1 4211 156 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 2 5826 37 STRESS SIGNAL NETWORK BETWEEN HYPOXIA AND ER STRESS IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY AN IRREVERSIBLE DECREASE IN KIDNEY FUNCTION AND INDUCTION OF VARIOUS METABOLIC DYSFUNCTIONS. ACCUMULATED FINDINGS REVEAL THAT CHRONIC HYPOXIC STRESS AND ENDOPLASMIC RETICULUM (ER) STRESS ARE INVOLVED IN A RANGE OF PATHOGENIC CONDITIONS, INCLUDING THE PROGRESSION OF CKD. BECAUSE OF THE PRESENCE OF AN ARTERIOVENOUS OXYGEN SHUNT, THE KIDNEY IS THOUGHT TO BE SUSCEPTIBLE TO HYPOXIA. CHRONIC KIDNEY HYPOXIA IS INDUCED BY A NUMBER OF PATHOGENIC CONDITIONS, INCLUDING RENAL ISCHEMIA, REDUCED PERITUBULAR CAPILLARY, AND TUBULOINTERSTITIAL FIBROSIS. THE ER IS AN ORGANELLE WHICH HELPS MAINTAIN THE QUALITY OF PROTEINS THROUGH THE UNFOLDED PROTEIN RESPONSE (UPR) PATHWAY, AND ER DYSFUNCTION ASSOCIATED WITH MALADAPTIVE UPR ACTIVATION IS NAMED ER STRESS. ER STRESS IS REPORTED TO BE RELATED TO SOME OF THE EFFECTS OF PATHOGENESIS IN KIDNEY, PARTICULARLY IN THE PODOCYTE SLIT DIAPHRAGM AND TUBULOINTERSTITIUM. FURTHERMORE, CHRONIC HYPOXIA MEDIATES ER STRESS IN BLOOD VESSEL ENDOTHELIAL CELLS AND TUBULOINTERSTITIUM VIA SEVERAL MECHANISMS, INCLUDING OXIDATIVE STRESS, EPIGENETIC ALTERATION, LIPID METABOLISM, AND THE AKT PATHWAY. IN SUMMARY, A GROWING CONSENSUS CONSIDERS THAT THESE STRESSES INTERACT VIA COMPLICATED STRESS SIGNAL NETWORKS, WHICH LEADS TO THE EXACERBATION OF CKD (FIGURE 1). THIS STRESS SIGNAL NETWORK MIGHT BE A TARGET FOR INTERVENTIONS AIMED AT AMELIORATING CKD. 2017 3 465 39 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT. 2017 4 6441 28 THERAPEUTIC APPROACHES FOR NONALCOHOLIC FATTY LIVER DISEASE: ESTABLISHED TARGETS AND DRUGS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), AS A MULTISYSTEMIC DISEASE, IS THE MOST PREVALENT CHRONIC LIVER DISEASE CHARACTERIZED BY EXTREMELY COMPLEX PATHOGENIC MECHANISMS AND MULTIFACTORIAL ETIOLOGY, WHICH OFTEN DEVELOPS AS A CONSEQUENCE OF OBESITY, METABOLIC SYNDROME. PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF NAFLD INCLUDE DIET, OBESITY, INSULIN RESISTANCE (IR), GENETIC AND EPIGENETIC DETERMINANTS, INTESTINAL DYSBIOSIS, OXIDATIVE/NITROSATIVE STRESS, AUTOPHAGY DYSREGULATION, HEPATIC INFLAMMATION, GUT-LIVER AXIS, GUT MICROBES, IMPAIRED MITOCHONDRIAL METABOLISM AND REGULATION OF HEPATIC LIPID METABOLISM. SOME OF THE NEW DRUGS FOR THE TREATMENT OF NAFLD ARE INTRODUCED HERE. ALL OF THEM ACHIEVE THERAPEUTIC OBJECTIVES BY INTERFERING WITH CERTAIN PATHOPHYSIOLOGICAL PATHWAYS OF NAFLD, INCLUDING FIBROBLAST GROWTH FACTORS (FGF) ANALOGUES, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) AGONISTS, GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS, G PROTEIN-COUPLED RECEPTORS (GPCRS), SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS (SGLT-2I), FARNESOID X RECEPTOR (FXR), FATTY ACID SYNTHASE INHIBITOR (FASNI), ANTIOXIDANTS, ETC. THIS REVIEW DESCRIBES SOME PATHOPHYSIOLOGICAL MECHANISMS OF NAFLD AND ESTABLISHED TARGETS AND DRUGS. 2023 5 1254 37 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 6 3554 39 IMPACT OF ADVANCED GLYCATION END PRODUCTS (AGES) AND ITS RECEPTOR (RAGE) ON CANCER METABOLIC SIGNALING PATHWAYS AND ITS PROGRESSION. CANCER IS A COMPLEX DISEASE WITH A 5-10% HEREDITARY BASE, BUT NUTRITION, LIFESTYLE, AND THE ENVIRONMENT WE ARE EXPOSED TO INFLUENCE 90-95% OF CANCERS. DUE TO RAPID WESTERNIZATION, THE DIET WE CONSUME IS RICH IN ADVANCED GLYCATION END PRODUCTS (AGES). AGES ARE THE HETEROGENEOUS GROUP OF COMPOUNDS FORMED BY NON-ENZYMATIC REACTIONS BETWEEN REDUCING SUGARS AND AMINO GROUPS OF PROTEINS, LIPIDS, AND NUCLEIC ACIDS. ITS IMPLICATION IS CONFIRMED IN MANY CHRONIC CONDITIONS SUCH AS DIABETES, RENAL, CARDIOVASCULAR DISEASES, AND AGING HOWEVER ITS ROLE IN CANCER DEVELOPMENT HAS BEEN UNDERSTUDIED. CANCER CELLS ARE CONTINUOUSLY EXPOSED TO AGES DUE TO THEIR INCREASED PRODUCTION, OWING TO ITS HIGH METABOLIC RATE AND AEROBIC GLYCOLYSIS. AGES ACCUMULATION LED TO GLYCATIVE STRESS WHICH IN TURN STIMULATES OXIDATIVE STRESS AND INFLAMMATION, THROUGH ITS RECEPTOR KNOWN AS RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE). RAGE MEDIATES CROSSTALK BETWEEN THE TUMOUR CELLS AND ITS MICROENVIRONMENT COMPONENTS TO INDUCE HYPOXIA, MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AUTOPHAGY, EPIGENETIC MODIFICATION, AND CANCER STEMNESS. THIS EMPHASIZES AGES AS AN ESSENTIAL DRIVING FACTOR IN DIFFERENT ASPECTS OF CANCER DEVELOPMENT, BUT THE EXACT MOLECULAR MECHANISM HAS TO BE EXPLORED. THUS, THIS REVIEW GIVES AN INSIGHT INTO THE PATHOLOGICAL ROLE OF AGES AT THE BIO-MOLECULAR LEVEL IN THE TUMOURIGENESIS AND PROGRESSION OF CANCER IN TERMS OF THE TUMOUR MICROENVIRONMENT, INVASION, AND METASTASIS. FURTHER, THE COMPILED CLINICAL DATA RELATING TO THE AGE-RAGE AXIS ASSOCIATED WITH DIFFERENT CANCERS AND ITS POTENTIAL INHIBITORS HAVE BEEN DISCUSSED. 2021 7 4170 31 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 8 5060 30 PHENYLBUTYRATE AND BETA-CELL FUNCTION: CONTRIBUTION OF HISTONE DEACETYLASES AND ER STRESS INHIBITION. INCIDENCES OF DIABETES ARE INCREASING GLOBALLY DUE TO INVOLVEMENT OF GENETIC AND EPIGENETIC FACTORS. PHENYLBUTYRATE (PBA) IS A US FDA APPROVED DRUG FOR TREATMENT OF UREA CYCLE DISORDER IN CHILDREN. PBA REDUCES ENDOPLASMIC RETICULUM (ER) STRESS AND IS PROVEN AS A POTENT HISTONE DEACETYLASES (HDACS) INHIBITOR. CHRONIC ER STRESS RESULTS IN UNFOLDING PROTEIN RESPONSE, WHICH TRIGGERS APOPTOSIS. ABNORMAL ER HOMOEOSTASIS IS RESPONSIBLE FOR DEFECTIVE PROCESSING OF SEVERAL GENES/PROTEINS AND CONTRIBUTES TO BETA-CELL DEATH/FAILURE. ACCUMULATED EVIDENCES INDICATED THAT HDACS MODULATE KEY BIOCHEMICAL PATHWAYS AND HDAC INHIBITORS IMPROVE BETA-CELL FUNCTION AND INSULIN RESISTANCE BY MODULATING MULTIPLE TARGETS. THIS REVIEW HIGHLIGHTS THE ROLE OF PBA ON BETA-CELL FUNCTIONS, INSULIN RESISTANCE FOR POSSIBLE TREATMENT OF DIABETES THROUGH INHIBITION OF ER STRESS AND HDACS. 2017 9 4891 35 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 10 5460 36 RESEARCH PERSPECTIVES ON THE REGULATION AND PHYSIOLOGICAL FUNCTIONS OF FGF21 AND ITS ASSOCIATION WITH NAFLD. FIBROBLAST GROWTH FACTOR 21 (FGF21) IS A METABOLIC HORMONE PRIMARILY SECRETED FROM THE LIVER AND FUNCTIONS IN MULTIPLE TISSUES. VARIOUS TRANSCRIPTION FACTORS INDUCE FGF21 EXPRESSION IN THE LIVER, WHICH INDICATES THAT FGF21 IS A MEDIATOR OF MULTIPLE ENVIRONMENTAL CUES. FGF21 ALTERS METABOLISM UNDER STARVATION CONDITIONS, PROTECTS THE BODY FROM ENERGY DEPLETION, AND EXTENDS LIFE SPAN. PHARMACOLOGICAL ADMINISTRATION OF FGF21 ALLEVIATES DYSLIPIDEMIA AND INDUCES WEIGHT LOSS IN OBESE ANIMALS. IN ADDITION TO THE WELL-STUDIED FUNCTIONS OF FG21, SEVERAL LINES OF RECENT EVIDENCE INDICATE A POSSIBLE LINK BETWEEN FGF21 AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). HIGH SERUM LEVELS OF FGF21 ARE ASSOCIATED WITH NAFLD AND ITS RISK FACTORS, SUCH AS ENDOPLASMIC RETICULUM STRESS AND CHRONIC INFLAMMATION. IN ADDITION, FGF21 ALLEVIATES THE MAJOR RISK FACTORS OF NAFLD, INCLUDING OBESITY, DYSLIPIDEMIA, AND INSULIN INSENSITIVITY. THUS, FGF21 IS A POTENTIAL DRUG CANDIDATE FOR DISEASES, SUCH AS NAFLD, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN THIS REVIEW, THE RESEARCH PERSPECTIVES OF FGF21 AND THERAPEUTIC POTENCIES OF FGF21 AS A MODULATOR OF NAFLD ARE SUMMARIZED. 2015 11 4459 47 MOLECULAR MECHANISMS OF DIABETIC VASCULAR COMPLICATIONS. DIABETIC COMPLICATIONS ARE THE MAJOR CAUSES OF MORBIDITY AND MORTALITY IN PATIENTS WITH DIABETES. MICROVASCULAR COMPLICATIONS INCLUDE RETINOPATHY, NEPHROPATHY AND NEUROPATHY, WHICH ARE LEADING CAUSES OF BLINDNESS, END-STAGE RENAL DISEASE AND VARIOUS PAINFUL NEUROPATHIES; WHEREAS MACROVASCULAR COMPLICATIONS INVOLVE ATHEROSCLEROSIS RELATED DISEASES, SUCH AS CORONARY ARTERY DISEASE, PERIPHERAL VASCULAR DISEASE AND STROKE. DIABETIC COMPLICATIONS ARE THE RESULT OF INTERACTIONS AMONG SYSTEMIC METABOLIC CHANGES, SUCH AS HYPERGLYCEMIA, LOCAL TISSUE RESPONSES TO TOXIC METABOLITES FROM GLUCOSE METABOLISM, AND GENETIC AND EPIGENETIC MODULATORS. CHRONIC HYPERGLYCEMIA IS RECOGNIZED AS A MAJOR INITIATOR OF DIABETIC COMPLICATIONS. MULTIPLE MOLECULAR MECHANISMS HAVE BEEN PROPOSED TO MEDIATE HYPERGLYCEMIA'S ADVERSE EFFECTS ON VASCULAR TISSUES. THESE INCLUDE INCREASED POLYOL PATHWAY, ACTIVATION OF THE DIACYLGLYCEROL/PROTEIN KINASE C PATHWAY, INCREASED OXIDATIVE STRESS, OVERPRODUCTION AND ACTION OF ADVANCED GLYCATION END PRODUCTS, AND INCREASED HEXOSAMINE PATHWAY. IN ADDITION, THE ALTERATIONS OF SIGNAL TRANSDUCTION PATHWAYS INDUCED BY HYPERGLYCEMIA OR TOXIC METABOLITES CAN ALSO LEAD TO CELLULAR DYSFUNCTIONS AND DAMAGE VASCULAR TISSUES BY ALTERING GENE EXPRESSION AND PROTEIN FUNCTION. LESS STUDIED THAN THE TOXIC MECHANISMS, HYPERGLYCEMIA MIGHT ALSO INHIBIT THE ENDOGENOUS VASCULAR PROTECTIVE FACTORS SUCH AS INSULIN, VASCULAR ENDOTHELIAL GROWTH FACTOR, PLATELET-DERIVED GROWTH FACTOR AND ACTIVATED PROTEIN C, WHICH PLAY IMPORTANT ROLES IN MAINTAINING VASCULAR HOMEOSTASIS. THUS, EFFECTIVE THERAPIES FOR DIABETIC COMPLICATIONS NEED TO INHIBIT MECHANISMS INDUCED BY HYPERGLYCEMIA'S TOXIC EFFECTS AND ALSO ENHANCE THE ENDOGENOUS PROTECTIVE FACTORS. THE PRESENT REVIEW SUMMARIZES THESE MULTIPLE BIOCHEMICAL PATHWAYS ACTIVATED BY HYPERGLYCEMIA AND THE POTENTIAL THERAPEUTIC INTERVENTIONS THAT MIGHT PREVENT DIABETIC COMPLICATIONS. (J DIABETES INVEST, DOI: 10.1111/J.2040-1124.2010.00018.X, 2010). 2010 12 4433 32 MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS OF DIABETES MELLITUS - A COMPREHENSIVE REVIEW. DIABETES IS A CHRONIC DISEASE, CHARACTERIZED BY HYPERGLYCEMIA, WHICH REFERS TO THE ELEVATED LEVELS OF GLUCOSE IN THE BLOOD, DUE TO THE INABILITY OF THE BODY TO PRODUCE OR USE INSULIN EFFECTIVELY. CHRONIC HYPERGLYCEMIA LEVELS LEAD TO MACROVASCULAR AND MICROVASCULAR COMPLICATIONS. THE MACROVASCULAR COMPLICATIONS CONSIST OF PERIPHERAL ARTERY DISEASE (PAD), CARDIOVASCULAR DISEASES (CVD) AND CEREBROVASCULAR DISEASES, WHILE THE MICROVASCULAR COMPLICATIONS COMPRISE OF DIABETIC MICROANGIOPATHY, DIABETIC NEPHROPATHY, DIABETIC RETINOPATHY AND DIABETIC NEUROPATHY. VASCULAR ENDOTHELIAL DYSFUNCTION PLAYS A CRUCIAL ROLE IN MEDIATING BOTH MACROVASCULAR AND MICROVASCULAR COMPLICATIONS UNDER HYPERGLYCEMIC CONDITIONS. IN DIABETIC MICROVASCULATURE, THE INTRACELLULAR HYPERGLYCEMIA CAUSES DAMAGE TO THE VASCULAR ENDOTHELIUM THROUGH - (I) ACTIVATION OF FOUR BIOCHEMICAL PATHWAYS, NAMELY THE POLYOL PATHWAY, PROTEIN KINASE C (PKC) PATHWAY, ADVANCED GLYCATION END PRODUCTS (AGE) PATHWAY AND HEXOSAMINE PATHWAY, ALL OF WHICH COMMUTES GLUCOSE AND ITS INTERMEDIATES LEADING TO OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DYSREGULATION OF GROWTH FACTORS AND CYTOKINES, (III) EPIGENETIC CHANGES WHICH CONCERN THE CHANGES IN DNA AS A RESPONSE TO INTRACELLULAR CHANGES, AND (IV) ABNORMALITIES IN NON-CODING RNAS, SPECIFICALLY MICRORNAS. THIS REVIEW WILL FOCUS ON GAINING AN UNDERSTANDING OF THE MOLECULAR COMPLEXITIES UNDERLYING THE VASCULAR COMPLICATIONS IN DIABETES MELLITUS, TO INCREASE OUR UNDERSTANDING TOWARDS THE DEVELOPMENT OF NEW MECHANISTIC THERAPEUTIC STRATEGIES TO PREVENT OR TREAT DIABETES-INDUCED VASCULAR COMPLICATIONS. 2020 13 6374 37 THE ROLE OF MITOCHONDRIA IN MYOCARDIAL DAMAGE CAUSED BY ENERGY METABOLISM DISORDERS: FROM MECHANISMS TO THERAPEUTICS. MYOCARDIAL DAMAGE IS THE MOST SERIOUS PATHOLOGICAL CONSEQUENCE OF CARDIOVASCULAR DISEASES AND AN IMPORTANT REASON FOR THEIR HIGH MORTALITY. IN RECENT YEARS, BECAUSE OF THE HIGH PREVALENCE OF SYSTEMIC ENERGY METABOLISM DISORDERS (E.G., OBESITY, DIABETES MELLITUS, AND METABOLIC SYNDROME), COMPLICATIONS OF MYOCARDIAL DAMAGE CAUSED BY THESE DISORDERS HAVE ATTRACTED WIDESPREAD ATTENTION. ENERGY METABOLISM DISORDERS ARE INDEPENDENT OF TRADITIONAL INJURY-RELATED RISK FACTORS, SUCH AS ISCHEMIA, HYPOXIA, TRAUMA, AND INFECTION. AN IMBALANCE OF MYOCARDIAL METABOLIC FLEXIBILITY AND MYOCARDIAL ENERGY DEPLETION ARE USUALLY THE INITIAL CHANGES OF MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS, AND ABNORMAL MORPHOLOGY AND FUNCTIONAL DESTRUCTION OF THE MITOCHONDRIA ARE THEIR IMPORTANT FEATURES. SPECIFICALLY, MITOCHONDRIA ARE THE CENTERS OF ENERGY METABOLISM, AND RECENT EVIDENCE HAS SHOWN THAT DECREASED MITOCHONDRIAL FUNCTION, CAUSED BY AN IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL, MAY PLAY A KEY ROLE IN MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS. UNDER CHRONIC ENERGY STRESS, MITOCHONDRIA UNDERGO PATHOLOGICAL FISSION, WHILE MITOPHAGY, MITOCHONDRIAL FUSION, AND BIOGENESIS ARE INHIBITED, AND MITOCHONDRIAL PROTEIN BALANCE AND TRANSFER ARE DISTURBED, RESULTING IN THE ACCUMULATION OF NONFUNCTIONAL AND DAMAGED MITOCHONDRIA. CONSEQUENTLY, DAMAGED MITOCHONDRIA LEAD TO MYOCARDIAL ENERGY DEPLETION AND THE ACCUMULATION OF LARGE AMOUNTS OF REACTIVE OXYGEN SPECIES, FURTHER AGGRAVATING THE IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL AND FORMING A VICIOUS CYCLE. IN ADDITION, IMPAIRED MITOCHONDRIA COORDINATE CALCIUM HOMEOSTASIS IMBALANCE, AND EPIGENETIC ALTERATIONS PARTICIPATE IN THE PATHOGENESIS OF MYOCARDIAL DAMAGE. THESE PATHOLOGICAL CHANGES INDUCE RAPID PROGRESSION OF MYOCARDIAL DAMAGE, EVENTUALLY LEADING TO HEART FAILURE OR SUDDEN CARDIAC DEATH. TO INTERVENE MORE SPECIFICALLY IN THE MYOCARDIAL DAMAGE CAUSED BY METABOLIC DISORDERS, WE NEED TO UNDERSTAND THE SPECIFIC ROLE OF MITOCHONDRIA IN THIS CONTEXT IN DETAIL. ACCORDINGLY, PROMISING THERAPEUTIC STRATEGIES HAVE BEEN PROPOSED. WE ALSO SUMMARIZE THE EXISTING THERAPEUTIC STRATEGIES TO PROVIDE A REFERENCE FOR CLINICAL TREATMENT AND DEVELOPING NEW THERAPIES. 2023 14 74 47 A MULTIDISCIPLINARY APPROACH AND CURRENT PERSPECTIVE OF NONALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW. IN RECENT TIMES, NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BEEN CONSIDERED ONE OF THE MAJOR CAUSES OF LIVER DISEASE ACROSS THE WORLD. NAFLD IS DEFINED AS THE DEPOSITION OF TRIGLYCERIDES IN THE LIVER AND IS ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME. HYPERINSULINEMIA, INSULIN RESISTANCE (IR), FATTY LIVER, HEPATOCYTE INJURY, UNBALANCED PROINFLAMMATORY CYTOKINES, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIVER INFLAMMATION, AND FIBROSIS ARE THE MAIN PATHOGENESIS IN NAFLD. RECENT STUDIES SUGGEST THAT THE ACTION OF INTESTINAL MICROBIOTA THROUGH CHRONIC INFLAMMATION, INCREASED INTESTINAL PERMEABILITY, AND ENERGY UPTAKE PLAYS A VITAL ROLE IN NAFLD. MOREOVER, POLYCYSTIC OVARIAN SYNDROME ALSO CAUSES NAFLD DEVELOPMENT THROUGH IR. AGE, GENDER, RACE, ETHNICITY, SLEEP, DIET, SEDENTARY LIFESTYLE, AND GENETIC AND EPIGENETIC PATHWAYS ARE SOME CONTRIBUTING FACTORS OF NAFLD THAT CAN EXACERBATE THE RISK OF LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC) AND EVENTUALLY LEAD TO DEATH. NAFLD HAS VARIOUS PRESENTATIONS, INCLUDING FATIGUE, UNEXPLAINED WEIGHT LOSS, BLOATING, UPPER ABDOMINAL PAIN, DECREASED APPETITE, HEADACHE, ANXIETY, POOR SLEEP, INCREASED THIRST, PALPITATION, AND A FEELING OF WARMTH. SOME STUDIES HAVE SHOWN THAT NAFLD WITH SEVERE CORONAVIRUS DISEASE 2019 (COVID-19) HAS POOR OUTCOMES. THE GOLD STANDARD FOR NAFLD DIAGNOSIS IS LIVER BIOPSY. OTHER DIAGNOSTIC TOOLS ARE IMAGING TESTS, SERUM BIOMARKERS, MICROBIOTA MARKERS, AND TESTS FOR EXTRAHEPATIC COMPLICATIONS. THERE ARE NO SPECIFIC TREATMENTS FOR NAFLD. THEREFORE, THE MAIN CONCERN FOR NAFLD IS TREATING THE COMORBID CONDITIONS SUCH AS ANTI-DIABETIC AGENTS FOR TYPE 2 DIABETES MELLITUS, STATINS TO REDUCE HCC PROGRESSION, ANTIOXIDANTS TO PREVENT HEPATOCELLULAR DAMAGE, AND BARIATRIC SURGERY FOR PATIENTS WITH A BMI OF >40 KG/M(2) AND >35 KG/M(2) WITH COMORBIDITIES. LIFESTYLE AND DIETARY CHANGES ARE CONSIDERED PREVENTIVE STRATEGIES AGAINST NAFLD ADVANCEMENT. INADEQUATE TREATMENT OF NAFLD FURTHER LEADS TO CARDIAC CONSEQUENCES, SLEEP APNEA, CHRONIC KIDNEY DISEASE, AND INFLAMMATORY BOWEL DISEASE. IN THIS SYSTEMATIC REVIEW, WE HAVE BRIEFLY DISCUSSED THE RISK FACTORS, PATHOGENESIS, CLINICAL FEATURES, AND NUMEROUS CONSEQUENCES OF NAFLD. WE HAVE ALSO REVIEWED VARIOUS GUIDELINES FOR NAFLD DIAGNOSIS ALONG WITH EXISTING THERAPEUTIC STRATEGIES FOR THE MANAGEMENT AND PREVENTION OF THE DISEASE. 2022 15 4895 48 OXIDATIVE STRESS DRIVERS AND MODULATORS IN OBESITY AND CARDIOVASCULAR DISEASE: FROM BIOMARKERS TO THERAPEUTIC APPROACH. THIS REVIEW ARTICLE IS INTENDED TO DESCRIBE HOW OXIDATIVE STRESS REGULATES CARDIOVASCULAR DISEASE DEVELOPMENT AND PROGRESSION. EPIGENETIC MECHANISMS RELATED TO OXIDATIVE STRESS, AS WELL AS MORE RELIABLE BIOMARKERS OF OXIDATIVE STRESS, ARE EMERGING OVER THE LAST YEARS AS POTENTIALLY USEFUL TOOLS TO DESIGN THERAPEUTIC APPROACHES AIMED AT MODULATING ENHANCED OXIDATIVE STRESS "IN VIVO", THEREBY MITIGATING THE CONSEQUENT ATHEROSCLEROTIC BURDEN. AS A PARADIGM, WE DESCRIBE THE CASE OF OBESITY, IN WHICH THE INTERTWINING AMONG OXIDATIVE STRESS, DUE TO CALORIC OVERLOAD, CHRONIC LOW-GRADE INFLAMMATION INDUCED BY ADIPOSE TISSUE DYSFUNCTION, AND PLATELET ACTIVATION REPRESENTS A VICIOUS CYCLE FAVORING THE PROGRESSION OF ATHEROTHROMBOSIS. OXIDATIVE STRESS IS A MAJOR PLAYER IN THE PATHOBIOLOGY OF CARDIOVASCULAR DISEASE (CVD). REACTIVE OXYGEN SPECIES (ROS)- DEPENDENT SIGNALING PATHWAYS PROMPT TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION, INDUCING CHRONIC LOW-GRADE INFLAMMATION, PLATELET ACTIVATION AND ENDOTHELIAL DYSFUNCTION. IN ADDITION, SEVERAL OXIDATIVE BIOMARKERS HAVE BEEN PROPOSED WITH THE POTENTIAL TO IMPROVE CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING CVD. THESE INCLUDE ROS-GENERATING AND/OR QUENCHING MOLECULES, AND ROS-MODIFIED COMPOUNDS, SUCH AS F2-ISOPROSTANES. THERE IS ALSO INCREASING EVIDENCE THAT NONCODING MICRO- RNA (MI-RNA) ARE CRITICALLY INVOLVED IN POST- TRANSCRIPTIONAL REGULATION OF CELL FUNCTIONS, INCLUDING ROS GENERATION, INFLAMMATION, REGULATION OF CELL PROLIFERATION, ADIPOCYTE DIFFERENTIATION, ANGIOGENESIS AND APOPTOSIS. THESE MOLECULES HAVE PROMISING TRANSLATIONAL POTENTIAL AS BOTH MARKERS OF DISEASE AND SITE OF TARGETED INTERVENTIONS. FINALLY, OXIDATIVE STRESS IS A CRITICAL TARGET OF SEVERAL CARDIOPROTECTIVE DRUGS AND NUTRACEUTICALS, INCLUDING ANTIDIABETIC AGENTS, STATINS, RENIN-ANGIOTENSIN SYSTEM BLOCKERS, POLYPHENOLS AND OTHER ANTIOXIDANTS. FURTHER UNDERSTANDING OF ROS-GENERATING MECHANISMS, THEIR BIOLOGICAL ROLE AS WELL AS POTENTIAL THERAPEUTIC IMPLICATIONS WOULD TRANSLATE INTO CONSISTENT BENEFITS FOR EFFECTIVE CV PREVENTION. 2015 16 2361 23 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020 17 6357 42 THE ROLE OF HYPERGLYCAEMIA IN THE DEVELOPMENT OF DIABETIC CARDIOMYOPATHY. DIABETES MELLITUS IS A METABOLIC DISORDER WITH A CHRONIC HYPERGLYCAEMIC STATE. CARDIOVASCULAR DISEASES ARE THE PRIMARY CAUSE OF MORTALITY IN PATIENTS WITH DIABETES. INCREASING EVIDENCE SUPPORTS THE EXISTENCE OF DIABETIC CARDIOMYOPATHY, A CARDIAC DYSFUNCTION WITH IMPAIRED CARDIAC CONTRACTION AND RELAXATION, INDEPENDENT OF CORONARY AND/OR VALVULAR COMPLICATIONS. DIABETIC CARDIOMYOPATHY CAN LEAD TO HEART FAILURE. SEVERAL PRECLINICAL AND CLINICAL STUDIES HAVE AIMED TO DECIPHER THE UNDERLYING MECHANISMS OF DIABETIC CARDIOMYOPATHY. AMONG ALL THE CO-FACTORS, HYPERGLYCAEMIA SEEMS TO PLAY AN IMPORTANT ROLE IN THIS PATHOLOGY. HYPERGLYCAEMIA HAS BEEN SHOWN TO ALTER CARDIAC METABOLISM AND FUNCTION THROUGH SEVERAL DELETERIOUS MECHANISMS, SUCH AS OXIDATIVE STRESS, INFLAMMATION, ACCUMULATION OF ADVANCED GLYCATED END-PRODUCTS AND UPREGULATION OF THE HEXOSAMINE BIOSYNTHESIS PATHWAY. THESE MECHANISMS ARE RESPONSIBLE FOR THE ACTIVATION OF HYPERTROPHIC PATHWAYS, EPIGENETIC MODIFICATIONS, MITOCHONDRIAL DYSFUNCTION, CELL APOPTOSIS, FIBROSIS AND CALCIUM MISHANDLING, LEADING TO CARDIAC STIFFNESS, AS WELL AS CONTRACTILE AND RELAXATION DYSFUNCTION. THIS REVIEW AIMS TO DESCRIBE THE HYPERGLYCAEMIC-INDUCED ALTERATIONS THAT PARTICIPATE IN DIABETIC CARDIOMYOPATHY, AND THEIR CORRELATION WITH THE SEVERITY OF THE DISEASE AND PATIENT MORTALITY, AND TO PROVIDE AN OVERVIEW OF CARDIAC OUTCOMES OF GLUCOSE-LOWERING THERAPY. 2021 18 3596 41 IMPLICATIONS OF SPHINGOLIPIDS ON AGING AND AGE-RELATED DISEASES. AGING IS A PROCESS LEADING TO A PROGRESSIVE LOSS OF PHYSIOLOGICAL INTEGRITY AND HOMEOSTASIS, AND A PRIMARY RISK FACTOR FOR MANY LATE-ONSET CHRONIC DISEASES. THE MECHANISMS UNDERLYING AGING HAVE LONG PIQUED THE CURIOSITY OF SCIENTISTS. HOWEVER, THE IDEA THAT AGING IS A BIOLOGICAL PROCESS SUSCEPTIBLE TO GENETIC MANIPULATION WAS NOT WELL ESTABLISHED UNTIL THE DISCOVERY THAT THE INHIBITION OF INSULIN/IGF-1 SIGNALING EXTENDED THE LIFESPAN OF C. ELEGANS. ALTHOUGH AGING IS A COMPLEX MULTISYSTEM PROCESS, LOPEZ-OTIN ET AL. DESCRIBED AGING IN REFERENCE TO NINE HALLMARKS OF AGING. THESE NINE HALLMARKS INCLUDE: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. DUE TO RECENT ADVANCES IN LIPIDOMIC, INVESTIGATION INTO THE ROLE OF LIPIDS IN BIOLOGICAL AGING HAS INTENSIFIED, PARTICULARLY THE ROLE OF SPHINGOLIPIDS (SL). SLS ARE A DIVERSE GROUP OF LIPIDS ORIGINATING FROM THE ENDOPLASMIC RETICULUM (ER) AND CAN BE MODIFIED TO CREATE A VASTLY DIVERSE GROUP OF BIOACTIVE METABOLITES THAT REGULATE ALMOST EVERY MAJOR CELLULAR PROCESS, INCLUDING CELL CYCLE REGULATION, SENESCENCE, PROLIFERATION, AND APOPTOSIS. ALTHOUGH SL BIOLOGY REACHES ALL NINE HALLMARKS OF AGING, ITS CONTRIBUTION TO EACH HALLMARK IS DISPROPORTIONATE. IN THIS REVIEW, WE WILL DISCUSS IN DETAIL THE MAJOR CONTRIBUTIONS OF SLS TO THE HALLMARKS OF AGING AND AGE-RELATED DISEASES WHILE ALSO SUMMARIZING THE IMPORTANCE OF THEIR OTHER MINOR BUT INTEGRAL CONTRIBUTIONS. 2021 19 1387 34 DIABETIC GUT MICROBIOTA DYSBIOSIS AS AN INFLAMMAGING AND IMMUNOSENESCENCE CONDITION THAT FOSTERS PROGRESSION OF RETINOPATHY AND NEPHROPATHY. THE INCREASED PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) AND LIFE EXPECTANCY OF DIABETIC PATIENTS FOSTERS THE WORLDWIDE PREVALENCE OF RETINOPATHY AND NEPHROPATHY, TWO MAJOR MICROVASCULAR COMPLICATIONS THAT HAVE BEEN DIFFICULT TO TREAT WITH CONTEMPORARY GLUCOSE-LOWERING MEDICATIONS. THE GUT MICROBIOTA (GM) HAS BECOME A LIVELY FIELD RESEARCH IN THE LAST YEARS; THERE IS A GROWING RECOGNITION THAT ALTERED INTESTINAL MICROBIOTA COMPOSITION AND FUNCTION CAN DIRECTLY IMPACT THE PHENOMENON OF AGEING AND AGE-RELATED DISORDERS. IN FACT, HUMAN GM, ENVISAGED AS A POTENTIAL SOURCE OF NOVEL THERAPEUTICS, STRONGLY MODULATES HOST IMMUNITY AND METABOLISM. IT IS NOW CLEAR THAT GUT DYSBIOSIS AND THEIR PRODUCTS (E.G. P-CRESYL SULFATE, TRIMETHYLAMINE?N?OXIDE) DICTATE A SECRETORY ASSOCIATED SENESCENCE PHENOTYPE AND CHRONIC LOW-GRADE INFLAMMATION, FEATURES SHARED IN THE PHYSIOLOGICAL PROCESS OF AGEING ("INFLAMMAGING") AS WELL AS IN T2DM ("METAFLAMMATION") AND IN ITS MICROVASCULAR COMPLICATIONS. THIS REVIEW PROVIDES AN IN-DEPTH LOOK ON THE CROSSTALK BETWEEN GM, HOST IMMUNITY AND METABOLISM. FURTHER, IT CHARACTERIZES HUMAN GM SIGNATURES OF ELDERLY AND T2DM PATIENTS. FINALLY, A COMPREHENSIVE SCRUTINY OF RECENT MOLECULAR FINDINGS (E.G. EPIGENETIC CHANGES) UNDERLYING CAUSAL RELATIONSHIPS BETWEEN GM DYSBIOSIS AND DIABETIC RETINOPATHY/NEPHROPATHY COMPLICATIONS IS PINPOINTED, WITH THE ULTIMATE GOAL TO UNRAVEL POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS THAT MAY BE EXPLORED, IN A NEAR FUTURE, AS PERSONALIZED DISEASE-MODIFYING THERAPEUTIC APPROACHES. 2019 20 6409 35 THE SIGNALING OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE (CKD) IN WESTERN COUNTRIES. NOTABLY, IT HAS A RAPIDLY RISING PREVALENCE IN CHINA. THE PATIENTS, COMMONLY COMPLICATED WITH CARDIOVASCULAR DISEASES AND NEUROLOGIC DISORDERS, ARE AT HIGH RISK TO PROGRESS INTO END-STAGE RENAL DISEASE (ESRD) AND DEATH. HOWEVER, THE PATHOGENIC MECHANISMS OF DIABETIC NEPHROPATHY HAVE NOT BEEN DETERMINED. CELLULAR SENESCENCE, WHICH RECENTLY HAS GAINED BROAD ATTENTION, IS THOUGHT TO BE AN IMPORTANT PLAYER IN THE ONSET AND DEVELOPMENT OF DIABETIC NEPHROPATHY. IN THIS ISSUE, WE GENERALLY REVIEW THE MECHANISMS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY, WHICH INVOLVE TELOMERE ATTRITION, DNA DAMAGE, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, LOSS OF KLOTHO, WNT/BETA-CATENIN SIGNALING ACTIVATION, PERSISTENT INFLAMMATION, AND ACCUMULATION OF UREMIC TOXINS. MOREOVER, WE HIGHLIGHT THE POTENTIAL THERAPEUTIC TARGETS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY AND PROVIDE IMPORTANT CLUES FOR CLINICAL STRATEGIES. 2019