO REVEAL THE MECHANISM UNDERLYING HBV INFECTION AND PATHOGENESIS. WE SHOW THAT COLLAGEN TRIPLE HELIX REPEAT CONTAINING 1 (CTHRC1) EXPRESSION IS ELEVATED IN HBV-INFECTED PATIENTS AND IN HBV-TRANSFECTED CELLS THROUGH EPIGENETIC MODIFICATION AND TRANSCRIPTIONAL REGULATION. CTHRC1 FACILITATES HBV REPLICATION IN CULTURED CELLS AND BALB/C MICE BY ACTIVATING THE PKCALPHA/ERK/JNK/C-JUN CASCADE TO REPRESS THE IFN/JAK/STAT PATHWAY. HBV-ACTIVATED CTHRC1 DOWNREGULATES THE ACTIVITY OF TYPE I INTERFERON (IFN), THE PRODUCTION OF IFN-STIMULATED GENES (ISGS), AND THE PHOSPHORYLATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1/2 (STAT1/2), WHEREAS IT UPREGULATES THE PHOSPHORYLATION AND UBIQUITINATION OF TYPE I IFN RECEPTORS (IFNARALPHA/BETA). THUS, OUR RESULTS SHOW THAT HBV USES A NOVEL MECHANISM TO HIJACK CELLULAR FACTORS AND SIGNAL CASCADES IN ORDER TO EVADE HOST ANTIVIRAL IMMUNITY AND MAINTAIN PERSISTENT INFECTION. WE ALSO DEMONSTRATE THAT CTHRC1 HAS A NOVEL ROLE IN VIRAL INFECTION. 2015 16 6869 13 [PATHOGENESIS OF RHEUMATOID ARTHRITIS]. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE SYSTEMIC DISEASE THAT PRIMARILY AFFECTS JOINTS. ETIOLOGY AND THE PATHOGENESIS OF RA ARE COMPLEX, INVOLVING MANY TYPES OF CELLS, AMONG OTHERS MACROPHAGES, T AND B CELLS, FIBRO- BLASTS, CHONDROCYTES AND DENDRITIC CELLS. DESPITE WELL DOCUMENTED ROLE OF MANY GENES AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT AND EVOLUTION OF THE DISEASE, IN MOST RA PATIENTS THERE IS NO CLEAR PREDISPOSING FACTOR PRESENT. ENVIRONMENTAL FACTORS INVOLVED IN RA PATHOGENESIS ARE CIGARETTE SMOKE, INDUSTRIAL POLLUTANTS LIKE SILICA CRYSTALS, DISTURBANCES OF INTESTINAL, LUNG, AND ORAL MICROBIOTA AND SOME SPECIFIC BACTERIAL AND VIRAL INFECTIOUS AGENTS AND THEIR COMPONENTS. IN THE INITIAL DISEASE STAGE THERE ARE QUALITATIVE AND QUANTITATIVE DISTURBANCES OFPEPTIDE CITRULINATION AS WELL AS OTHER PROTEIN MODIFICATIONS, FOLLOWED BY ANTIGEN PRESENTING CELL (APC) (MACROPHAGES AND DENDRITIC CELLS) AND FIBROBLAST LIKE SYNOVIOCYTES (FLS) ACTIVATION. SOME MICROBES FOSTER THIS PROCESSES BY APC AND FLS DIRECT AND INDIRECT ACTIVATION. IN THE SECOND STAGE APC'S ELICIT SPECIFIC HUMORAL B CELL RE- SPONSE RESULTING IN SPECIFIC ANTIBODIES PRODUCTION AND T CELL AUTOREACTIVITY. INHERITED AND ACQUIRED DEFECTS IN T AND B CELL RESPONSES CAUSED BY REPEATED ACTIVATION OF INNATE IMMUNITY AS WELL AS LOSS OF TOLERANCE, ELICIT CHRONIC AUTOIMMUNE INFLAMMATION, PRIMARILY OF SYNOVIAL MEMBRANES, AND DEVELOPMENT OF CELLULAR PANUS. PATHOLOGIC ACTIVATION OF THE OSTEOCLASTS AND RELEASE OF THE IMMUNE SYSTEM EFFECTOR MOLECULES AND THE PROTEOLYTIC ENZYMES DAMAGE THE CARTILAGE, BONE AND TENDONS COMPOSITION AND STRUCTURE. PERSISTENT INFLAMMATION THROUGH ITS COMPLEX MECHANISMS RESULTS IN MANY SYSTEMIC AND EXTRAARTICULAR RA MANIFESTATIONS OF ALMOST ALL ORGAN SYSTEMS, RESULTING IN SEVERE COMPLICATIONS AND COMORBIDITIES SUCH AS RHEUMATOID LUNG, CARDITIS, VASCULITIS, CAHEXIA, ANEMIA, ACCELERATED ATHEROSCLEROSIS, MYOCARDIAL AND CEREBROVASCULAR VASCULAR DISEASE, LYMPHOMA, OSTEOPOROSIS, DEPRESSION ETC. ACCUMULATED COMPLICATIONS AND COMORBIDITIES FINALLY RESULT IN HANDICAP, SOCIAL DYSFUNCTION AND PREMATURE DEATH. 2014 17 4416 15 MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO JOINT DAMAGE IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE SYNDROME ASSOCIATED WITH SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AFFECTING THE ARTICULAR JOINTS CONTRIBUTING TO CARTILAGE AND BONE DAMAGE. ALTHOUGH ETIOLOGY OF THIS DISEASE IS NOT CLEAR, SEVERAL IMMUNE PATHWAYS, INVOLVING IMMUNE (T CELLS, B CELLS, DENDRITIC CELLS, MACROPHAGES, AND NEUTROPHILS) AND NONIMMUNE (FIBROBLASTS AND CHONDROCYTES) CELLS, PARTICIPATE IN THE SECRETION OF MANY PROINFLAMMATORY CYTOKINES, CHEMOKINES, PROTEASES (MMPS, ADAMTS), AND OTHER MATRIX LYSING ENZYMES THAT COULD DISTURB THE IMMUNE BALANCE LEADING TO CARTILAGE AND BONE DAMAGE. THE PRESENCE OF AUTOANTIBODIES PRECEDING THE CLINICAL ONSET OF ARTHRITIS AND THE INDUCTION OF BONE EROSION EARLY IN THE DISEASE COURSE CLEARLY SUGGEST THAT INITIATION EVENTS DAMAGING THE CARTILAGE AND BONE START VERY EARLY DURING THE AUTOIMMUNE PHASE OF THE ARTHRITIS DEVELOPMENT. DURING THIS PROCESS, SEVERAL SIGNALING MOLECULES (RANKL-RANK, NF-KAPPAB, MAPK, NFATC1, AND SRC KINASE) ARE ACTIVATED IN THE OSTEOCLASTS, CELLS RESPONSIBLE FOR BONE RESORPTION. HENCE, COMPREHENSIVE KNOWLEDGE ON PATHOGENESIS IS A PREREQUISITE FOR PREVENTION AND DEVELOPMENT OF TARGETED CLINICAL TREATMENT FOR RA PATIENTS THAT CAN RESTORE THE IMMUNE BALANCE IMPROVING CLINICAL THERAPY. 2020 18 3861 22 ISOLATION OF HUMAN ANTIGEN-SPECIFIC REGULATORY T CELLS WITH HIGH SUPPRESSIVE FUNCTION. ADOPTIVE TRANSFER OF REGULATORY T (TREG) CELLS COULD BE AN ALTERNATIVE TO CHRONIC IMMUNOSUPPRESSION FOR PREVENTION OF ALLOGENEIC GRAFT REJECTION. WHILE POLYSPECIFIC TREG CELLS CAN PREVENT IMMUNE RESPONSES UNDER LYMPHOPENIC CONDITIONS, AG-SPECIFIC TREG CELLS ARE NEEDED TO TREAT AUTOIMMUNITY AND GRAFT REJECTION. YET, RELIABLE MARKERS FOR AG-SPECIFIC TREG CELLS ARE MISSING. WE REPORT THAT LATENCY-ASSOCIATED PEPTIDE (LAP) AND GLYCOPROTEIN A REPETITIONS PREDOMINANT (GARP) CAN IDENTIFY HUMAN AG-SPECIFIC TREG CELLS. IN ADDITION, WE SHOW THAT THE DEPLETION OF CD154(+) CELLS FROM LAP(+) OR GARP(+) TREG CELLS INCREASES THE TREG-CELL PURITY TO OVER 90%, AS ASSESSED BY EPIGENETIC ANALYSIS. THESE AG-SPECIFIC TREG CELLS CAN BE ISOLATED MAGNETICALLY AND MIGHT CONTRIBUTE TO THE DEVELOPMENT OF GMP-BASED PROTOCOLS. IN ADDITION, AG-SPECIFIC TREG CELLS ARE FUNCTIONALLY FAR SUPERIOR TO CD4(+) CD25(HIGH) OR CD4(+) CD25(HIGH) CD127(LOW) TREG CELLS IN VITRO AND IN PREVENTING STRONG ALLOREACTIONS IN HUMANIZED MICE. THEY COULD, THEREFORE, HAVE A HIGH THERAPEUTIC POTENTIAL FOR THE CONTROL OF ALLOIMMUNE, AUTOIMMUNE, AND ALLERGIC IMMUNE RESPONSES IN PATIENTS. 2014 19 5481 15 RESVERATROL-INDUCED APOPTOSIS DEPENDS ON THE LIPID KINASE ACTIVITY OF VPS34 AND ON THE FORMATION OF AUTOPHAGOLYSOSOMES. IN HUMAN COLORECTAL DLD1 CANCER CELLS, THE DIETARY BIOFLAVONOID RESVERATROL (RV) RAPIDLY INDUCED AUTOPHAGY. THIS EFFECT WAS REVERSIBLE (ON REMOVAL OF THE DRUG) AND WAS ASSOCIATED WITH INCREASED EXPRESSION AND CYTOSOLIC REDISTRIBUTION OF THE PROTEINS BECLIN1 AND LC3 II. SUPPLEMENTING THE CELLS WITH ASPARAGINE (ASN) ABROGATED THE BECLIN-DEPENDENT AUTOPHAGY. WHEN APPLIED ACUTELY (2 H), RV WAS NOT TOXIC; HOWEVER, REITERATE CHRONIC (48 H) EXPOSURE TO RV EVENTUALLY LED TO ANNEXIN V- AND TERMINAL DEOXINUCLEOTIDYL TRANSFERASE-MEDIATED DUTP-BIOTIN NICK END LABELING-POSITIVE CELL DEATH. THIS TOXIC EFFECT WAS AUTOPHAGY DEPENDENT, AS IT WAS PREVENTED EITHER BY ASN, BY EXPRESSING A DOMINANT-NEGATIVE LIPID KINASE-DEFICIENT CLASS III PHOSPHOINOSITIDE 3-PHOSPHATE KINASE, OR BY RNA INTERFERENCE KNOCKDOWN OF BECLIN1. LAMP2B SILENCING ABOLISHED THE FUSION OF AUTOPHAGOSOMES WITH LYSOSOMES AND PRESERVED CELL VIABILITY DESPITE THE ONGOING FORMATION OF AUTOPHAGOSOMES IN CELLS CHRONICALLY EXPOSED TO RV. THE PAN-CASPASE INHIBITOR BENZYLOXYCARBONYL-VAL-ALA-ASP-FLUOROMETHYLKETONE INHIBITED RV-INDUCED CELL DEATH, BUT NOT AUTOPHAGY. THESE RESULTS UNCOVER A NOVEL PATHWAY OF RV CYTOTOXICITY IN WHICH AUTOPHAGY PLAYS A DUAL ROLE: (I) AT FIRST, IT ACTS AS A PROSURVIVAL STRESS RESPONSE AND (II) AT A LATER TIME, IT SWITCHES TO A CASPASE-DEPENDENT APOPTOSIS PATHWAY. THE PRESENT DATA ALSO INDICATE THAT GENETIC OR EPIGENETIC INACTIVATION OF AUTOPHAGY PROTEINS IN CANCER CELLS MAY CONFER RESISTANCE TO RV-MEDIATED KILLING. 2008 20 1449 14 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