1 5707 159 SIRT1 AS A THERAPEUTIC TARGET IN DIABETIC COMPLICATIONS. BACKGROUND: SIRTUIN1 IS AN EPIGENETIC ENZYME INVOLVED IN HISTONE AND NONHISTONE PROTEIN DEACETYLATION. IT ACTS PRIMARILY AS A METABOLIC SENSOR, WHICH RESPONSES TO CHANGING ENERGY STATUS BY DEACETYLATING CRUCIAL TRANSCRIPTION FACTORS AND COFACTORS. IN THIS WAY, SIRTUIN1 REGULATES MITOCHONDRIAL FUNCTION AND BIOGENESIS, OXIDATIVE STRESS, INFLAMMATION, APOPTOSIS AND CELLULAR SENESCENCE. DISTURBANCE OF ALL OF THESE PHENOMENA PROMOTES THE PATHOGENESIS OF DIABETIC COMPLICATIONS. THESE DISORDERS ARE INSEPARABLY CONNECTED WITH CHRONIC HYPERGLYCEMIA, WHICH POSSESSES A STRONG EPIGENETIC DETERMINANT. OBJECTIVE: TO SUMMARIZE THE CONTEMPORARY KNOWLEDGE REGARDING THE ROLE OF SIRTUIN1 IN THE DEVELOPMENT, PROGRESSION AND THERAPY OF DIABETIC COMPLICATIONS. METHODS: WE EXTENSIVELY SEARCHED LITERATURE DESCRIBING THE IMPORTANCE OF SIRTUIN1 IN PATHOPHYSIOLOGY AND TREATMENT OF ALL KINDS OF DIABETIC COMPLICATIONS TILL SEPTEMBER 2017. WE FOCUSED ON THE EXAMPLES OF SYNTHETIC AND NATURAL COMPOUNDS-MEDIATED SIRTUIN1 UPREGULATION ALONG WITH SIRTUIN1-ASSOCIATED EPIGENETICS. RESULTS: REDUCTION OF SIRTUIN1 IS IMPLICATED IN ENDOTHELIAL DYSFUNCTION AND METABOLIC MEMORY, UNDERLYING THE DEVELOPMENT OF MICRO- AND MACROVASCULAR COMPLICATIONS. DECLINED SIRTUIN1 ALSO PARTICIPATES IN DIABETIC TESTICULAR AND ERECTILE DYSFUNCTION. SIRTUIN1 IS ELEVATED BY NATURALLY OCCURRING ANTI-OXIDANT AND ANTI-INFLAMMATORY COMPOUNDS SUCH AS RESVERATROL, TRANS-DELTA-VINIFERIN, VITAMIN D AND MORE. SIMILARLY, SIRTUIN1 LEVEL INCREASES AFTER TREATMENT WITH STANDARD ANTIHYPERGLYCEMIC (METFORMIN, EXENATIDE, LIRAGLUTIDE), ANTIHYPERTENSIVE (SARTANS), LIPID-LOWERING (FIBRATES, STATINS) AND ANTICOAGULANT (FIDARESTAT) DRUGS. REGARDING EPIGENETICS, A NUMBER OF MIRNAS TRIGGER SIRTUIN1 DECREASE, WHICH FURTHER CONTRIBUTES TO HISTONE ACETYLATION OF SIRTUIN1-REGULATED AND RELEVANT FOR DIABETES GENES. CONCLUSION: EVIDENCE STRONGLY SUGGEST THAT SIRTUIN1 UPREGULATION MAY SERVE AS A POTENT THERAPEUTIC APPROACH AGAINST DEVELOPMENT AND PROGRESSION OF DIABETIC COMPLICATIONS. 2018 2 5719 27 SIRTUINS IN NEURODEGENERATIVE DISEASES: AN UPDATE ON POTENTIAL MECHANISMS. SILENT INFORMATION REGULATOR 2 PROTEINS (SIRTUINS OR SIRTS) ARE A GROUP OF DEACETYLASES (OR DEACYLASES) WHOSE ACTIVITIES ARE DEPENDENT ON AND REGULATED BY NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)). COMPELLING EVIDENCE SUPPORTS THAT SIRTUINS PLAY MAJOR ROLES IN MANY ASPECTS OF PHYSIOLOGY, ESPECIALLY IN PATHWAYS RELATED TO AGING - THE PREDOMINANT AND UNIFYING RISK FACTOR FOR NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE MOLECULAR MECHANISMS UNDERLYING THE PROTECTIVE EFFECTS OF SIRTUINS IN NEURODEGENERATIVE DISEASES, FOCUSING ON PROTEIN HOMEOSTASIS, NEURAL PLASTICITY, MITOCHONDRIAL FUNCTION, AND SUSTAINED CHRONIC INFLAMMATION. WE WILL ALSO EXAMINE THE POTENTIAL AND CHALLENGES OF TARGETING SIRTUIN PATHWAYS TO BLOCK THESE PATHOGENIC PATHWAYS. 2013 3 6022 33 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 4 3801 41 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 5 6103 46 THE EMERGING ROLE OF HDACS: PATHOLOGY AND THERAPEUTIC TARGETS IN DIABETES MELLITUS. DIABETES MELLITUS (DM) IS ONE OF THE PRINCIPAL MANIFESTATIONS OF METABOLIC SYNDROME AND ITS PREVALENCE WITH MODERN LIFESTYLE IS INCREASING INCESSANTLY. CHRONIC HYPERGLYCEMIA CAN INDUCE SEVERAL VASCULAR COMPLICATIONS THAT WERE REFERRED TO BE THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN DM. ALTHOUGH SEVERAL THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED AND ACCESSED CLINICALLY, THE IMMINENT RISK OF DM AND ITS PREVALENCE ARE STILL ASCENDING. SUBSTANTIAL PIECES OF EVIDENCE REVEALED THAT HISTONE DEACETYLASE (HDAC) ISOFORMS CAN REGULATE VARIOUS MOLECULAR ACTIVITIES IN DM VIA EPIGENETIC AND POST-TRANSLATIONAL REGULATION OF SEVERAL TRANSCRIPTION FACTORS. TO DATE, 18 HDAC ISOFORMS HAVE BEEN IDENTIFIED IN MAMMALS THAT WERE CATEGORIZED INTO FOUR DIFFERENT CLASSES. CLASSES I, II, AND IV ARE REGARDED AS CLASSICAL HDACS, WHICH OPERATE THROUGH A ZN-BASED MECHANISM. IN CONTRAST, CLASS III HDACS OR SIRTUINS DEPEND ON NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) FOR THEIR MOLECULAR ACTIVITY. FUNCTIONALLY, MOST OF THE HDAC ISOFORMS CAN REGULATE BETA CELL FATE, INSULIN RELEASE, INSULIN EXPRESSION AND SIGNALING, AND GLUCOSE METABOLISM. MOREOVER, THE ROLES OF HDAC MEMBERS HAVE BEEN IMPLICATED IN THE REGULATION OF OXIDATIVE STRESS, INFLAMMATION, APOPTOSIS, FIBROSIS, AND OTHER PATHOLOGICAL EVENTS, WHICH SUBSTANTIALLY CONTRIBUTE TO DIABETES-RELATED VASCULAR DYSFUNCTIONS. THEREFORE, HDACS COULD SERVE AS THE POTENTIAL THERAPEUTIC TARGET IN DM TOWARDS DEVELOPING NOVEL INTERVENTION STRATEGIES. THIS REVIEW SHEDS LIGHT ON THE EMERGING ROLE OF HDACS/ISOFORMS IN DIABETIC PATHOPHYSIOLOGY AND EMPHASIZED THE SCOPE OF THEIR TARGETING IN DM FOR CONSTITUTING NOVEL INTERVENTIONAL STRATEGIES FOR METABOLIC DISORDERS/COMPLICATIONS. 2021 6 4902 44 OXIDATIVE-STRESS-INDUCED EPIGENETIC CHANGES IN CHRONIC DIABETIC COMPLICATIONS. OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. DIABETES CAUSES MITOCHONDRIAL SUPEROXIDE OVERPRODUCTION IN THE ENDOTHELIAL CELLS OF BOTH LARGE AND SMALL VESSELS. THIS INCREASED SUPEROXIDE PRODUCTION CAUSES THE ACTIVATION OF SEVERAL SIGNAL PATHWAYS INVOLVED IN THE PATHOGENESIS OF CHRONIC COMPLICATIONS. IN PARTICULAR, ENDOTHELIAL CELLS ARE MAJOR TARGETS OF GLUCOSE-INDUCED OXIDATIVE DAMAGE IN THE TARGET ORGANS. OXIDATIVE STRESS ACTIVATES CELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS IN ENDOTHELIAL CELLS INCLUDING PROTEIN KINASE C (PKC), C-JUN-N-TERMINAL KINASE (JNK), P38 MITOGEN-ACTIVATED PROTEIN KINASE (MAPK), FORKHEAD BOX O (FOXO), AND NUCLEAR FACTOR KAPPA-B (NF-KAPPAB). OXIDATIVE STRESS ALSO CAUSES DNA DAMAGE AND ACTIVATES DNA NUCLEOTIDE EXCISION REPAIR ENZYMES INCLUDING THE EXCISION REPAIR CROSS COMPLIMENTING 1(ERCC1), ERCC4, AND POLY(ADP-RIBOSE) POLYMERASE (PARP). AUGMENTED PRODUCTION OF HISTONE ACETYLTRANSFERASE P300, AND ALTERATIONS OF HISTONE DEACETYLASES, INCLUDING CLASS III DEACETYLASES SIRTUINS, ARE ALSO INVOLVED IN THIS PROCESS. RECENT RESEARCH HAS FOUND THAT SMALL NONCODING RNAS, LIKE MICRORNA, ARE A NEW KIND OF REGULATOR ASSOCIATED WITH CHRONIC DIABETIC COMPLICATIONS. THERE ARE EXTENSIVE AND COMPLICATED INTERACTIONS AND AMONG THESE MOLECULES. THE PURPOSE OF THIS REVIEW IS TO DEMONSTRATE THE ROLE OF OXIDATIVE STRESS IN THE DEVELOPMENT OF DIABETIC COMPLICATIONS IN RELATION TO EPIGENETIC CHANGES SUCH AS ACETYLATION AND MICRORNA ALTERATIONS. 2013 7 6200 38 THE INFLAMMATORY EFFECT OF EPIGENETIC FACTORS AND MODIFICATIONS IN TYPE 2 DIABETES. INFLAMMATION HAS A CENTRAL ROLE IN THE ETIOLOGY OF TYPE 2 DIABETES (T2D) AND ITS COMPLICATIONS. BOTH GENETIC AND EPIGENETIC FACTORS HAVE BEEN IMPLICATED IN THE DEVELOPMENT OF T2D-ASSOCIATED INFLAMMATION. EPIGENETIC MECHANISMS REGULATE THE FUNCTION OF SEVERAL COMPONENTS OF THE IMMUNE SYSTEM. DIABETIC CONDITIONS TRIGGER ABERRANT EPIGENETIC ALTERATIONS THAT CONTRIBUTE TO THE PROGRESSION OF INSULIN RESISTANCE AND BETA-CELL DYSFUNCTION BY INDUCTION OF INFLAMMATORY RESPONSES. THUS, TARGETING EPIGENETIC FACTORS AND MODIFICATIONS, AS ONE OF THE UNDERLYING CAUSES OF INFLAMMATION, COULD LEAD TO THE DEVELOPMENT OF NOVEL IMMUNE-BASED STRATEGIES FOR THE TREATMENT OF T2D. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE EPIGENETIC MECHANISMS INVOLVED IN THE PROPAGATION AND PERPETUATION OF CHRONIC INFLAMMATION IN T2D. WE ALSO DISCUSS THE POSSIBLE ANTI-INFLAMMATORY APPROACHES THAT TARGET EPIGENETIC FACTORS FOR THE TREATMENT OF T2D. 2020 8 4013 41 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 9 4597 28 NATURAL PRODUCTS WITH ANTI-AGING POTENTIAL: AFFECTED TARGETS AND MOLECULAR MECHANISMS. IN RECENT YEARS, THERE HAS BEEN A GREAT DEAL OF ATTENTION TOWARD THE MOLECULAR MACHINERY RELEVANT TO AGE-RELATED PROGRESSION CONTROLLED THROUGH THE EXTERNAL INTERVENTION OF POLYPHENOLS- AN EPIGENETIC-MODULATING DIET. NATURAL PRODUCTS MODULATE CELLULAR LONGEVITY THROUGH HISTONE POST-TRANSLATIONAL MODIFICATION AND CAN ALSO INDUCE THE UPREGULATION OF AUTOPHAGY, THUS REDUCING THE LEVEL OF ACETYL COENZYME A (ACCOA). IN ADDITION, THE EFFECT OF CALORIC RESTRICTION (CR) ON CANCER-RELATED CHRONIC INFLAMMATION IS OF GREAT SIGNIFICANCE IN AGING. IN LINE WITH THIS, SIRT1 PROTEIN LEVELS ARE EXPANDED IN RESPONSE TO CALORIE RESTRICTION MIMETICS (CRM), IN THIS WAY ACTING AS AUTOPHAGY INDUCERS RELEVANT TO CANCER PREVENTION. 2018 10 1254 32 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 11 2965 49 GENETIC AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC RETINOPATHY: A MOLECULAR LINK TO REGULATE GENE EXPRESSION. INTENSIFICATION IN THE FREQUENCY OF DIABETES AND THE ASSOCIATED VASCULAR COMPLICATIONS HAS BEEN A ROOT CAUSE OF BLINDNESS AND VISUAL IMPAIRMENT WORLDWIDE. ONE SUCH VASCULAR COMPLICATION WHICH HAS BEEN THE PROMINENT CAUSE OF BLINDNESS; RETINAL VASCULATURE, NEURONAL AND GLIAL ABNORMALITIES IS DIABETIC RETINOPATHY (DR), A CHRONIC COMPLICATED OUTCOME OF TYPE 1 AND TYPE 2 DIABETES. IT HAS ALSO BECOME CLEAR THAT "GENETIC" VARIATIONS IN POPULATION ALONE CAN'T EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETES AND ITS COMPLICATIONS INCLUDING DR. DR EXPERIENCES ENGAGEMENT OF FOREMOST MEDIATORS OF DIABETES SUCH AS HYPERGLYCEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS THAT LEAD TO THE DYSREGULATION OF "EPIGENETIC" MECHANISMS INVOLVING HISTONE ACETYLATION AND HISTONE AND DNA METHYLATION, CHROMATIN REMODELING AND EXPRESSION OF A COMPLEX SET OF STRESS-REGULATED AND DISEASE-ASSOCIATED GENES. IN ADDITION, BOTH ELEVATED GLUCOSE CONCENTRATION AND INSULIN RESISTANCE LEAVE A ROBUST EFFECT ON EPIGENETIC REPROGRAMMING OF THE ENDOTHELIAL CELLS TOO, SINCE ENDOTHELIUM ASSOCIATED WITH THE EYE AIDS IN MAINTAINING THE VASCULAR HOMEOSTASIS. FURTHERMORE, SEVERAL STUDIES CONDUCTED ON THE DISEASE SUGGEST THAT THE MODIFICATIONS OF THE EPIGENOME MIGHT BE THE FUNDAMENTAL MECHANISM(S) FOR THE PROPOSED METABOLIC MEMORY' RESULTING INTO PROLONGED GENE EXPRESSION FOR INFLAMMATION AND CELLULAR DYSFUNCTION EVEN AFTER ATTAINING THE GLYCEMIC CONTROL IN DIABETICS. HENCEFORTH, THE PRESENT REVIEW FOCUSES ON THE ASPECTS OF GENETIC AND EPIGENETIC ALTERATIONS IN GENES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR AND ALDOSE REDUCTASE CONSIDERED BEING ASSOCIATED WITH DR. IN ADDITION, WE DISCUSS BRIEFLY THE ROLE OF THE THIOREDOXIN-INTERACTING PROTEIN TXNIP, WHICH IS STRONGLY INDUCED BY HIGH GLUCOSE AND DIABETES, IN CELLULAR OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION POTENTIALLY LEADING TO CHROMATIN REMODELING AND OCULAR COMPLICATIONS OF DIABETES. THE IDENTIFICATION OF DISEASE-ASSOCIATED GENES AND THEIR EPIGENETIC REGULATIONS WILL LEAD TO POTENTIAL NEW DRUGS AND GENE THERAPIES AS WELL AS PERSONALIZED MEDICINE TO PREVENT OR SLOW DOWN THE PROGRESSION OF DR. 2016 12 1487 34 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 13 4719 31 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 14 2332 35 EPIGENETIC REGULATION OF INFLAMMATION IN INSULIN RESISTANCE. EPIGENETICS FOCUSES ON THE STUDY OF CHANGES IN GENE EXPRESSION BASED ON MODIFICATIONS THAT DO NOT INTERFERE WITH THE DNA SEQUENCE, SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATION, AND NON-CODING RNA. EPIGENETIC CHANGES REGULATE THE EXPRESSION OF MANY GENES, INCLUDING INFLAMMATORY ONES. CHRONIC INFLAMMATION IS OFTEN ACCOMPANIED BY INSULIN RESISTANCE (IR), WHICH IS CHARACTERISTIC OF INTER ALIA TYPE 2 DIABETES. RECENTLY, IT HAS BEEN REPORTED THAT ALTERED EPIGENETIC SIGNATURE IN THE PROMOTER REGIONS OF INFLAMMATORY GENES MAY CONTRIBUTE TO THE DEVELOPMENT OF IR. THEREFORE, THE AIM OF THIS REVIEW IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC REGULATION OF INFLAMMATION IN IR. IT INCLUDES ORIGINAL PAPERS PUBLISHED FROM 2014 TO 2022. IT APPEARS THAT HYPOMETHYLATION OF THE SOCS3 GENE INCREASES THE RISK OF IR, WHILE THE ALTERATION OF H3K4ME IN THE NF-KB PROMOTER PROMOTES CHANGES IN INFLAMMATORY PHENOTYPE. FINALLY, IN HYPERGLYCEMIC STATES ASSOCIATED WITH IR, ALTERED LEVELS OF H3K4/K9M3 AND H3K9/K14AC RESULT IN INCREASED EXPRESSION OF THE INFLAMMATORY CYTOKINE IL-6. IN ADDITION, NUMEROUS MIRNAS HAVE BEEN IDENTIFIED THAT MAY BECOME A TARGET IN THE FIGHT AGAINST DISEASES RELATED TO INFLAMMATION AND IR. FUTURE STUDIES SHOULD EXAMINE THE EPIGENETIC MODIFICATIONS OF IR INFLAMMATORY MARKERS ASSOCIATED WITH ENVIRONMENTAL FACTORS. 2022 15 5721 32 SIRTUINS-NOVEL REGULATORS OF EPIGENETIC ALTERATIONS IN AIRWAY INFLAMMATION. HISTONE MODIFICATION IS AN IMPORTANT EPIGENETIC ALTERATION, AND HISTONE DEACETYLASES ARE INVOLVED IN THE OCCURRENCE AND DEVELOPMENT OF VARIOUS RESPIRATORY DISEASES. SIRTUINS (SIRTS) HAVE BEEN DEMONSTRATED TO PLAY AN IMPORTANT ROLE IN THE FORMATION AND PROGRESSION OF CHRONIC INFLAMMATORY DISEASES OF THE RESPIRATORY TRACT. SIRTS PARTICIPATE IN THE REGULATION OF OXIDATIVE STRESS AND INFLAMMATION AND ARE RELATED TO CELL STRUCTURE AND CELLULAR LOCALIZATION. THIS PAPER SUMMARIZES THE ROLES AND MECHANISMS OF SIRTS IN AIRWAY INFLAMMATION AND DESCRIBES THE LATEST RESEARCH ON SIRT MODULATORS, AIMING TO PROVIDE A THEORETICAL BASIS FOR THE STUDY OF POTENTIAL EPIGENETIC ALTERATION-INDUCING DRUG TARGETS. 2022 16 2230 28 EPIGENETIC MODIFICATIONS OF KLOTHO EXPRESSION IN KIDNEY DISEASES. DEVELOPMENTS OF MANY RENAL DISEASES ARE SUBSTANTIALLY INFLUENCED BY EPIGENETIC MODIFICATIONS OF NUMEROUS GENES, MAINLY MEDIATED BY DNA METHYLATIONS, HISTONE MODIFICATIONS, AND MICRORNA INTERFERENCE; HOWEVER, NOT ALL GENE MODIFICATIONS CAUSALLY AFFECT THE DISEASE ONSET OR PROGRESSION. KLOTHO IS A CRITICAL GENE WHOSE REPRESSIONS IN VARIOUS PATHOLOGICAL CONDITIONS REPORTEDLY INVOLVE EPIGENETIC REGULATORY MECHANISMS. KLOTHO IS ALMOST UNEXCEPTIONALLY REPRESSED EARLY AFTER ACUTE OR CHRONIC RENAL INJURIES AND ITS LEVELS INVERSELY CORRELATED WITH THE DISEASE PROGRESSION AND SEVERITY. MOREOVER, THE STRATEGIES OF KLOTHO DEREPRESSION VIA EPIGENETIC MODULATIONS BENEFICIALLY CHANGE THE PATHOLOGICAL COURSES BOTH IN VITRO AND IN VIVO. HENCE, KLOTHO IS NOT ONLY CONSIDERED A BIOMARKER OF THE RENAL DISEASE BUT ALSO A POTENTIAL OR EVEN AN IDEAL TARGET OF THERAPEUTIC EPIGENETIC INTERVENTION. HERE, WE SUMMARIZE AND DISCUSS STUDIES THAT INVESTIGATE THE KLOTHO REPRESSION AND INTERVENTION IN RENAL DISEASES FROM AN EPIGENETIC POINT OF VIEW. THESE INFORMATION MIGHT SHED NEW SIGHTS INTO THE EFFECTIVE THERAPEUTIC STRATEGIES TO PREVENT AND TREAT VARIOUS RENAL DISORDERS. 2021 17 4336 34 MICRORNAS: THE UNDERLYING MEDIATORS OF PATHOGENETIC PROCESSES IN VASCULAR COMPLICATIONS OF DIABETES. DIABETES MELLITUS CAUSES CHRONIC COMPLICATIONS PRIMARILY AFFECTING THE VASCULATURE OF VARIOUS ORGANS, RISKING PATIENTS FOR RENAL FAILURE, VISION LOSS AND HEART FAILURE. A NEWLY DISCOVERED CLASS OF MOLECULES, MICRORNAS, MAY BE IMPORTANT IN THE GENESIS OF THESE PATHOLOGIC PROCESSES. MICRORNAS REGULATE GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL BY INHIBITING TARGET MESSENGER RNA TRANSLATION. IN DISEASE STATES, HOWEVER, THE EXPRESSION OF MICRORNAS OFTEN IS ALTERED, RESULTING IN FURTHER ALTERED EXPRESSION (MOSTLY OVEREXPRESSION) OF DOWNSTREAM TARGET GENES. INTERESTINGLY, RESTORING MICRORNA EXPRESSION TO NORMAL LEVELS CAN CORRECT DOWNSTREAM EFFECTS AND PREVENT DIABETES-ASSOCIATED CHANGES. INVESTIGATIONS INTO MICRORNA INVOLVED IN VARIOUS PATHOGENETIC PROCESSES MEDIATING DIABETIC NEPHROPATHY, RETINOPATHY AND CARDIOMYOPATHY ARE HIGHLIGHTED IN THIS REVIEW. FUTURE DIRECTIONS OF MICRORNA IN THERAPEUTICS AND DIAGNOSTICS ARE ALSO DISCUSSED. IT IS OUR INTENT TO HELP THE READER APPRECIATE THE DIVERSE INTERACTIONS MICRORNAS HAVE IN CELLULAR SIGNALLING AND HOW UNDERSTANDING EPIGENETIC ELEMENTS, SUCH AS MICRORNAS, POTENTIALLY CAN YIELD NEW THERAPEUTIC STRATEGIES. 2013 18 125 38 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 19 6129 39 THE EPIGENETIC REGULATION OF PODOCYTE FUNCTION IN DIABETES. CHRONIC HYPERGLYCEMIA EARLY IN THE COURSE OF DIABETES CONFERS A SUSTAINED INCREASE IN THE RISK OF COMPLICATIONS DEVELOPMENT. IN RECENT YEARS, EFFORTS TO UNDERSTAND THE MOLECULAR BASIS FOR THIS "METABOLIC MEMORY" HAVE FOCUSED ON EPIGENETIC MECHANISMS AS A MEANS BY WHICH TRANSIENT HIGH GLUCOSE CAN CAUSE PERSISTENT AND PROPAGATED CHANGES IN CELL FUNCTION. FOR INSTANCE, IN VASCULAR ENDOTHELIAL CELLS, SMOOTH MUSCLE CELLS AND PERIPHERAL BLOOD CELLS, TEMPORARY EXPOSURE TO HIGH GLUCOSE CAUSES CHANGES IN EPIGENETIC MARKS THAT PROMOTE A SHIFT TOWARDS A PRO-INFLAMMATORY PHENOTYPE. HOWEVER, THE INFLUENCE OF EPIGENETIC PROCESSES IN COMPLICATIONS DEVELOPMENT EXTENDS BEYOND THEIR CONTRIBUTION TO METABOLIC MEMORY. PODOCYTES, FOR EXAMPLE, ARE TERMINALLY DIFFERENTIATED CELLS OF THE RENAL GLOMERULUS WHOSE INJURY IS A MAJOR CONTRIBUTOR TO THE PATHOGENESIS OF NEPHROPATHY. OVER RECENT MONTHS, SEVERAL REPORTS HAVE EMERGED DESCRIBING THE ESSENTIAL ACTIONS OF HISTONE-MODIFYING ENZYMES AND DNA METHYLATION PATTERNS (THE TWO PRINCIPAL EPIGENETIC MECHANISMS) IN MAINTAINING PODOCYTE INTEGRITY, ESPECIALLY UNDER DIABETIC CONDITIONS. HERE, WE REVIEW THE KNOWN AND POTENTIAL ROLE OF EPIGENETIC PROCESSES WITHIN PODOCYTES, FOCUSING ON THE EVIDENCE LINKING THESE PROCESSES TO OXIDATIVE STRESS, CROSSTALK WITH TUBULE CELLS, AUTOPHAGY AND SLIT-PORE PROTEIN EXPRESSION. WHETHER PODOCYTES THEMSELVES EXHIBIT A METABOLIC MEMORY AWAITS TO BE SEEN. 2015 20 1505 37 DNA METHYLATION AND HISTONE MODIFICATION IN HYPERTENSION. SYSTEMIC HYPERTENSION, WHICH EVENTUALLY RESULTS IN HEART FAILURE, RENAL FAILURE OR STROKE, IS A COMMON CHRONIC HUMAN DISORDER THAT PARTICULARLY AFFECTS ELDERS. ALTHOUGH MANY SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF HYPERTENSION HAVE BEEN REPORTED OVER THE PAST DECADES, WHICH HAS LED TO THE IMPLEMENTATION OF A WIDE VARIETY OF ANTI-HYPERTENSIVE THERAPIES, ONE HALF OF ALL HYPERTENSIVE PATIENTS STILL DO NOT HAVE THEIR BLOOD PRESSURE CONTROLLED. THE FRONTIER IN UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING HYPERTENSION HAS NOW ADVANCED TO THE LEVEL OF EPIGENOMICS. PARTICULARLY, INCREASING EVIDENCE IS EMERGING THAT DNA METHYLATION AND HISTONE MODIFICATIONS PLAY AN IMPORTANT ROLE IN GENE REGULATION AND ARE INVOLVED IN ALTERATION OF THE PHENOTYPE AND FUNCTION OF VASCULAR CELLS IN RESPONSE TO ENVIRONMENTAL STRESSES. THIS REVIEW SEEKS TO HIGHLIGHT THE RECENT ADVANCES IN OUR KNOWLEDGE OF THE EPIGENETIC REGULATIONS AND MECHANISMS OF HYPERTENSION, FOCUSING ON THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATION IN THE VASCULAR WALL. A BETTER UNDERSTANDING OF THE EPIGENOMIC REGULATION IN THE HYPERTENSIVE VESSEL MAY LEAD TO THE IDENTIFICATION OF NOVEL TARGET MOLECULES THAT, IN TURN, MAY LEAD TO NOVEL DRUG DISCOVERIES FOR THE TREATMENT OF HYPERTENSION. 2018