1 5837 156 STRESSED MITOCHONDRIA: A TARGET TO INTRUDE ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE INOPERABLE, INCAPACITATING, NEUROPSYCHIATRIC, AND DEGENERATIVE MANIFESTATION THAT DRASTICALLY AFFECTS HUMAN LIFE QUALITY. THE CURRENT MEDICATIONS TARGET EXTRA-NEURONAL SENILE PLAQUES, OXIDATIVE STRESS, NEUROINFLAMMATION, INTRANEURONAL NEUROFIBRILLARY TANGLES, CHOLINERGIC DEFICITS, AND EXCITOTOXICITY. AMONG NOVEL PATHWAYS AND TARGETS, BIOENERGETIC AND RESULTANT MITOCHONDRIAL DYSFUNCTION HAS BEEN RECOGNIZED AS ESSENTIAL FACTORS THAT DECIDE THE NEURONAL FATE AND CONSEQUENT NEURODEGENERATION IN AD. THE CRUCIAL ATTRIBUTES OF MITOCHONDRIA, INCLUDING BIOENERGESIS, SIGNALING, SENSING, INTEGRATING, AND TRANSMITTING BIOLOGICAL SIGNALS CONTRIBUTE TO OPTIMUM NETWORKING OF NEURONAL DYNAMICS AND MAKE THEM INDISPENSABLE FOR CELL SURVIVAL. IN AD, MITOCHONDRIAL DYSFUNCTION AND MITOPHAGY ARE A PRELIMINARY AND CRITICAL EVENT THAT AGGRAVATES THE PATHOLOGICAL CASCADE. STRESS IS KNOWN TO PROMOTE AND EXAGGERATE THE NEUROPATHOLOGICAL ALTERATION DURING NEURODEGENERATION AND METABOLIC IMPAIRMENTS, ESPECIALLY IN THE CORTICO-LIMBIC SYSTEM, BESIDES ADVERSELY AFFECTING THE NORMAL PHYSIOLOGY AND MITOCHONDRIAL DYNAMICS. STRESS INVOLVES THE ALLOCATION OF ENERGY RESOURCES FOR NEURONAL SURVIVAL. CHRONIC AND AGGRAVATED STRESS RESPONSE LEADS TO EXCESSIVE RELEASE OF GLUCOCORTICOIDS BY ACTIVATION OF THE HYPOTHALAMIC-PITUITARYADRENAL (HPA) AXIS. BY ACTING THROUGH THEIR RECEPTORS, GLUCOCORTICOIDS INFLUENCE ADVERSE MITOCHONDRIAL CHANGES AND ALTER MTDNA TRANSCRIPTION, MTRNA EXPRESSION, HIPPOCAMPAL MITOCHONDRIAL NETWORK, AND ULTIMATELY MITOCHONDRIAL PHYSIOLOGY. CHRONIC STRESS ALSO AFFECTS MITOCHONDRIAL DYNAMICS BY CHANGING METABOLIC AND NEURO-ENDOCRINAL SIGNALLING, AGGRAVATING OXIDATIVE STRESS, PROVOKING INFLAMMATORY MEDIATORS, ALTERING TROPIC FACTORS, INFLUENCING GENE EXPRESSION, AND MODIFYING EPIGENETIC PATHWAYS. THUS, EXPLORING CHRONIC STRESS-INDUCED GLUCOCORTICOID DYSREGULATION AND RESULTANT BIO-BEHAVIORAL AND PSYCHOSOMATIC MITOCHONDRIAL ALTERATIONS MAY BE A FEASIBLE NARRATIVE TO INVESTIGATE AND UNRAVEL THE MYSTERIOUS PATHOBIOLOGY OF AD. 2021 2 5432 20 REJUVENATION OF MESENCHYMAL STEM CELLS TO AMELIORATE SKELETAL AGING. ADVANCED AGE IS A SHARED RISK FACTOR FOR MANY CHRONIC AND DEBILITATING SKELETAL DISEASES INCLUDING OSTEOPOROSIS AND PERIODONTITIS. MESENCHYMAL STEM CELLS DEVELOP VARIOUS AGING PHENOTYPES INCLUDING THE ONSET OF SENESCENCE, INTRINSIC LOSS OF REGENERATIVE POTENTIAL AND EXACERBATION OF INFLAMMATORY MICROENVIRONMENT VIA SECRETORY FACTORS. THIS REVIEW ELABORATES ON THE EMERGING CONCEPTS ON THE MOLECULAR AND EPIGENETIC MECHANISMS OF MSC SENESCENCE, SUCH AS THE ACCUMULATION OF OXIDATIVE STRESS, DNA DAMAGE AND MITOCHONDRIAL DYSFUNCTION. SENESCENT MSCS AGGRAVATE LOCAL INFLAMMATION, DISRUPT BONE REMODELING AND BONE-FAT BALANCE, THEREBY CONTRIBUTING TO THE PROGRESSION OF AGE-RELATED BONE DISEASES. VARIOUS REJUVENATION STRATEGIES TO TARGET SENESCENT MSCS COULD PRESENT A PROMISING PARADIGM TO RESTORE SKELETAL AGING. 2023 3 2864 29 FUNCTION OF PM2.5 IN THE PATHOGENESIS OF LUNG CANCER AND CHRONIC AIRWAY INFLAMMATORY DISEASES. PREVIOUS RESEARCH HAS IDENTIFIED THAT AIR POLLUTION IS ASSOCIATED WITH VARIOUS RESPIRATORY DISEASES, BUT FEW STUDIES HAVE INVESTIGATED THE FUNCTION SERVED BY PARTICULATE MATTER 2.5 (PM2.5) IN THESE DISEASES. PM2.5 IS KNOWN TO CAUSE EPIGENETIC AND MICROENVIRONMENTAL ALTERATIONS IN LUNG CANCER, INCLUDING TUMOR-ASSOCIATED SIGNALING PATHWAY ACTIVATION MEDIATED BY MICRORNA DYSREGULATION, DNA METHYLATION, AND INCREASED LEVELS OF CYTOKINES AND INFLAMMATORY CELLS. AUTOPHAGY AND APOPTOSIS OF TUMOR CELLS MAY ALSO BE DETECTED IN LUNG CANCER ASSOCIATED WITH PM2.5 EXPOSURE. A NUMBER OF MECHANISMS ARE INVOLVED IN TRIGGERING AND AGGRAVATING ASTHMA AND COPD, INCLUDING PM2.5-INDUCED CYTOKINE RELEASE AND OXIDATIVE STRESS. THE PRESENT REVIEW IS AN OVERVIEW OF THE UNDERLYING MOLECULAR MECHANISMS OF PM2.5-INDUCED PATHOGENESIS IN LUNG CANCER AND CHRONIC AIRWAY INFLAMMATORY DISEASES. 2018 4 2227 25 EPIGENETIC MODIFICATIONS OF CHRONIC HYPOXIA-MEDIATED NEURODEGENERATION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON NEURODEGENERATIVE DISORDER AFFECTING THE ELDERLY PEOPLE. AD IS CHARACTERIZED BY PROGRESSIVE AND GRADUAL DECLINE IN COGNITIVE FUNCTION AND MEMORY LOSS. WHILE FAMILIAL EARLY-ONSET AD IS USUALLY ASSOCIATED WITH GENE MUTATIONS, THE ETIOLOGY OF SPORADIC LATE-ONSET FORM OF AD IS LARGELY UNKNOWN. IT HAS BEEN REPORTED THAT ENVIRONMENTAL FACTORS AND EPIGENETIC ALTERATIONS SIGNIFICANTLY CONTRIBUTE TO THE PROCESS OF AD. OUR PREVIOUS STUDIES HAVE DOCUMENTED THAT CHRONIC HYPOXIA IS ONE OF THE ENVIRONMENTAL FACTORS THAT MAY TRIGGER THE AD DEVELOPMENT AND AGGRAVATE THE DISEASE PROGRESSION. IN THIS REVIEW, WE WILL SUMMARIZE THE PATHOLOGICAL EFFECTS OF CHRONIC HYPOXIA ON THE ONSET AND DEVELOPMENT OF AD AND PUT FORWARD THE POSSIBLE MOLECULE MECHANISMS UNDERLYING THE CHRONIC HYPOXIA MEDIATED AD PATHOGENESIS. FINALLY, WE PROPOSE THAT EPIGENETIC REGULATIONS MAY REPRESENT NEW OPPORTUNITY FOR THE THERAPEUTIC INTERVENTION OF THIS DISEASE. 2014 5 6374 31 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 6 3680 27 INFLAMMATION IN ALCOHOLIC LIVER DISEASE. FRANK BURR MALLORY'S LANDMARK OBSERVATION IN 1911 ON THE HISTOPATHOLOGY OF ALCOHOLIC LIVER DISEASE (ALD) WAS THE FIRST IDENTIFICATION OF A LINK BETWEEN INFLAMMATION AND ALD. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES REGARDING THE ORIGINS AND ROLES OF VARIOUS INFLAMMATORY COMPONENTS IN ALD. METABOLISM OF ETHANOL GENERATES A NUMBER OF METABOLITES, INCLUDING ACETATE, REACTIVE OXYGEN SPECIES, ACETALDEHYDE, AND EPIGENETIC CHANGES, THAT CAN INDUCE INFLAMMATORY RESPONSES. ALCOHOL AND ITS METABOLITES CAN ALSO INITIATE AND AGGRAVATE INFLAMMATORY CONDITIONS BY PROMOTING GUT LEAKINESS OF MICROBIAL PRODUCTS, BY SENSITIZING IMMUNE CELLS TO STIMULATION, AND BY ACTIVATING INNATE IMMUNE PATHWAYS, SUCH AS COMPLEMENT. CHRONIC ALCOHOL CONSUMPTION ALSO SENSITIZES NONIMMUNE CELLS, E.G., HEPATOCYTES, TO INFLAMMATORY SIGNALS AND IMPAIRS THEIR ABILITY TO RESPOND TO PROTECTIVE SIGNALS. BASED ON THESE ADVANCES, A NUMBER OF INFLAMMATORY TARGETS HAVE BEEN IDENTIFIED WITH POTENTIAL FOR THERAPEUTIC INTERVENTION IN ALD, PRESENTING NEW OPPORTUNITIES AND CHALLENGES FOR TRANSLATIONAL RESEARCH. 2012 7 4928 26 PARP-1 AND PARP-2 ACTIVITY IN CANCER-INDUCED CACHEXIA: POTENTIAL THERAPEUTIC IMPLICATIONS. SKELETAL MUSCLE DYSFUNCTION AND MASS LOSS IS A CHARACTERISTIC FEATURE IN PATIENTS WITH CHRONIC DISEASES INCLUDING CANCER AND ACUTE CONDITIONS SUCH AS CRITICAL ILLNESS. MAINTENANCE OF AN ADEQUATE MUSCLE MASS IS CRUCIAL FOR THE PATIENTS' PROGNOSIS IRRESPECTIVE OF THE UNDERLYING CONDITION. MOREOVER, AGING-RELATED SARCOPENIA MAY FURTHER AGGRAVATE THE MUSCLE WASTING PROCESS ASSOCIATED WITH CHRONIC DISEASES AND CANCER. POLY(ADENOSINE DIPHOSPHATE-RIBOSE) POLYMERASE (PARP) ACTIVATION HAS BEEN DEMONSTRATED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY OF MUSCLE MASS LOSS AND DYSFUNCTION IN ANIMAL MODELS OF CANCER-INDUCED CACHEXIA. GENETIC INHIBITION OF PARP ACTIVITY ATTENUATED THE DELETERIOUS EFFECTS SEEN ON DEPLETED MUSCLES IN MOUSE MODELS OF ONCOLOGIC CACHEXIA. IN THE PRESENT MINIREVIEW THE MECHANISMS WHEREBY PARP ACTIVITY INHIBITION MAY IMPROVE MUSCLE MASS AND PERFORMANCE IN MODELS OF CANCER-INDUCED CACHEXIA ARE DISCUSSED. SPECIFICALLY, THE BENEFICIAL EFFECTS OF INHIBITION OF PARP ACTIVITY ON ATTENUATION OF INCREASED OXIDATIVE STRESS, PROTEIN CATABOLISM, POOR MUSCLE ANABOLISM AND MITOCHONDRIAL CONTENT AND EPIGENETIC MODULATION OF MUSCLE PHENOTYPE ARE REVIEWED IN THIS ARTICLE. FINALLY, THE POTENTIAL THERAPEUTIC STRATEGIES OF PHARMACOLOGICAL PARP ACTIVITY INHIBITION FOR THE TREATMENT OF CANCER-INDUCED CACHEXIA ARE ALSO BEING DESCRIBED IN THIS REVIEW. 2018 8 3466 22 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 9 5541 29 ROLE OF DIETARY PHENOLS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. CHRONIC NEUROINFLAMMATION IS A PATHOLOGICAL FEATURE OF A NUMBER OF CENTRAL NERVOUS SYSTEM (CNS) DISEASES AND IS MEDIATED BY SUSTAINED ACTIVATION OF MICROGLIAL CELLS, THE INNATE IMMUNE CELLS OF THE CNS. STUDIES HAVE MAINLY FOCUSED ON IDENTIFYING THE MOLECULAR AND EPIGENETIC MECHANISMS OF MICROGLIAL ACTIVATION. THIS IS CRUCIAL IN DESIGNING THERAPEUTIC STRATEGIES FOR NEUROPATHOLOGIES IN WHICH PROLONGED MICROGLIAL ACTIVATION IS KNOWN TO EXACERBATE DISEASE CONDITION. IN RECENT YEARS, INCREASING EVIDENCE SHOW THAT NATURALLY OCCURRING COMPOUNDS PRESENT IN REGULAR DIET COULD FUNCTION AS "NUTRACEUTICALS," ARRESTING MICROGLIAL ACTIVATION, AND THUS CONFERRING NEUROPROTECTION. THIS REVIEW SUMMARIZES OUR UNDERSTANDING OF THE ROLE OF DIETARY PHENOLIC NUTRACEUTICALS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. STUDIES SHOW THAT THESE NATURAL PHENOLS INHIBIT KEY SIGNALING PATHWAYS IN ACTIVATED MICROGLIA SUCH AS THE NFKAPPAB, MAPK AND JAK-STAT THAT TRIGGER MICROGLIA-MEDIATED INFLAMMATION IN VARIOUS NEUROPATHOLOGICAL CONDITIONS SUCH AS INJURY, INFECTION, STROKE, AUTISM AND NEURODEGENERATIVE DISEASES, I.E., ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE. THE ANTI-INFLAMMATORY AND ANTIOXIDANT EFFECT EXERTED BY THESE NATURAL PHENOLS HAVE SHOWN CONSIDERABLE SUCCESS IN IMPROVING DISEASE CONDITION IN ANIMAL MODELS OF NEUROPATHOLOGIES, AND THUS SEEM TO BE SUITABLE CANDIDATES FOR DEVELOPING THERAPEUTIC STRATEGIES. 2016 10 6504 29 TRAINED INNATE IMMUNITY AND ITS IMPLICATIONS FOR MUCOSAL IMMUNITY AND INFLAMMATION. THE LONG-STANDING DOGMA THAT IMMUNOLOGICAL MEMORY IS THE EXCLUSIVE PREROGATIVE OF THE ADAPTIVE IMMUNE SYSTEM HAS BEEN CHALLENGED BY EMERGING EVIDENCE THAT INNATE IMMUNITY CAN ALSO MAINTAIN MEMORY OF PAST EVENTS. SUCH IMMUNOLOGICAL IMPRINTING TAKES TWO FORMS, TRAINED INNATE IMMUNITY AND TOLERANCE. TRAINED IMMUNITY INVOLVES METABOLIC AND EPIGENETIC ADAPTATIONS IN INNATE IMMUNE CELLS AND THEIR PROGENITORS IN THE BONE MARROW UPON EXPOSURE TO CERTAIN MICROBIAL AND/OR INFLAMMATORY STIMULI SO THAT THE "TRAINED" CELLS WOULD BE POISED TO RESPOND MUCH FASTER AND STRONGER TO A SUBSEQUENT CHALLENGE (E.G., A NEW INFECTION THAT IS NOT NECESSARILY THE SAME AS THE EARLIER ONE). CONVERSELY, TOLERANCE LEADS TO ATTENUATED IMMUNE RESPONSES TO SECONDARY STIMULI. THIS REVIEW FOCUSES ON TRAINED IMMUNITY AND DISCUSSES EVIDENCE FOR ITS EXISTENCE FROM LOWER ORGANISMS TO HUMANS, ITS MECHANISTIC UNDERPINNINGS, AND ITS TRANSLATIONAL RAMIFICATIONS. ALTHOUGH TRAINED IMMUNITY CAN BE CONSIDERED AS AN EVOLUTIONARILY CONSERVED BENEFICIAL RESPONSE AGAINST REINFECTIONS, IN THE SETTING OF MODERN SOCIETIES WITH HIGH PREVALENCE OF CHRONIC MUCOSAL AND SYSTEMIC INFLAMMATORY DISEASES, TRAINED IMMUNITY COULD ALSO PROMOTE MALADAPTIVE IMMUNE RESPONSES THAT AGGRAVATE PATHOLOGY. THUS, DEPENDING ON CONTEXT, INNATE IMMUNE MEMORY COULD BE THERAPEUTICALLY MANIPULATED USING DEFINED AGONISTS TO EITHER PROMOTE INNATE IMMUNE RESPONSES (PARTICULARLY USEFUL FOR THE TREATMENT OF INFECTIONS OR CHEMOTHERAPY-INDUCED MYELOSUPPRESSION) OR SUPPRESS EXCESSIVE INFLAMMATION IN INFLAMMATORY AND AUTOIMMUNE DISEASES. 2019 11 4380 36 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 12 6022 28 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 13 6058 33 THE DEFICIENCY OF N6-METHYLADENOSINE DEMETHYLASE ALKBH5 ENHANCES THE NEURODEGENERATIVE DAMAGE INDUCED BY COBALT. COBALT EXPOSURE, EVEN AT LOW CONCENTRATIONS, INDUCES NEURODEGENERATIVE DAMAGE, SUCH AS ALZHEIMER'S DISEASE (AD). THE SPECIFIC UNDERLYING MECHANISMS REMAIN UNCLEAR. OUR PREVIOUS STUDY DEMONSTRATED THAT M(6)A METHYLATION ALTERATION IS INVOLVED IN COBALT-INDUCED NEURODEGENERATIVE DAMAGE, SUCH AS IN AD. HOWEVER, THE ROLE OF M(6)A RNA METHYLATION AND ITS UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. IN THIS STUDY, BOTH EPIDEMIOLOGICAL AND LABORATORY STUDIES SHOWED THAT COBALT EXPOSURE COULD DOWNREGULATE THE EXPRESSION OF THE M(6)A DEMETHYLASE ALKBH5, SUGGESTING A KEY ROLE FOR ALKBH5. MOREOVER, METHYLATED RNA IMMUNOPRECIPITATION AND SEQUENCING (MERIP-SEQ) ANALYSIS REVEALED THAT ALKBH5 DEFICIENCY IS ASSOCIATED WITH NEURODEGENERATIVE DISEASES. KEGG PATHWAY AND GENE ONTOLOGY ANALYSES FURTHER REVEALED THAT THE DIFFERENTIALLY M(6)A-MODIFIED GENES RESULTING FROM ALKBH5 DOWNREGULATION AND COBALT EXPOSURE WERE AGGREGATED IN THE PATHWAYS OF PROLIFERATION, APOPTOSIS, AND AUTOPHAGY. SUBSEQUENTLY, ALKBH5 DEFICIENCY WAS SHOWN TO EXACERBATE CELL VIABILITY DECLINE, MOTIVATE CELL APOPTOSIS AND ATTENUATE CELL AUTOPHAGY INDUCED BY COBALT WITH EXPERIMENTAL TECHNIQUES OF GENE OVEREXPRESSION/INHIBITION. IN ADDITION, MORPHOLOGICAL CHANGES IN NEURONS AND THE EXPRESSION OF AD-RELATED PROTEINS, SUCH AS APP, P-TAU, AND TAU, IN THE CEREBRAL HIPPOCAMPUS OF WILD-TYPE AND ALKBH5 KNOCKOUT MICE AFTER CHRONIC COBALT EXPOSURE WERE ALSO INVESTIGATED. BOTH IN VITRO AND IN VIVO RESULTS SHOWED THAT LOWER EXPRESSION OF ALKBH5 AGGRAVATED COBALT-INDUCED NEURODEGENERATIVE DAMAGE. THESE RESULTS SUGGEST THAT ALKBH5, AS AN EPIGENETIC REGULATOR, COULD BE A POTENTIAL TARGET FOR ALLEVIATING COBALT-INDUCED NEURODEGENERATIVE DAMAGE. IN ADDITION, WE PROPOSE A NOVEL STRATEGY FOR THE PREVENTION AND TREATMENT OF ENVIRONMENTAL TOXICANT-RELATED NEURODEGENERATION FROM AN EPIGENETIC PERSPECTIVE. 2023 14 2788 32 FACTORS AFFECTING THE TRANSITION OF ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE: POTENTIAL MECHANISMS AND FUTURE PERSPECTIVES. ACUTE KIDNEY INJURY (AKI) IS DEFINED AS A RAPID LOSS OF KIDNEY FUNCTION CHARACTERISED BY INFLAMMATION AND CELL DEATH, ULTIMATELY LEADING TO FURTHER FUNCTIONAL AND STRUCTURAL RENAL ALTERATIONS. BASED ON EXPERIMENTAL AND EPIDEMIOLOGICAL PIECES OF EVIDENCE, AKI MAY PROGRESS TO CHRONIC KIDNEY DISEASE (CKD) EVEN AFTER A RECOVERY PERIOD DUE TO MALADAPTIVE REPAIR AND OTHER UNDERLYING MECHANISMS SUCH AS HEIGHTENED WNT SIGNALLING, OVERSTIMULATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM (RAAS) PATHWAY, EPIGENETIC ALTERATIONS AND INHIBITION OF HYPOXIA-INDUCIBLE FACTOR (HIF) DEPENDENT DEFENCES. IT HAS BEEN REPORTED THAT RAAS ACTIVATION SUBSEQUENT TO RENAL INSULT MEDIATES INFLAMMATORY AND FIBROTIC MECHANISMS, WHICH ARE A HALLMARK OF CKD. MOREOVER, INTERESTING EVIDENCE REGARDING THE EXPOSURE-DEPENDENT DUAL ROLE OF WNT SIGNALLING IN BOTH INJURY AND REPAIR, EPIGENETIC CHANGES UNDERLYING KIDNEY DISEASE SUGGEST A POTENTIAL THERAPEUTIC ROLE OF THESE PATHWAYS IN AKI TO CKD CONTINUUM. IN ADDITION, THE HYPOXIA-INDEPENDENT RENAL BENEFITS OF ERYTHROPOIETIN SUCH AS ANTI-APOPTOSIS AND TUBULAR REGENERATION ALSO PRESENT AN AUSPICIOUS TARGET WHICH COULD BE USEFUL IN CLINICAL SETTINGS. IN THIS REVIEW, THE SPECIFIC ROLES OF THESE PATHWAYS IN KIDNEY DISEASE, THEIR PATHOLOGICAL MECHANISMS AND THERAPEUTIC STRATEGIES ARE DISCUSSED. MOREOVER, NOTABLE REPORTS CONCERNING STEM CELL THERAPY WHICH HOLD PROMISE IN HALTING AKI-CKD CONTINUUM WILL BE ELABORATED. 2019 15 4488 29 MONOCYTE AND HAEMATOPOIETIC PROGENITOR REPROGRAMMING AS COMMON MECHANISM UNDERLYING CHRONIC INFLAMMATORY AND CARDIOVASCULAR DISEASES. A LARGE NUMBER OF CARDIOVASCULAR EVENTS ARE NOT PREVENTED BY CURRENT THERAPEUTIC REGIMENS. IN SEARCH FOR ADDITIONAL, INNOVATIVE STRATEGIES, IMMUNE CELLS HAVE BEEN RECOGNIZED AS KEY PLAYERS CONTRIBUTING TO ATHEROSCLEROTIC PLAQUE PROGRESSION AND DESTABILIZATION. PARTICULARLY THE ROLE OF INNATE IMMUNE CELLS IS OF MAJOR INTEREST, FOLLOWING THE RECENT PARADIGM SHIFT THAT INNATE IMMUNITY, LONG CONSIDERED TO BE INCAPABLE OF LEARNING, DOES EXHIBIT IMMUNOLOGICAL MEMORY MEDIATED VIA EPIGENETIC REPROGRAMMING. COMPELLING EVIDENCE SHOWS THAT ATHEROSCLEROTIC RISK FACTORS PROMOTE IMMUNE CELL MIGRATION BY PRE-ACTIVATION OF CIRCULATING INNATE IMMUNE CELLS. INNATE IMMUNE CELL ACTIVATION VIA METABOLIC AND EPIGENETIC REPROGRAMMING PERPETUATES A SYSTEMIC LOW-GRADE INFLAMMATORY STATE IN CARDIOVASCULAR DISEASE (CVD) THAT IS ALSO COMMON IN OTHER CHRONIC INFLAMMATORY DISORDERS. THIS OPENS A NEW THERAPEUTIC AREA IN WHICH METABOLIC OR EPIGENETIC MODULATION OF INNATE IMMUNE CELLS MAY RESULT IN DECREASED SYSTEMIC CHRONIC INFLAMMATION, ALLEVIATING CVD, AND ITS CO-MORBIDITIES. 2018 16 4635 34 NEUROINFLAMMATORY MECHANISMS IN PARKINSON'S DISEASE: POTENTIAL ENVIRONMENTAL TRIGGERS, PATHWAYS, AND TARGETS FOR EARLY THERAPEUTIC INTERVENTION. MOST ACUTE AND CHRONIC NEURODEGENERATIVE CONDITIONS ARE ACCOMPANIED BY NEUROINFLAMMATION; YET THE EXACT NATURE OF THE INFLAMMATORY PROCESSES AND WHETHER THEY MODIFY DISEASE PROGRESSION IS NOT WELL UNDERSTOOD. IN THIS REVIEW, WE DISCUSS THE KEY EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL EVIDENCE IMPLICATING INFLAMMATORY PROCESSES IN THE PROGRESSIVE DEGENERATION OF THE DOPAMINERGIC (DA) NIGROSTRIATAL PATHWAY AND THEIR POTENTIAL CONTRIBUTION TO THE PATHOPHYSIOLOGY OF PARKINSON'S DISEASE (PD). GIVEN THAT INTERPLAY BETWEEN GENETICS AND ENVIRONMENT ARE LIKELY TO CONTRIBUTE TO RISK FOR DEVELOPMENT OF IDIOPATHIC PD, RECENT DATA SHOWING INTERACTIONS BETWEEN PRODUCTS OF GENES LINKED TO HERITABLE PD THAT FUNCTION TO PROTECT DA NEURONS AGAINST OXIDATIVE OR PROTEOLYTIC STRESS AND INFLAMMATION PATHWAYS WILL BE DISCUSSED. CELLULAR MECHANISMS ACTIVATED OR ENHANCED BY INFLAMMATORY PROCESSES THAT MAY CONTRIBUTE TO MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, OR APOPTOSIS OF DOPAMINERGIC (DA) NEURONS WILL BE REVIEWED, WITH SPECIAL EMPHASIS ON TUMOR NECROSIS FACTOR (TNF) AND INTERLEUKIN-1-BETA (IL-1BETA) SIGNALING PATHWAYS. EPIGENETIC FACTORS WHICH HAVE THE POTENTIAL TO TRIGGER NEUROINFLAMMATION, INCLUDING ENVIRONMENTAL EXPOSURES AND AGE-ASSOCIATED CHRONIC INFLAMMATORY CONDITIONS, WILL BE DISCUSSED AS POSSIBLE 'SECOND-HIT' TRIGGERS THAT MAY AFFECT DISEASE ONSET OR PROGRESSION OF IDIOPATHIC PD. IF INFLAMMATORY PROCESSES HAVE AN ACTIVE ROLE IN NIGROSTRIATAL PATHWAY DEGENERATION, THEN EVIDENCE SHOULD EXIST TO INDICATE THAT SUCH PROCESSES BEGIN IN THE EARLY STAGES OF DISEASE AND THAT THEY CONTRIBUTE TO NEURONAL DYSFUNCTION AND/OR HASTEN NEURODEGENERATION OF THE NIGROSTRIATAL PATHWAY. THERAPEUTICALLY, IF ANTI-INFLAMMATORY INTERVENTIONS CAN BE SHOWN TO RESCUE NIGRAL DA NEURONS FROM DEGENERATION AND LOWER PD RISK, THEN TIMELY USE OF ANTI-INFLAMMATORY THERAPIES SHOULD BE INVESTIGATED FURTHER IN WELL-DESIGNED CLINICAL TRIALS FOR THEIR ABILITY TO PREVENT OR DELAY THE PROGRESSIVE LOSS OF NIGRAL DA NEURONS IN GENETICALLY SUSCEPTIBLE POPULATIONS. 2007 17 5822 17 STRESS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES. DESPITE SUBSTANTIAL GROUNDS FOR SUCH RESEARCH, THE ROLE OF CHRONIC EXPOSURE TO STRESSORS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES (LDS) IS LARGELY UNEXPLORED. IN THIS REVIEW, WE FIRST CONSIDER THE HORMONAL, (EPI)GENETIC, AND NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THE IMPACT OF ADVERSE CHILDHOOD EXPERIENCES, A FORM OF CHRONIC STRESSORS, ON THE ONSET OF LDS. WE THEN FOUND THAT STRESS FACTORS COMBINED WITH FEELINGS OF INFERIORITY, LOW SELF-ESTEEM, AND PEER VICTIMIZATION COULD POTENTIALLY FURTHER AGGRAVATE ACADEMIC FAILURES IN CHILDREN WITH LDS. SINCE EFFECTIVE EVIDENCE-BASED INTERVENTIONS FOR REDUCING CHRONIC STRESS IN CHILDREN WITH LDS COULD IMPROVE THEIR ACADEMIC PERFORMANCE, CONSIDERATION OF THE ROLE OF EXPOSURE TO STRESSORS IN CHILDREN WITH LDS HAS BOTH THEORETICAL AND PRACTICAL IMPORTANCE, ESPECIALLY WHEN DELIVERED IN COMBINATION WITH ACADEMIC INTERVENTIONS. 2021 18 4646 26 NEUROPATHOLOGICAL MECHANISMS ASSOCIATED WITH PESTICIDES IN ALZHEIMER'S DISEASE. ENVIRONMENTAL TOXICANTS HAVE BEEN IMPLICATED IN NEURODEGENERATIVE DISEASES, AND PESTICIDE EXPOSURE IS A SUSPECTED ENVIRONMENTAL RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). SEVERAL EPIDEMIOLOGICAL ANALYSES HAVE AFFIRMED A LINK BETWEEN PESTICIDES AND INCIDENCE OF SPORADIC AD. MEANWHILE, IN VITRO AND ANIMAL MODELS OF AD HAVE SHED LIGHT ON POTENTIAL NEUROPATHOLOGICAL MECHANISMS. IN THIS PAPER, A PERSPECTIVE ON NEUROPATHOLOGICAL MECHANISMS UNDERLYING PESTICIDES' INDUCTION OF AD IS PROVIDED. PROPOSED MECHANISMS RANGE FROM GENERIC OXIDATIVE STRESS INDUCTION IN NEURONS TO MORE AD-SPECIFIC PROCESSES INVOLVING AMYLOID-BETA (ABETA) AND HYPERPHOSPHORYLATED TAU (P-TAU). MECHANISMS THAT ARE MORE SPECULATIVE OR INDIRECT IN NATURE, INCLUDING SOMATIC MUTATION, EPIGENETIC MODULATION, IMPAIRMENT OF ADULT NEUROGENESIS, AND MICROBIOTA DYSBIOSIS, ARE ALSO DISCUSSED. CHRONIC TOXICITY MECHANISMS OF ENVIRONMENTAL PESTICIDE EXPOSURE CROSSTALKS IN COMPLEX WAYS AND COULD POTENTIALLY BE MUTUALLY ENHANCING, THUS MAKING THE DECIPHERING OF SIMPLISTIC CAUSAL RELATIONSHIPS DIFFICULT. 2020 19 4611 30 NEONATAL IMMUNE CHALLENGE FOLLOWED BY ADULT IMMUNE CHALLENGE INDUCES EPIGENETIC-SUSCEPTIBILITY TO AGGRAVATED VISCERAL HYPERSENSITIVITY. BACKGROUND: ABDOMINAL PAIN IS ONE OF THE MAJOR SYMPTOMS OF INFLAMMATORY BOWEL DISEASE (IBD). THE INFLAMMATORY MEDIATORS RELEASED BY COLON INFLAMMATION ARE KNOWN TO SENSITIZE THE AFFERENT NEURONS, WHICH IS ONE OF THE CONTRIBUTORS TO ABDOMINAL PAIN. HOWEVER, NOT ALL IBD PATIENTS HAVE ABDOMINAL PAIN, AND SOME PATIENTS REPORT ABDOMINAL PAIN DURING REMISSION, SUGGESTING CONTRIBUTIONS OF OTHER PATHOLOGICAL FACTORS TO ABDOMINAL PAIN IN IBD. EPIDEMIOLOGICAL STUDIES FOUND EARLY-LIFE GASTROINTESTINAL INFECTIONS A RISK FACTOR FOR IBD SYMPTOMS AND ADULT-LIFE GASTROINTESTINAL INFECTIONS MAY TRIGGER THE ONSET OF IBD. WE INVESTIGATED THE HYPOTHESIS THAT NEONATAL COLON IMMUNE CHALLENGE FOLLOWED BY AN ADULT COLON IMMUNE CHALLENGE UPREGULATES SPINAL CORD BDNF THAT AGGRAVATES VISCERAL SENSITIVITY OVER AND ABOVE THAT INDUCED BY ADULT COLON IMMUNE CHALLENGE ALONE. METHODS: WE INDUCED NEONATAL AND ADULT COLON IMMUNE CHALLENGES BY INTRALUMINAL ADMINISTRATION OF TRINITROBENZENE SULFONIC ACID TO THE RAT COLON. KEY RESULTS: WE FOUND THAT NEONATAL IMMUNE CHALLENGE TRIGGERS EPIGENETIC PROGRAMMING THAT UPREGULATES TYROSINE HYDROXYLASE IN THE LOCUS CERULEUS WHEN THESE RATS ARE SUBJECTED TO AN ADULT COLON IMMUNE CHALLENGE. THE UPREGULATION OF LOCUS CERULEUS TYROSINE HYDROXYLASE, UPREGULATES NOREPINEPHRINE IN THE CEREBROSPINAL FLUID THAT ACTS ON ADRENERGIC RECEPTORS TO ENHANCE PCREB BINDING TO THE CAMP RESPONSE ELEMENT, WHICH RECRUITS HISTONE ACETYLENE TRANSFERASE (HAT) TO THE BDNF GENE TO ENHANCE ITS TRANSCRIPTION RESULTING IN AGGRAVATED VISCEROMOTOR RESPONSE TO COLORECTAL DISTENSION. HAT AND ADRENERGIC RECEPTOR ANTAGONISTS BLOCK THE AGGRAVATION OF VISCERAL SENSITIVITY. CONCLUSION & INFERENCES: HAT AND ADRENERGIC RECEPTOR INHIBITORS MAY SERVE AS ALTERNATES TO OPIOIDS AND NSAIDS IN SUPPRESSING ABDOMINAL PAIN IN IBD. 2017 20 4381 31 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020