1 4170 127 MEETING REPORT: ISN FOREFRONTS IN NEPHROLOGY ON ENDOTHELIAL BIOLOGY AND RENAL DISEASE: FROM BENCH TO PREVENTION. THIS ISN-SPONSORED FOREFRONT IN NEPHROLOGY MEETING, WHICH HAS BROUGHT TOGETHER 120 SCIENTISTS FROM 21 COUNTRIES, HAS BEEN CONCERNED WITH VARIOUS ASPECTS OF ENDOTHELIAL FUNCTION AND DYSFUNCTION AND THEIR CONTRIBUTION TO PROGRESSION OF CHRONIC KIDNEY DISEASE AND/OR ITS CARDIOVASCULAR COMPLICATIONS. THE FOLLOWING THEMES WERE DISCUSSED IN GREAT DEPTH: (1) PHENOTYPICAL CHANGES IN THE VASCULAR ENDOTHELIUM - PERMEABILITY, SENESCENCE, AND APOPTOSIS; (2) REGULATION OF ENDOTHELIAL NITRIC OXIDE (NO) SYNTHASE FUNCTION - CAVEOLAR AND SHEAR STRESS MECHANISMS, EPIGENETIC REGULATION, S-NITROSYLATION, AND RHO-KINASE REGULATION; (3) OXIDATIVE STRESS AND HYPOXIA-INDUCED CHANGES; (4) ORGANELLAR DYSFUNCTION - LYSOSOMES, MITOCHONDRIA, AND ENDOPLASMIC RETICULUM; (5) NO-INDEPENDENT MECHANISMS OF VASOMOTION - EPOXIDES, HEME OXYGENASE-1 AND CARBON MONOXIDE, THROMBOXANE, TUMOR NECROSIS FACTOR-ALPHA, AND URIC ACID; (6) ENDOTHELIAL CROSSTALK WITH PODOCYTES, MONOCYTES, SMOOTH MUSCLE CELLS, AND PLATELETS; (7) CANDIDATE CLINICAL BIOMARKERS OF ENDOTHELIAL DYSFUNCTION - FUNCTIONAL TESTING OF MACRO- AND MICRO-VASCULAR FUNCTIONS, SURROGATE MARKERS, CIRCULATING DETACHED ENDOTHELIAL CELLS, AND ENDOTHELIAL PRECURSOR CELLS; AND CULMINATED IN ROUND TABLE DISCUSSION ON THE DIAGNOSIS OF ENDOTHELIAL DYSFUNCTION AND ITS TREATMENT OPTIONS. IN CONCLUSION, THIS MEETING HAS FOCUSED ON SEVERAL KEY PROBLEMS OF ENDOTHELIAL CELL PATHOBIOLOGY RELEVANT TO CHRONIC KIDNEY DISEASE. 2006 2 3152 24 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 3 4013 30 LOW-DENSITY LIPOPROTEIN-CHOLESTEROL-INDUCED ENDOTHELIAL DYSFUNCTION AND OXIDATIVE STRESS: THE ROLE OF STATINS. SIGNIFICANCE: CARDIOVASCULAR DISEASES (CVD) REPRESENT A MAJOR PUBLIC HEALTH BURDEN. HIGH LOW-DENSITY LIPOPROTEIN (LDL)-CHOLESTEROL IS A RECOGNIZED PATHOGENIC FACTOR FOR ATHEROSCLEROSIS, AND ITS COMPLICATIONS AND STATINS REPRESENT THE MOST POTENT AND WIDELY USED THERAPEUTIC APPROACH TO PREVENT AND CONTROL THESE DISORDERS. RECENT ADVANCES: A NUMBER OF CLINICAL AND EXPERIMENTAL STUDIES CONCUR TO IDENTIFY ENDOTHELIAL DYSFUNCTION AS A PRIMARY STEP IN THE DEVELOPMENT OF ATHEROSCLEROSIS, AS WELL AS A RISK FACTOR FOR SUBSEQUENT CLINICAL EVENTS. OXIDANT STRESS RESULTING FROM CHRONIC ELEVATION OF PLASMA LDL-CHOLESTEROL (LDL-CHOL) IS A MAJOR CONTRIBUTOR TO BOTH ENDOTHELIAL DYSFUNCTION AND ITS COMPLICATIONS, FOR EXAMPLE, THROUGH ALTERATIONS OF ENDOTHELIAL NITRIC OXIDE SIGNALING. CRITICAL ISSUES: STATIN TREATMENT REDUCES MORBIDITY AND MORTALITY OF CVD, BUT INCREASING EVIDENCE QUESTIONS THAT THIS IS EXCLUSIVELY THROUGH REDUCTION OF PLASMA LDL-CHOL. THE IDENTIFICATION OF ANCILLARY EFFECTS ON (CARDIO)VASCULAR BIOLOGY, FOR EXAMPLE, THROUGH THEIR MODULATION OF OXIDATIVE STRESS, WILL NOT ONLY INCREASE OUR UNDERSTANDING OF THEIR MECHANISMS OF ACTION, WITH A POTENTIAL BROADENING OF THEIR INDICATION(S), BUT ALSO LEAD TO THE IDENTIFICATION OF NEW MOLECULAR TARGETS FOR FUTURE THERAPEUTIC DEVELOPMENTS IN CVD. FUTURE DIRECTIONS: FURTHER CHARACTERIZATION OF MOLECULAR PATHWAYS TARGETED BY STATINS, FOR EXAMPLE, NOT DIRECTLY MEDIATED BY CHANGES IN PLASMA LIPID CONCENTRATIONS, SHOULD ENABLE A MORE COMPREHENSIVE APPROACH TO THE PATHOGENESIS OF (CARDIO)VASCULAR DISEASE, INCLUDING, FOR EXAMPLE, EPIGENETIC REGULATION AND FINE TUNING OF CELL METABOLISM. 2014 4 1898 22 ENDOTHELINS IN CARDIOVASCULAR BIOLOGY AND THERAPEUTICS. CARDIOVASCULAR DISEASE IS A MAJOR CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY AND IS THE COMMON END POINT OF MANY CHRONIC DISEASES. THE ENDOTHELINS COMPRISE THREE STRUCTURALLY SIMILAR PEPTIDES OF 21 AMINO ACIDS IN LENGTH. ENDOTHELIN 1 (ET-1) AND ET-2 ACTIVATE TWO G PROTEIN-COUPLED RECEPTORS - ENDOTHELIN RECEPTOR TYPE A (ET(A)) AND ENDOTHELIN RECEPTOR TYPE B (ET(B)) - WITH EQUAL AFFINITY, WHEREAS ET-3 HAS A LOWER AFFINITY FOR ET(A). ET-1 IS THE MOST POTENT VASOCONSTRICTOR IN THE HUMAN CARDIOVASCULAR SYSTEM AND HAS REMARKABLY LONG-LASTING ACTIONS. ET-1 CONTRIBUTES TO VASOCONSTRICTION, VASCULAR AND CARDIAC HYPERTROPHY, INFLAMMATION, AND TO THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE. ENDOTHELIN RECEPTOR ANTAGONISTS HAVE REVOLUTIONIZED THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION. CLINICAL TRIALS CONTINUE TO EXPLORE NEW APPLICATIONS OF ENDOTHELIN RECEPTOR ANTAGONISTS, PARTICULARLY IN TREATMENT-RESISTANT HYPERTENSION, CHRONIC KIDNEY DISEASE AND PATIENTS RECEIVING ANTIANGIOGENIC THERAPIES. TRANSLATIONAL STUDIES HAVE IDENTIFIED IMPORTANT ROLES FOR THE ENDOTHELIN ISOFORMS AND NEW THERAPEUTIC TARGETS DURING DEVELOPMENT, IN FLUID-ELECTROLYTE HOMEOSTASIS, AND IN CARDIOVASCULAR AND NEURONAL FUNCTION. NOVEL PHARMACOLOGICAL STRATEGIES ARE EMERGING IN THE FORM OF SMALL-MOLECULE EPIGENETIC MODULATORS, BIOLOGICS (SUCH AS MONOCLONAL ANTIBODIES FOR ET(B)) AND POSSIBLY SIGNALLING PATHWAY-BIASED AGONISTS AND ANTAGONISTS. 2019 5 4456 18 MOLECULAR MECHANISMS IN RENAL DEGENERATIVE DISEASE. CHRONIC KIDNEY DISEASE (CKD) HAS BECOME A MAJOR PUBLIC HEALTH PROBLEM WORLDWIDE. THEREFORE, A CONSIDERABLE EFFORT IS CURRENTLY DIRECTED TO UNDERSTAND THE MOLECULAR MECHANISMS OF RENAL DEGENERATIVE PROCESSES. REGARDLESS OF THEIR INITIATING CAUSE, ALL CHRONIC KIDNEY DISEASES (CKD) DEVELOP AT SOME LEVEL ORGAN FIBROSIS THAT INTERFERES WITH KIDNEY FUNCTION. THIS IS ALSO TRUE FOR THE TWO MOST COMMON INHERITED CKD SYNDROMES, NEPHRONOPHTHITIS AND POLYCYSTIC KIDNEY DISEASE, WHOSE PRIMARY DEFECTS RESIDE WITHIN THE CILIUM OF KIDNEY EPITHELIAL CELLS. A COHORT OF ELEGANT RECENT STUDIES HAS ELICITED THE ROLE OF THE PRIMARY CILIUM AS A VERSATILE MECHANOSENSORY ORGANELLE THAT ALSO MIGHT COORDINATE CROSS-TALK BETWEEN MULTIPLE SIGNALING PATHWAYS. IN ADDITION, EPIGENETIC MECHANISMS ARE NOW REALIZED TO BE ESSENTIAL IN THE MAINTENANCE OF ADULT RENAL ARCHITECTURE. IN THIS REVIEW, WE WILL DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF THE SIGNALING SYSTEMS IMPLICATED IN KIDNEY HOMEOSTASIS AND REPAIR. 2010 6 4719 20 NONCODING RNA AND EPIGENETIC GENE REGULATION IN RENAL DISEASES. KIDNEYS HAVE A MAJOR ROLE IN NORMAL PHYSIOLOGY AND METABOLIC HOMEOSTASIS. LOSS OR IMPAIRMENT OF KIDNEY FUNCTION IS A COMMON OCCURRENCE IN SEVERAL METABOLIC DISORDERS, INCLUDING HYPERTENSION AND DIABETES. CHRONIC KIDNEY DISEASE (CKD) AFFECT NEARLY 10% OF THE POPULATION WORLDWIDE; RANKS 18TH IN THE LIST OF CAUSES OF DEATH; AND CONTRIBUTES TO A SIGNIFICANT PROPORTION OF HEALTHCARE COSTS. THE TISSUE REPAIR AND REGENERATIVE POTENTIAL OF KIDNEYS ARE LIMITED AND THEY DECLINE DURING AGING. RECENT STUDIES HAVE DEMONSTRATED A KEY ROLE FOR EPIGENETIC PROCESSES AND PLAYERS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NONCODING (NC)RNA, AND SO ON, IN BOTH KIDNEY DEVELOPMENT AND DISEASE. IN THIS REVIEW, WE HIGHLIGHT THESE RECENT FINDINGS WITH AN EMPHASIS ON ABERRANT EPIGENETIC CHANGES THAT ACCOMPANY RENAL DISEASES, KEY TARGETS, AND THEIR THERAPEUTIC VALUE. 2017 7 1487 26 DNA DAMAGE AND EPIGENETIC CHANGES IN KIDNEY DISEASES - FOCUSED ON TRANSCRIPTION FACTORS IN PODOCYTES. RECENTLY IT HAS BEEN SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF CARIDIOVASCULAR AND METABOLIC DISEASES, INCLUDING DIABETES, OBESITY, ATHEROSCLEROSIS, HEART FAILURE, HYPERTENSION AND KIDNEY DISEASES. IN THESE CHRONIC DISEASES, VARIOUS EXOGENOUS AND ENDOGENOUS STRESSES CAUSE DNA DAMAGE, FOLLOWED BY DNA REPAIR PROCESS. ACCUMULATION OF DNA DAMAGES AND IMPAIRED REPAIR PROCESS CAN LEAD TO EPIGENETIC CHANGES, WHICH MAY CONTRIBUTE TO ONSET AND PROGRESSION OF DISEASES. RECENTLY WE HAVE SHOWN THAT THERAPEUTIC EFFECT OF TRANSCRIPTION FACTOR KLF4 (KRUPPEL-LIKE FACTOR 4) IN KIDNEY GLOMERULAR EPITHELIAL CELLS (PODOCYTES) ON PROTEINURIC KIDNEY DISEASES THROUGH EPIGENETIC MECHANISMS. OUR RESULT SUGGESTS THE POSSIBILITY OF TRANSCRIPTION FACTORS AS A TARGET OF SELECTIVE EPIGENETIC THERAPY. MOREOVER, WE HAVE REPORTED THAT RENIN-ANGIOTENSIN SYSTEM (RAS) BLOCKERS, WHICH ARE WIDELY PRESCRIBED FOR THE TREATMENT OF CARDIOVASCULAR DISEASES, CAN RESTORE EPIGENETIC CHANGES THROUGH KLF4 IN PART. THESE RESULTS SUGGEST THAT ACTIVATION OF RAS CAUSES EPIGENETIC CHANGES IN DISEASE STATES, AND ELUCIDATION OF THE PRECISE MECHANISM MAY LEAD TO ESTABLISHMENT OF NOVEL THERAPEUTIC TARGET OF KIDNEY DISEASES. IN THIS REVIEW WE FOCUS ON DNA DAMAGE REPAIR SYSTEM AND EPIGENETIC MODULATORS IN DISEASE STATES, AND SPECULATE A CANDIDATE FOR EPIGENETIC THERAPY OF KIDNEY DISEASES. 2016 8 6906 20 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 9 3801 23 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 10 6511 22 TRANSCRIPTION FACTORS AS THERAPEUTIC TARGETS IN CHRONIC KIDNEY DISEASE. THE GROWING NUMBER OF PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS RECOGNIZED AS AN EMERGING PROBLEM WORLDWIDE. RECENT STUDIES HAVE INDICATED THAT DEREGULATION OF TRANSCRIPTION FACTORS IS ASSOCIATED WITH THE ONSET OR PROGRESSION OF KIDNEY DISEASE. SEVERAL CLINICAL TRIALS INDICATED THAT REGRESSION OF CKD MAY BE FEASIBLE VIA ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR ERYTHROID-2 RELATED FACTOR 2 (NRF2), WHICH SUGGESTS THAT TRANSCRIPTION FACTORS MAY BE POTENTIAL DRUG TARGETS FOR CKD. AGENTS STABILIZING HYPOXIA-INDUCIBLE FACTOR (HIF), WHICH MAY BE BENEFICIAL FOR RENAL ANEMIA AND RENAL PROTECTION, ARE ALSO NOW UNDER CLINICAL TRIAL. RECENTLY, WE HAVE REPORTED THAT THE TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (KLF4) REGULATES THE GLOMERULAR PODOCYTE EPIGENOME, AND THAT THE ANTIPROTEINURIC EFFECT OF THE RENIN(-)ANGIOTENSIN SYSTEM BLOCKADE MAY BE PARTIALLY MEDIATED BY KLF4. KLF4 IS ONE OF THE YAMANAKA FACTORS THAT INDUCES IPS CELLS AND IS REPORTED TO BE INVOLVED IN EPIGENETIC REMODELING. IN THIS ARTICLE, WE SUMMARIZE THE TRANSCRIPTION FACTORS ASSOCIATED WITH CKD AND PARTICULARLY FOCUS ON THE POSSIBILITY OF TRANSCRIPTION FACTORS BEING NOVEL DRUG TARGETS FOR CKD THROUGH EPIGENETIC MODULATION. 2018 11 6022 21 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 12 2597 26 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 13 1515 24 DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A GLOBAL EPIDEMIC, AND ITS MAJOR RISK FACTORS INCLUDE OBESITY AND TYPE 2 DIABETES. OBESITY NOT ONLY PROMOTES METABOLIC DYSREGULATION AND THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE BUT ALSO MAY INDEPENDENTLY LEAD TO CKD BY A VARIETY OF MECHANISMS, INCLUDING ENDOCRINE AND METABOLIC DYSFUNCTION, INFLAMMATION, OXIDATIVE STRESS, ALTERED RENAL HEMODYNAMICS, AND LIPOTOXICITY. DELETERIOUS RENAL EFFECTS OF OBESITY CAN ALSO BE TRANSMITTED FROM ONE GENERATION TO THE NEXT, AND IT IS INCREASINGLY RECOGNIZED THAT OFFSPRING OF OBESE MOTHERS ARE PREDISPOSED TO CKD. EPIGENETIC MODIFICATIONS ARE CHANGES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. OF THESE, DNA METHYLATION IS THE MOST STUDIED. EPIGENETIC IMPRINTS, PARTICULARLY DNA METHYLATION, ARE LAID DOWN DURING CRITICAL PERIODS OF FETAL DEVELOPMENT, AND THEY MAY PROVIDE A MECHANISM BY WHICH MATERNAL-FETAL TRANSMISSION OF CHRONIC DISEASE OCCURS. OUR CURRENT REVIEW EXPLORES THE EVIDENCE FOR THE ROLE OF DNA METHYLATION IN THE DEVELOPMENT OF CKD, DIABETIC KIDNEY DISEASE, DIABETES, AND OBESITY. DNA METHYLATION HAS BEEN IMPLICATED IN RENAL FIBROSIS-THE FINAL PATHOPHYSIOLOGIC PATHWAY IN THE DEVELOPMENT OF END-STAGE KIDNEY DISEASE-WHICH SUPPORTS THE NOTION THAT DEMETHYLATING AGENTS MAY PLAY A POTENTIAL THERAPEUTIC ROLE IN PREVENTING DEVELOPMENT AND PROGRESSION OF CKD.-LARKIN, B. P., GLASTRAS, S. J., CHEN, H., POLLOCK, C. A., SAAD, S. DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. 2018 14 4377 26 MITOCHONDRIAL AGING: FOCUS ON MITOCHONDRIAL DNA DAMAGE IN ATHEROSCLEROSIS - A MINI-REVIEW. ATHEROSCLEROSIS IS A COMPLEX DISEASE WHICH CAN BE DESCRIBED AS AN EXCESSIVE FIBROFATTY, PROLIFERATIVE, INFLAMMATORY RESPONSE TO DAMAGE TO THE ARTERY WALL INVOLVING SEVERAL CELL TYPES SUCH AS SMOOTH MUSCLE CELLS, MONOCYTE-DERIVED MACROPHAGES, LYMPHOCYTES, DENDRITIC CELLS AND PLATELETS. ON THE OTHER HAND, ATHEROSCLEROSIS IS A TYPICAL AGE-RELATED DEGENERATIVE PATHOLOGY, WHICH IS CHARACTERIZED BY SIGNS OF CELL SENESCENCE IN THE ARTERIAL WALL INCLUDING REDUCED CELL PROLIFERATION, IRREVERSIBLE GROWTH ARREST AND APOPTOSIS, INCREASED DNA DAMAGE, THE PRESENCE OF EPIGENETIC MODIFICATIONS, SHORTENING OF TELOMERE LENGTH AND MITOCHONDRIAL DYSFUNCTION. THE MOST PROMINENT CHARACTERISTICS OF MITOCHONDRIAL AGING ARE THEIR STRUCTURAL ALTERATIONS AND MITOCHONDRIAL DNA DAMAGE. THE MECHANISMS OF MITOCHONDRIAL GENOME DAMAGE IN THE DEVELOPMENT OF CHRONIC AGE-RELATED DISEASES SUCH AS ATHEROSCLEROSIS ARE NOT YET WELL UNDERSTOOD. THIS REVIEW FOCUSES ON THE LATEST FINDINGS FROM STUDIES OF THOSE MUTATIONS OF THE MITOCHONDRIAL GENOME WHICH MAY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ATHEROSCLEROSIS AND WHICH ARE, AT THE SAME TIME, ALSO MARKERS OF MITOCHONDRIAL AGING AND CELL SENESCENCE. 2015 15 6510 23 TRANSCRIPTION FACTORS AND EPIGENETIC MODULATION: ITS THERAPEUTIC IMPLICATION IN CHRONIC KIDNEY DISEASE. RECENTLY EMERGING EVIDENCE HAS SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF VARIOUS DISEASES, INCLUDING KIDNEY DISEASES. IN THE PRESENT ARTICLE, WE REVIEW THE CURRENT DATA REGARDING THE ROLE OF EPIGENETIC MODULATION IN CHRONIC KIDNEY DISEASE (CKD) AND KIDNEY FIBROSIS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION. ESPECIALLY WE FOCUSED ON THE ROLE OF TRANSCRIPTION FACTORS IN EPIGENETIC MODULATION AND THE POSSIBILITY OF THERAPEUTIC TARGET OF CKD. WE HAVE RECENTLY REPORTED THAT TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (ALSO KNOWN AS GUT-ENRICHED KRUPPEL-LIKE FACTOR) IS EXPRESSED IN KIDNEY PODOCYTES (VISCERAL EPITHELIAL CELLS) AND MODULATES PODOCYTE PHENOTYPE BY GENE-SELECTIVE EPIGENETIC CONTROL. TARGETING TRANSCRIPTION FACTORS FOR EPIGENETIC MODIFICATION MAY BE A GOOD CANDIDATE FOR REMISSION AND REGRESSION OF CKD. IT IS NECESSARY FOR THE THERAPY OF CKD WITH AN EPIGENETIC-BASED APPROACH TO INVESTIGATE ORGAN-, TISSUE-, OR GENE-SPECIFIC TREATMENT METHODS FOR REDUCTION OF SIDE EFFECTS. 2015 16 1254 27 CURRENT PROGRESS ON THE MECHANISMS OF HYPERHOMOCYSTEINEMIA-INDUCED VASCULAR INJURY AND USE OF NATURAL POLYPHENOL COMPOUNDS. CARDIOVASCULAR DISEASE IS ONE OF THE MOST COMMON DISEASES IN THE ELDERLY POPULATION, AND ITS INCIDENCE HAS RAPIDLY INCREASED WITH THE PROLONGATION OF LIFE EXPECTANCY. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT RISK FACTOR FOR VARIOUS CARDIOVASCULAR DISEASES, INCLUDING ATHEROSCLEROSIS, AND DAMAGE TO VASCULAR FUNCTION PLAYS AN INITIAL ROLE IN ITS PATHOGENESIS. THIS REVIEW PRESENTS THE LATEST KNOWLEDGE ON THE MECHANISMS OF VASCULAR INJURY CAUSED BY HYPERHOMOCYSTEINEMIA, INCLUDING OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS, PROTEIN N-HOMOCYSTEINIZATION, AND EPIGENETIC MODIFICATION, AND DISCUSSES THE THERAPEUTIC TARGETS OF NATURAL POLYPHENOLS. STUDIES HAVE SHOWN THAT NATURAL POLYPHENOLS IN PLANTS CAN REDUCE HOMOCYSTEINE LEVELS AND REGULATE DNA METHYLATION BY ACTING ON OXIDATIVE STRESS AND ENDOPLASMIC RETICULUM STRESS-RELATED SIGNALING PATHWAYS, THUS IMPROVING HYPERHOMOCYSTEINEMIA-INDUCED VASCULAR INJURY. NATURAL POLYPHENOLS OBTAINED VIA DAILY DIET ARE SAFER AND HAVE MORE PRACTICAL SIGNIFICANCE IN THE PREVENTION AND TREATMENT OF CHRONIC DISEASES THAN TRADITIONAL DRUGS. 2021 17 220 28 ACUTE KIDNEY DISEASE: AN OVERVIEW OF THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT. ACUTE KIDNEY INJURY (AKI) INCREASES THE RISK OF CHRONIC KIDNEY DISEASE (CKD), AND AKI AND CKD ARE SEEN AS INTERCONNECTED SYNDROMES. ACUTE KIDNEY DISEASE (AKD) IS DEFINED AS SUBACUTE DAMAGE AND/OR LOSS OF KIDNEY FUNCTION OCCURRING 7 TO 90 DAYS AFTER AKI, DURING WHICH PERIOD KEY INTERVENTIONS MAY BE INITIATED TO HINDER THE DEVELOPMENT OF CKD. WHILE AKD IS USUALLY UNDER-RECOGNIZED, IT IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY GLOBALLY. THIS REVIEW ARTICLE AIMS TO SUMMARIZE THE CURRENT KNOWLEDGE CONCERNING THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT OF AKD WITH THE AIM TO DEVELOP MONITORING STRATEGIES AND THERAPEUTIC AGENTS OF AKD. GENERALLY, AKD TENDS TO OCCUR MORE FREQUENTLY IN THE ELDERLY AND THOSE WITH CHRONIC DISEASES, SUCH AS HYPERTENSION, DIABETES MELLITUS, AND METABOLIC SYNDROME. IN ADDITION, THE SEVERITY, DURATION, AND FREQUENCY OF AKI ARE INDEPENDENT RISK FACTORS FOR AKD. INVESTIGATIONS OF SEVERAL MECHANISMS OF AKD, SUCH AS RENAL TUBULAR EPITHELIUM CELL-CYCLE ARREST, EPIGENETIC CHANGE, CHRONIC INFLAMMATION, MITOCHONDRIA DYSFUNCTION, FAILED REGENERATION OF TUBULAR CELLS, METABOLIC REPROGRAMMING, AND RENIN-ANGIOTENSIN SYSTEM (RAS) ACTIVATION, HAVE IDENTIFIED ADDITIONAL POTENTIAL PHARMACOTHERAPY TARGETS. MANAGEMENT OF AKD INCLUDES PREVENTION OF REPEATED AKI, EARLY AND REGULAR FOLLOW-UP BY A NEPHROLOGIST, RESUMPTION AND ADJUSTMENT OF ESSENTIAL MEDICATION, OPTIMIZATION OF BLOOD PRESSURE CONTROL AND NUTRITION MANAGEMENT, AND DEVELOPMENT OF NEW PHARMACEUTICAL AGENTS INCLUDING RAS INHIBITORS. FINALLY, WE OUTLINE A CARE BUNDLE FOR AKD PATIENTS BASED ON IMPORTANT LESSONS LEARNED FROM STUDIES AND REGISTRIES AND IDENTIFY THE NEED FOR CLINICAL TRIALS OF RAS INHIBITORS OR OTHER NOVEL AGENTS TO IMPEDE ENSUING CKD DEVELOPMENT. 2023 18 5281 18 PROMOTION AND SELECTION BY SERUM GROWTH FACTORS DRIVE FIELD CANCERIZATION, WHICH IS ANTICIPATED IN VIVO BY TYPE 2 DIABETES AND OBESITY. INDIVIDUALS SUFFERING FROM TYPE 2 DIABETES OR OBESITY EXHIBIT A SIGNIFICANT INCREASE IN THE INCIDENCE OF VARIOUS TYPES OF CANCER. IT IS GENERALLY ACCEPTED THAT THOSE CONDITIONS ARISE FROM OVERNUTRITION AND A SEDENTARY LIFESTYLE, WHICH LEAD TO INSULIN RESISTANCE CHARACTERIZED BY OVERPRODUCTION OF INSULIN ACTING AS A GROWTH FACTOR. THERE IS A CONSENSUS BASED LARGELY ON EPIDEMIOLOGICAL DATA THAT CHRONIC OVERPRODUCTION OF INSULIN IS RESPONSIBLE FOR THE INCREASED INCIDENCE OF CANCER. A MODEL SYSTEM IN CULTURE OF NIH 3T3 CELLS INDUCES THE COLLECTIVE EFFECTS OF SERUM GROWTH FACTORS ON PROGRESSION THROUGH THE STAGES OF FIELD CANCERIZATION. IT SHOWS THAT THE DRIVING FORCE OF PROGRESSION IS PROMOTION OF CELL GROWTH UNDER SELECTION AT HIGH CELL DENSITY, WITH NO REQUIREMENT FOR EXOGENOUS CARCINOGENIC AGENTS. THE EARLY EFFECT IS GRADUAL SELECTION AMONG MANY PREEXISTING, LOW-PENETRANCE PRENEOPLASTIC MUTATIONS OR STABLE EPIGENETIC VARIANTS, FOLLOWED BY SPORADIC, HIGH-PENETRANCE TRANSFORMING VARIANTS, ALL DEPENDENT ON ENDOGENOUS PROCESSES. THE SIGNIFICANCE OF THE RESULTS FOR CANCER IN DIABETIC AND OBESE INDIVIDUALS IS THAT THE INITIAL STAGES OF THE PROCESS INVOLVE MULTIORGAN METABOLIC INTERACTIONS THAT PRODUCE A SYSTEMIC INSULIN RESISTANCE WITH CHRONIC OVERPRODUCTION OF INSULIN AND LOCALIZED FIELD CANCERIZATION. HYPOMAGNESEMIA IS PREVALENT IN THE FOREGOING METABALO/SYSTEMIC DISORDERS, AND MAY ALSO PROVIDE A SELECTIVE MICROENVIRONMENT FOR TUMOR DEVELOPMENT. 2013 19 289 21 AGING AND INTERSTITIAL LUNG DISEASES: UNRAVELING AN OLD FORGOTTEN PLAYER IN THE PATHOGENESIS OF LUNG FIBROSIS. AGING IS A NATURAL PROCESS CHARACTERIZED BY A PROGRESSIVE FUNCTIONAL IMPAIRMENT AND REDUCED CAPACITY TO RESPOND ADAPTIVELY TO ENVIRONMENTAL STIMULI. AGING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO A VARIETY OF CHRONIC DISEASES, INCLUDING TYPE 2 DIABETES MELLITUS, CANCER, AND NEUROLOGICAL DISEASES. LUNG PATHOLOGIES ARE NOT THE EXCEPTION, AND THE PREVALENCE OF SEVERAL INTERSTITIAL LUNG DISEASES (ILDS), PRIMARILY IDIOPATHIC PULMONARY FIBROSIS, HAS BEEN FOUND TO INCREASE CONSIDERABLY WITH AGE. ALTHOUGH OUR UNDERSTANDING OF THE BIOLOGY OF AGING HAS ADVANCED REMARKABLY IN THE LAST 2 DECADES, THE MOLECULAR MECHANISMS LINKING AGING TO ILD REMAIN UNCLEAR. IMMUNOSENESCENCE, OXIDATIVE STRESS, ABNORMAL SHORTENING OF TELOMERES, APOPTOSIS, AND EPIGENETIC CHANGES AFFECTING GENE EXPRESSION HAVE BEEN PROPOSED TO CONTRIBUTE TO THE AGING PROCESS, AND AGING-ASSOCIATED DISEASES. HERE, WE REVIEW THE EMERGING CONCEPTS HIGHLIGHTING THE PUTATIVE AGING-ASSOCIATED ABNORMALITIES INVOLVED IN SOME HUMAN ILDS. 2010 20 125 23 A SYSTEMS BIOLOGY OVERVIEW ON HUMAN DIABETIC NEPHROPATHY: FROM GENETIC SUSCEPTIBILITY TO POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL MODIFICATIONS. DIABETIC NEPHROPATHY (DN), A MICROVASCULAR COMPLICATION OCCURRING IN APPROXIMATELY 20-40% OF PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2DM), IS CHARACTERIZED BY THE PROGRESSIVE IMPAIRMENT OF GLOMERULAR FILTRATION AND THE DEVELOPMENT OF KIMMELSTIEL-WILSON LESIONS LEADING TO END-STAGE RENAL FAILURE (ESRD). THE CAUSES AND MOLECULAR MECHANISMS MEDIATING THE ONSET OF T2DM CHRONIC COMPLICATIONS ARE YET SKETCHY AND IT IS NOT CLEAR WHY DISEASE PROGRESSION OCCURS ONLY IN SOME PATIENTS. WE PERFORMED A SYSTEMATIC ANALYSIS OF THE MOST RELEVANT STUDIES INVESTIGATING GENETIC SUSCEPTIBILITY AND SPECIFIC TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND METABOLOMIC PATTERNS IN ORDER TO SUMMARIZE THE MOST SIGNIFICANT TRAITS ASSOCIATED WITH THE DISEASE ONSET AND PROGRESSION. THE PICTURE THAT EMERGES IS COMPLEX AND FASCINATING AS IT INCLUDES THE REGULATION/DYSREGULATION OF NUMEROUS BIOLOGICAL PROCESSES, CONVERGING TOWARD THE ACTIVATION OF INFLAMMATORY PROCESSES, OXIDATIVE STRESS, REMODELING OF CELLULAR FUNCTION AND MORPHOLOGY, AND DISTURBANCE OF METABOLIC PATHWAYS. THE GROWING INTEREST IN THE CHARACTERIZATION OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS AND THE IMPORTANCE OF HANDLING LARGE DATASETS USING A SYSTEMS BIOLOGY APPROACH ARE ALSO DISCUSSED. 2016