1 1881 98 EMERGING TREATMENTS FOR NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A SERIES OF WELL-KNOWN CONDITIONS CAUSED BY DISEASES OR LESIONS TO THE SOMATOSENSORY SYSTEM. DUE TO THE BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF NEUROPATHIC PAIN, PREVIOUSLY UNEXPLORED THERAPIES HAVE BEEN USED WITH ENCOURAGING RESULTS. AS SUCH, ACETYL-L-CARNITINE (ALC), ALPHA-LIPOIC-ACID (ALA), CANNABINOIDS, CLONIDINE, EMA401, BOTULINUM TOXIN TYPE A, AND NEW VOLTAGE-GATED SODIUM CHANNEL BLOCKERS, CAN BE CITED. FURTHERMORE, NEW MODALITIES IN NEUROMODULATION SUCH AS HIGH-FREQUENCY SPINAL CORD STIMULATION, BURST STIMULATION, DORSAL ROOT GANGLION STIMULATION, TRANSCRANIAL DIRECT CURRENT STIMULATION, AND MANY OTHERS HAVE BEEN SHOWING EXCITING RESULTS. BESIDES, CHANGING PARADIGMS MAY OCCUR WITH THE ADVENT OF OPTOGENETICS AND A BETTER UNDERSTANDING OF EPIGENETIC REGULATION. THIS ARTICLE REVIEWS THE PUBLISHED LITERATURE ON THE TREATMENT OF NP. DESPITE THE INTERESTING RESULTS, RANDOMIZED CONTROLLED TRIALS ARE DEMANDED FOR THE MAJORITY OF THE THERAPIES PREVIOUSLY MENTIONED. 2015 2 4644 71 NEUROPATHIC PAIN TREATMENT: STILL A CHALLENGE. NEUROPATHIC PAIN (NP) IS THE RESULT OF A SERIES OF CONDITIONS CAUSED BY DISEASES OR LESIONS TO THE SOMATOSENSORY SYSTEM. DUE TO THE BETTER UNDERSTANDING OF NP PATHOPHYSIOLOGY PREVIOUSLY UNEXPLORED THERAPIES HAVE BEEN USED WITH ENCOURAGING RESULTS. IN THIS GROUP, ACETYL-L-CARNITINE, ALPHA-LIPOIC-ACID, CANNABINOIDS, CLONIDINE, EMA401, BOTULINUM TOXIN TYPE A AND NEW VOLTAGE-GATED SODIUM CHANNEL BLOCKERS, CAN BE INCLUDED. BESIDES, CHANGING PARADIGMS MAY OCCUR WITH THE ADVENT OF OPTOGENETICS AND A BETTER UNDERSTANDING OF EPIGENETIC REGULATION. WE REVIEWED THE PUBLISHED LITERATURE ON THE PHARMACOLOGICAL TREATMENT OF NP. DESPITE THE INTERESTING RESULTS, RANDOMIZED CONTROLLED TRIALS ARE DEMANDED THE MAJORITY OF THE THERAPIES PREVIOUSLY MENTIONED. IN SPITE OF SEVERAL STUDIES FOR THE RELIEF OF NP, PAIN CONTROL CONTINUES BEING A CHALLENGE. 2016 3 6446 27 THERAPEUTIC INSIGHTS IN CHRONIC KIDNEY DISEASE PROGRESSION. CHRONIC KIDNEY DISEASE (CKD) HAS BEEN RECOGNIZED AS A LEADING PUBLIC HEALTH PROBLEM WORLDWIDE. THROUGH ITS EFFECT ON CARDIOVASCULAR RISK AND END-STAGE KIDNEY DISEASE, CKD DIRECTLY AFFECTS THE GLOBAL BURDEN OF MORBIDITY AND MORTALITY. CLASSICAL OPTIMAL MANAGEMENT OF CKD INCLUDES BLOOD PRESSURE CONTROL, TREATMENT OF ALBUMINURIA WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS OR ANGIOTENSIN II RECEPTOR BLOCKERS, AVOIDANCE OF POTENTIAL NEPHROTOXINS AND OBESITY, DRUG DOSING ADJUSTMENTS, AND CARDIOVASCULAR RISK REDUCTION. DIABETES MIGHT ACCOUNT FOR MORE THAN HALF OF CKD BURDEN, AND OBESITY IS THE MOST IMPORTANT PROMPTED FACTOR FOR THIS DISEASE. NEW ANTIHYPERGLYCEMIC DRUGS, SUCH AS SODIUM-GLUCOSE-COTRANSPORTER 2 INHIBITORS HAVE SHOWN TO SLOW THE DECLINE OF GFR, BRINGING ADDITIONAL BENEFIT IN WEIGHT REDUCTION, CARDIOVASCULAR, AND OTHER KIDNEY OUTCOMES. ON THE OTHER HAND, A NEW GENERATION OF NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST HAS RECENTLY BEEN DEVELOPED TO OBTAIN A SELECTIVE RECEPTOR INHIBITION REDUCING SIDE EFFECTS LIKE HYPERKALEMIA AND THEREBY MAKING THE DRUGS SUITABLE FOR ADMINISTRATION TO CKD PATIENTS. MOREOVER, TWO NEW POTASSIUM-LOWERING THERAPIES HAVE SHOWN TO IMPROVE TOLERANCE, ALLOWING FOR HIGHER DOSAGE OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND THEREFORE ENHANCING THEIR NEPHROPROTECTIVE EFFECT. REGARDLESS OF ITS CAUSE, CKD IS CHARACTERIZED BY REDUCED RENAL REGENERATION CAPACITY, MICROVASCULAR DAMAGE, OXIDATIVE STRESS AND INFLAMMATION, RESULTING IN FIBROSIS AND PROGRESSIVE, AND IRREVERSIBLE NEPHRON LOSS. THEREFORE, A HOLISTIC APPROACH SHOULD BE TAKEN TARGETING THE DIVERSE PROCESSES AND BIOLOGICAL CONTEXTS THAT ARE ASSOCIATED WITH CKD PROGRESSION. TO DATE, THERAPEUTIC INTERVENTIONS WHEN TUBULOINTERSTITIAL FIBROSIS IS ALREADY ESTABLISHED HAVE PROVED TO BE INSUFFICIENT, THUS RESEARCH EFFORT SHOULD FOCUS ON UNRAVELING EARLY DISEASE MECHANISMS. AN ARRAY OF NOVEL THERAPEUTIC APPROACHES TARGETING EPIGENETIC REGULATORS ARE NOW UNDERGOING PHASE II OR PHASE III TRIALS AND MIGHT PROVIDE A SIMULTANEOUS REGULATORY ACTIVITY THAT COORDINATELY REGULATE DIFFERENT ASPECTS OF CKD PROGRESSION. 2021 4 6648 20 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 5 4895 27 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 6 4756 24 NOVEL THERAPEUTIC TARGET(S) FOR PSORIATIC DISEASE. PSORIASIS AND PSORIATIC ARTHRITIS, TOGETHER KNOWN AS PSORIATIC DISEASE, IS HIGHLY PREVALENT CHRONIC RELAPSING INFLAMMATORY DISEASE AFFECTING SKIN, JOINTS OR BOTH AND IS ASSOCIATED WITH SEVERAL COMORBIDITIES SUCH AS CARDIOVASCULAR, METABOLIC, PSYCHIATRIC, RENAL DISEASE ETC. THE ETIOPATHOGENESIS OF PSORIASIS IS COMPLEX AND MAINLY DRIVEN BY ABERRANT IMMUNE RESPONSE OWING TO THE GENETIC SUSCEPTIBILITY AND VARIOUS ENVIRONMENTAL FACTORS SUCH AS TRAUMA, INFECTIONS AND DRUGS. RECENT ADVANCES IN UNDERSTANDING MOLECULAR AND CELLULAR PATHWAYS HAVE IDENTIFIED TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-17 (IL-17), IL-23, IL-22 AS MAJOR CONTRIBUTORS IN PSORIASIS PATHOGENESIS. ADVANCES IN THE KNOWLEDGE OF PATHOPHYSIOLOGY, THE INTERACTION OF AUTOINFLAMMATION AND CLINICAL PHENOTYPES HAVE LED TO THE DEVELOPMENT OF HIGHLY EFFECTIVE TARGETED THERAPEUTIC AGENTS WHICH INCLUDE TNF-ALPHA, IL-17, IL-23, IL-1 ALPHA/BETA OR IL-36 INHIBITORS OR RECEPTOR BLOCKERS, SMALL MOLECULE DRUGS LIKE PHOSPHODIESTERASE-4 INHIBITORS (APREMILAST), JANUS KINASE (JAK) INHIBITORS, RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) INHIBITORS. THESE NOVEL DRUGS HAVE PROMISED THE POTENTIAL OF IMPROVED DISEASE CONTROL. IN RECENT YEARS, THE TRANSITION FROM BIOLOGICS TO BIOSIMILARS ESPECIALLY WITH TNF-ALPHA INHIBITORS HAD SIGNIFICANT IMPACT ON DECREASING HEALTH CARE COST AND INCREASING THERAPEUTIC OPTIONS TO THE PATIENTS. HOWEVER, SELECTION OF RIGHT TREATMENT FOR AN INDIVIDUAL PATIENT STILL REMAINS CHALLENGING. MOREOVER, INTERPLAY BETWEEN DIFFERENT EPIGENETIC MECHANISMS SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND NONCODING RNA REGULATION HAS RECENTLY BEEN STARTED TO BE DECIPHERED. ENZYMES INHIBITORS INVOLVED IN EPIGENETIC PATHWAYS SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES DEMONSTRATED TO RESTORE NORMAL EPIGENETIC PATTERNS IN CLINICAL SETTINGS AND HAVE PROVIDED THE POTENTIAL AS NOVEL THERAPEUTIC TARGETS FOR PSORIASIS. IN THIS REVIEW, WE WILL DISCUSS NOVEL BIOLOGIC AGENTS AND NEWER THERAPEUTIC APPROACHES IN TREATMENT OF PSORIATIC DISEASE. 2022 7 3160 30 GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: PATHOPHYSIOLOGY-BASED REVIEW ON CURRENT APPROACHES AND FUTURE DIRECTIONS. GRAFT-VERSUS-HOST DISEASE (GVHD) WAS FIRST DESCRIBED IN 1959, SINCE THEN MAJOR EFFORTS HAVE BEEN MADE IN ORDER TO UNDERSTAND ITS PHYSIOPATHOLOGY AND ANIMAL MODELS HAVE PLAYED A KEY ROLE. THREE STEPS, INVOLVING DIFFERENT PATHWAYS, HAVE BEEN RECOGNISED IN EITHER ACUTE AND CHRONIC GVHD, IDENTIFYING THEM AS TWO DISTINCT ENTITIES. IN ORDER TO REDUCE GVHD INCIDENCE AND SEVERITY, PROPHYLACTIC MEASURES WERE ADDED TO TRANSPLANT PROTOCOLS. THE COMBINATION OF A CALCINEURIN INHIBITOR (CNI) PLUS AN ANTIMETABOLITE REMAINS THE STANDARD OF CARE. BETTER KNOWLEDGE OF GVHD PATHOPHYSIOLOGY HAS MOVED THIS FIELD FORWARD AND NOWADAYS DIFFERENT DRUGS ARE BEING USED ON A DAILY BASIS. IMPROVING GVHD PROPHYLAXIS IS A MAJOR GOAL AS IT WOULD TRANSLATE INTO LESS NON-RELAPSE MORTALITY AND BETTER OVERALL SURVIVAL. AS COMPARED TO CNI PLUS METHOTREXATE THE COMBINATION OF CNI PLUS MYCOPHENOLATE MOPHETIL (MMF) ALLOWS US TO OBTAIN SIMILAR RESULTS IN TERMS OF GVHD INCIDENCE BUT A LOWER TOXICITY RATE IN TERMS OF NEUTROPENIA OR MUCOSITIS. THE USE OF ATG HAS BEEN RELATED TO A LOWER RISK OF ACUTE AND CHRONIC GVHD IN PROSPECTIVE RANDOMIZED TRIALS AS WELL AS THE USE OF POSTTRANSPLANT CYCLOPHOSPHAMIDE, WITH NO OR MARGINAL IMPACT ON OVERALL SURVIVAL BUT WITH AN IMPROVEMENT IN GVHD-RELAPSE FREE SURVIVAL (GRFS). THE USE OF SIROLIMUS HAS BEEN RELATED TO A LOWER RISK OF ACUTE GVHD AND SIGNIFICANTLY INFLUENCED OVERALL SURVIVAL IN ONE PROSPECTIVE RANDOMIZED TRIAL. OTHER PROSPECTIVE TRIALS HAVE EVALUATED THE USE OF RECEPTORS SUCH AS CCR5 OR ALPHA4BETA7 TO AVOID T-CELLS TRAFFICKING INTO GVHD TARGET ORGANS, CYTOKINE BLOCKERS OR IMMUNE CHECK POINT AGONISTS. ALSO, EPIGENETIC MODIFIERS HAVE SHOWN PROMISING RESULTS IN PHASE II TRIALS. ATTENTION SHOULD BE PAID TO GRAFT-VERSUS-LEUKEMIA, INFECTIONS AND IMMUNE RECOVERY BEFORE BRINGING NEW PROPHYLACTIC STRATEGIES TO CLINICAL PRACTICE. ALTHOUGH THE LIST OF NOVEL AGENTS FOR GVHD PROPHYLAXIS IS GROWING, RANDOMIZED TRIALS ARE STILL LACKING FOR MANY OF THEM. 2021 8 6318 24 THE RENIN-ANGIOTENSIN SYSTEM AND REACTIVE OXYGEN SPECIES: IMPLICATIONS IN PANCREATITIS. SIGNIFICANCE: THE RENIN-ANGIOTENSIN SYSTEM (RAS) IS A CIRCULATING HORMONAL SYSTEM INVOLVED IN THE REGULATION OF BLOOD PRESSURE AND CIRCULATING FLUID ELECTROLYTES. RECENT FINDINGS HAVE REVEALED THAT LOCALLY GENERATED ANGIOTENSIN (ANG) II PLAYS A PIVOTAL ROLE IN NORMAL PHYSIOLOGY AS WELL AS PATHOPHYSIOLOGY IN VARIOUS TISSUES AND ORGANS, INCLUDING THE PANCREAS. THIS REVIEW ARTICLE SUMMARIZES CURRENT PROGRESS THAT HAS BEEN MADE IN ELUCIDATING THE PUTATIVE ROLES OF ANG II IN BOTH ACUTE AND CHRONIC PANCREATITIS. RECENT ADVANCES: A CONVERGENCE OF EVIDENCE SUGGESTS THAT THE UNDERLYING MECHANISM MAY INVOLVE REACTIVE OXYGEN SPECIES (ROS)-GENERATING SYSTEMS, SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE, AND SUBSEQUENT ELEVATION OF PROINFLAMMATORY AND PROFIBROGENIC GENE EXPRESSION AS WELL AS PROTEIN ACTIVITY. MORE IMPORTANTLY, ANG II-INDUCED ROS INTERACTS WITH OTHER ROS-GENERATING SYSTEMS TO POSITIVELY FEED-FORWARD THE ROS-INDUCED SIGNALING. CRITICAL ISSUES AND FUTURE DIRECTIONS: ADVANCES IN BASIC RESEARCH INDICATE THAT RAS BLOCKERS MAY PROVIDE POTENTIAL THERAPEUTIC ROLE FOR THE MANAGEMENT OF PANCREATIC INFLAMMATION AND, MORE IMPORTANTLY, PANCREATITIS-ASSOCIATED COMPLICATIONS. GENETIC ALTERATIONS RESULTING FROM A MALFUNCTION IN THE EPIGENETIC CONTROL OF PANCREATIC RAS COULD BE A CAUSATIVE FACTOR IN THE DEVELOPMENT OF PANCREATITIS. 2011 9 4971 28 PATHOPHYSIOLOGIC MECHANISMS IN DIABETIC KIDNEY DISEASE: A FOCUS ON CURRENT AND FUTURE THERAPEUTIC TARGETS. DIABETIC KIDNEY DISEASE (DKD) IS THE PRIMARY CAUSE OF CHRONIC KIDNEY DISEASE AROUND THE GLOBE AND IS ONE OF THE MAIN COMPLICATIONS IN PATIENTS WITH TYPE 1 AND 2 DIABETES. THE STANDARD TREATMENT FOR DKD IS DRUGS CONTROLLING HYPERGLYCEMIA AND HIGH BLOOD PRESSURE. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE AND SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITION HAVE YIELDED PROMISING RESULTS IN DKD, BUT MANY DIABETIC PATIENTS ON SUCH TREATMENTS NEVERTHELESS CONTINUE TO DEVELOP DKD, LEADING TO KIDNEY FAILURE AND CARDIOVASCULAR COMORBIDITIES. NEW THERAPEUTIC OPTIONS ARE URGENTLY REQUIRED. WE REVIEW HERE THE PROMISING THERAPEUTIC AVENUES BASED ON INSIGHTS INTO THE MECHANISMS OF DKD THAT HAVE RECENTLY EMERGED, INCLUDING MINERALOCORTICOID RECEPTOR ANTAGONISTS, SGLT2 INHIBITORS, GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST, ENDOTHELIN RECEPTOR A INHIBITION, ANTI-INFLAMMATORY AGENTS, AUTOPHAGY ACTIVATORS AND EPIGENETIC REMODELLING. THE INVOLVEMENT OF SEVERAL MOLECULAR MECHANISMS IN DKD PATHOGENESIS, TOGETHER WITH THE GENETIC AND EPIGENETIC VARIABILITY OF THIS CONDITION, MAKES IT DIFFICULT TO TARGET THIS HETEROGENEOUS PATIENT POPULATION WITH A SINGLE DRUG. PERSONALIZED MEDICINE, TAKING INTO ACCOUNT THE GENETIC AND MECHANISTIC VARIABILITY, MAY THEREFORE IMPROVE RENAL AND CARDIOVASCULAR PROTECTION IN DIABETIC PATIENTS WITH DKD. 2020 10 1384 24 DIABETES AND KIDNEY DISEASE: EMPHASIS ON TREATMENT WITH SGLT-2 INHIBITORS AND GLP-1 RECEPTOR AGONISTS. KIDNEY DISEASE IS A FREQUENT MICROVASCULAR COMPLICATION OF BOTH TYPE 1 AND TYPE 2 DIABETES. HISTORIC TRIALS HAVE DEMONSTRATED THAT A TIGHT GLYCAEMIC CONTROL IS THE MOST POWERFUL APPROACH TO DECREASE THE CHANCES OF DEVELOPING DIABETIC NEPHROPATHY. HOWEVER, HAVING AN HBA1C < 7% DOES NOT COMPLETELY SUPPRESS THE RISK OF KIDNEY DISEASE. THE OBSERVED RESIDUAL RISK IS LIKELY ASCRIBABLE TO TWO PHENOMENA: 1- THE PRESENCE OF RISK FACTORS AND ALTERATIONS ADDITIVE TO AND INDEPENDENT OF GLYCAEMIA, AND 2- THE ACTIVATION OF LONG-LASTING IMBALANCES BY PERIODS OF EXPOSURE TO UNCONTROLLED GLYCEMIA, A PHENOMENON REFERRED TO AS METABOLIC MEMORY OR LEGACY EFFECT. LONG-LASTING OXIDATIVE STRESS, EPIGENETIC ALTERATIONS, CELLULAR SENESCENCE, AND THE RESULTING CHRONIC LOW-GRADE INFLAMMATION ARE ALL CANDIDATE MECHANISMS EXPLAINING THE DEVELOPMENT OF NEPHROPATHY DESPITE PROPER CONTROL OF RISK FACTORS. RECENTLY, TWO CLASSES OF DRUGS, I.E. GLUCAGON-LIKE PEPTIDE (GLP) 1 RECEPTOR AGONISTS (RA) AND SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS (SGLT-I) HAVE CHANGED THIS SCENARIO. INDEED, CARDIOVASCULAR OUTCOME AND OTHER TRIALS HAVE CLEARLY SHOWN A RENOPROTECTIVE EFFECT FOR THESE DRUGS, WELL-BEYOND THEIR GLUCOSE-LOWERING PROPERTIES. IN THIS REVIEW, WE SUMMARIZE: 1- SELECTED KEY TRIALS AND MECHANISMS UNDERLYING THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE AND 2- THE RESULTS RELATIVE TO RENAL ENDPOINTS IN CLINICAL TRIALS OF GLP-1 RA AND SGLT-2I. THEN, WE BRIEFLY DISCUSS SOME OF THE HYPOTHESES POSITED TO EXPLAIN THE MARKED RENOPROTECTIVE PROPERTIES OF THESE TWO CLASSES, EVIDENCING THE STILL EXISTING GAPS IN KNOWLEDGE AND PROPOSING FUTURE DIRECTIONS TO FURTHER IMPLEMENT THE USE OF THESE POWERFUL, DISEASE-MODIFYING DRUGS. 2021 11 2112 18 EPIGENETIC GENE SILENCING UNDERLIES C-FIBER DYSFUNCTIONS IN NEUROPATHIC PAIN. PERIPHERAL NERVE INJURY CAUSES NEUROPATHIC PAIN, WHICH IS CHARACTERIZED BY THE PARADOXICAL SENSATIONS OF POSITIVE AND NEGATIVE SYMPTOMS. CLINICALLY, NEGATIVE SIGNS ARE FREQUENTLY OBSERVED; HOWEVER, THEIR UNDERLYING MOLECULAR MECHANISMS ARE LARGELY UNKNOWN. DYSFUNCTION OF C-FIBERS IS ASSUMED TO UNDERLIE NEGATIVE SYMPTOMS AND IS ACCOMPANIED BY LONG-LASTING DOWNREGULATION OF NA(V)1.8 SODIUM CHANNEL AND MU-OPIOID RECEPTOR (MOP) IN THE DORSAL ROOT GANGLION (DRG). IN THE PRESENT STUDY, WE FOUND THAT NERVE INJURY UPREGULATES NEURON-RESTRICTIVE SILENCER FACTOR (NRSF) EXPRESSION IN THE DRG NEURONS MEDIATED THROUGH EPIGENETIC MECHANISMS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT NERVE INJURY PROMOTES NRSF BINDING TO THE NEURON-RESTRICTIVE SILENCER ELEMENT WITHIN MOP AND NA(V)1.8 GENES, THEREBY CAUSING EPIGENETIC SILENCING. FURTHERMORE, NRSF KNOCKDOWN SIGNIFICANTLY BLOCKED NERVE INJURY-INDUCED DOWNREGULATIONS OF MOP AND NA(V)1.8 GENE EXPRESSIONS, C-FIBER HYPOESTHESIA, AND THE LOSSES OF PERIPHERAL MORPHINE ANALGESIA AND NA(V)1.8-SELECTIVE BLOCKER-INDUCED HYPOESTHESIA. TOGETHER, THESE DATA SUGGEST THAT NRSF CAUSES PATHOLOGICAL AND PHARMACOLOGICAL DYSFUNCTION OF C-FIBERS, WHICH UNDERLIES THE NEGATIVE SYMPTOMS IN NEUROPATHIC PAIN. 2010 12 6575 25 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 13 5600 18 ROLES OF VOLTAGE-DEPENDENT SODIUM CHANNELS IN NEURONAL DEVELOPMENT, PAIN, AND NEURODEGENERATION. BESIDES INITIATING AND PROPAGATING ACTION POTENTIALS IN ESTABLISHED NEURONAL CIRCUITS, VOLTAGE-DEPENDENT SODIUM CHANNELS SCULPT AND BOLSTER THE FUNCTIONAL NEURONAL NETWORK FROM EARLY IN EMBRYONIC DEVELOPMENT THROUGH ADULTHOOD (E.G., DIFFERENTIATION OF OLIGODENDROCYTE PRECURSOR CELLS INTO OLIGODENDROCYTES, MYELINATING AXON; COMPETITION BETWEEN NEIGHBORING EQUIPOTENTIAL NEURITES FOR DEVELOPMENT INTO A SINGLE AXON; ENHANCING AND OPPOSING FUNCTIONAL INTERACTIONS WITH ATTRACTIVE AND REPULSIVE MOLECULES FOR AXON PATHFINDING; EXTENDING AND RETRACTING TERMINAL ARBORIZATION OF AXON FOR CORRECT SYNAPSE FORMATION; EXPERIENCE-DRIVEN COGNITION; NEURONAL SURVIVAL; AND REMYELINATION OF DEMYELINATED AXONS). SURPRISINGLY, DIFFERENT PATTERNS OF ACTION POTENTIALS DIRECT HOMEOSTASIS-BASED EPIGENETIC SELECTION FOR NEUROTRANSMITTER PHENOTYPE, THUS EXCITABILITY BY SODIUM CHANNELS SPECIFYING EXPRESSION OF INHIBITORY NEUROTRANSMITTERS. MECHANISMS FOR THESE PLEIOTROPIC EFFECTS OF SODIUM CHANNELS INCLUDE RECIPROCAL INTERACTIONS BETWEEN NEURONS AND GLIA VIA NEUROTRANSMITTERS, GROWTH FACTORS, AND CYTOKINES AT SYNAPSES AND AXONS. SODIUM CHANNELOPATHIES CAUSING PAIN (E.G., ALLODYNIA) AND NEURODEGENERATION (E.G., MULTIPLE SCLEROSIS) DERIVE FROM 1) ELECTROPHYSIOLOGICAL DISTURBANCES BY INSULTS (E.G., ISCHEMIA/HYPOXIA, TOXINS, AND ANTIBODIES); 2) LOSS-OF-PHYSIOLOGICAL FUNCTION OR GAIN-OF-PATHOLOGICAL FUNCTION OF MUTANT SODIUM CHANNEL PROTEINS; 3) SPATIOTEMPORAL INAPPROPRIATE EXPRESSION OF NORMAL SODIUM CHANNEL PROTEINS; OR 4) DE-REPRESSED EXPRESSION OF OTHERWISE SILENT SODIUM CHANNEL GENES. NA(V)1.7 PROVED TO ACCOUNT FOR PAIN IN HUMAN ERYTHERMALGIA AND INFLAMMATION, BEING THE CONVINCING MOLECULAR TARGET OF PAIN TREATMENT. 2006 14 6441 19 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 15 5778 22 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015 16 191 24 ACETYL-L-CARNITINE: FROM A BIOLOGICAL CURIOSITY TO A DRUG FOR THE PERIPHERAL NERVOUS SYSTEM AND BEYOND. ACETYL-L-CARNITINE (ALC) IS A MOLECULE DERIVED FROM ACETYLATION OF CARNITINE IN THE MITOCHONDRIA. CARNITINE ACETYLATION ENABLES THE FUNCTION OF COA AND FACILITATES ELIMINATION OF OXIDATIVE PRODUCTS. BEYOND THIS METABOLIC ACTIVITY, ALC PROVIDES ACETYL GROUPS FOR ACETYLCHOLINE SYNTHESIS, EXERTS A CHOLINERGIC EFFECT AND OPTIMIZES THE BALANCE OF ENERGY PROCESSES. ACETYLCARNITINE SUPPLEMENTATION INDUCES NEUROPROTECTIVE, NEUROTROPHIC AND ANALGESIC EFFECTS IN THE PERIPHERAL NERVOUS SYSTEM. IN THE RECENT STUDIES, ALC, BY ACTING AS A DONOR OF ACETYL GROUPS TO NF-KB P65/RELA, ENHANCED THE TRANSCRIPTION OF THE GRM2 GENE ENCODING THE MGLU2 RECEPTORS, INDUCING LONG-TERM UPREGULATION OF THE MGLUR2, EVIDENCING THEREFORE THAT ITS LONG-TERM ANALGESIC EFFECTS ARE DEPENDENT ON EPIGENETIC MODIFICATIONS. SEVERAL STUDIES, INCLUDING DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP STUDIES AND FEW OPEN STUDIES SHOWED THE EFFECT OF ALC IN DISEASES CHARACTERIZED BY NEUROPATHIES AND NEUROPATHIC PAIN: THE STUDIES INCLUDED DIABETIC NEUROPATHY, HIV AND ANTIRETROVIRAL THERAPY-INDUCED NEUROPATHIES, NEUROPATHIES DUE TO COMPRESSION AND CHEMOTHERAPEUTIC AGENTS. DOUBLE-BLINDED STUDIES INVOLVED 1773 PATIENTS. STATISTICAL EVALUATIONS EVIDENCED REDUCTION OF PAIN, IMPROVEMENTS OF NERVE FUNCTION AND TROPHISM. IN CONCLUSION, ALC REPRESENTS A CONSISTENT THERAPEUTIC OPTION FOR PERIPHERAL NEUROPATHIES, AND ITS COMPLEX EFFECTS, NEUROTROPHIC AND ANALGESIC, BASED ON EPIGENETIC MECHANISM, OPEN NEW PATHWAYS IN THE STUDY OF PERIPHERAL NERVE DISEASE MANAGEMENT. 2013 17 4136 21 MECHANISMS OF MANGANESE-INDUCED NEUROTOXICITY AND THE PURSUIT OF NEUROTHERAPEUTIC STRATEGIES. CHRONIC EXPOSURE TO ELEVATED LEVELS OF MANGANESE VIA OCCUPATIONAL OR ENVIRONMENTAL SETTINGS CAUSES A NEUROLOGICAL DISORDER KNOWN AS MANGANISM, RESEMBLING THE SYMPTOMS OF PARKINSON'S DISEASE, SUCH AS MOTOR DEFICITS AND COGNITIVE IMPAIRMENT. NUMEROUS STUDIES HAVE BEEN CONDUCTED TO CHARACTERIZE MANGANESE'S NEUROTOXICITY MECHANISMS IN SEARCH OF EFFECTIVE THERAPEUTICS, INCLUDING NATURAL AND SYNTHETIC COMPOUNDS TO TREAT MANGANESE TOXICITY. SEVERAL POTENTIAL MOLECULAR TARGETS OF MANGANESE TOXICITY AT THE EPIGENETIC AND TRANSCRIPTIONAL LEVELS HAVE BEEN IDENTIFIED RECENTLY, WHICH MAY CONTRIBUTE TO DEVELOP MORE PRECISE AND EFFECTIVE GENE THERAPIES. THIS REVIEW UPDATES FINDINGS ON MANGANESE-INDUCED NEUROTOXICITY MECHANISMS ON INTRACELLULAR INSULTS SUCH AS OXIDATIVE STRESS, INFLAMMATION, EXCITOTOXICITY, AND MITOPHAGY, AS WELL AS TRANSCRIPTIONAL DYSREGULATIONS INVOLVING YIN YANG 1, RE1-SILENCING TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR EB, AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 THAT COULD BE TARGETS OF MANGANESE NEUROTOXICITY THERAPIES. THIS REVIEW ALSO FEATURES INTRACELLULAR PROTEINS SUCH AS PTEN-INDUCIBLE KINASE 1, PARKIN, SIRTUINS, LEUCINE-RICH REPEAT KINASE 2, AND ALPHA-SYNUCLEIN, WHICH ARE ASSOCIATED WITH MANGANESE-INDUCED DYSREGULATION OF AUTOPHAGY/MITOPHAGY. IN ADDITION, NEWER THERAPEUTIC APPROACHES TO TREAT MANGANESE'S NEUROTOXICITY INCLUDING NATURAL AND SYNTHETIC COMPOUNDS MODULATING EXCITOTOXICITY, AUTOPHAGY, AND MITOPHAGY, WERE REVIEWED. TAKEN TOGETHER, IN-DEPTH MECHANISTIC KNOWLEDGE ACCOMPANIED BY ADVANCES IN GENE AND DRUG DELIVERY STRATEGIES WILL MAKE SIGNIFICANT PROGRESS IN THE DEVELOPMENT OF RELIABLE THERAPEUTIC INTERVENTIONS AGAINST MANGANESE-INDUCED NEUROTOXICITY. 2022 18 189 23 ACETYL-L-CARNITINE IN CHRONIC PAIN: A NARRATIVE REVIEW. ACETYL-L-CARNITINE (ALC) IS AN ENDOGENOUS MOLECULE THAT NOT ONLY PLAYS A ROLE IN ENERGY METABOLISM, BUT ALSO HAS ANTIOXIDANT PROPERTIES, PROTECTS FROM OXIDATIVE STRESS, MODULATES BRAIN NEUROTRANSMITTERS SUCH AS ACETYLCHOLINE, SEROTONIN AND DOPAMINE, AND ACTS ON NEUROTROPHIC FACTORS SUCH AS NERVE GROWTH FACTOR (NGF) AND METABOTROPIC GLUTAMATE (MGLU) RECEPTORS BY MEANS OF EPIGENETIC MECHANISMS. IMPORTANTLY, IT INDUCES MGLU2 EXPRESSION AT NERVE TERMINALS, THUS GIVING RISE TO ANALGESIA AND PREVENTING SPINAL SENSITISATION. IT HAS ALSO BEEN FOUND TO HAVE EVEN LONG-TERM NEUROTROPHIC AND ANALGESIC ACTIVITY IN EXPERIMENTAL MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN. THE AIM OF THIS NARRATIVE REVIEW IS TO SUMMARISE THE CURRENT EVIDENCE REGARDING THE USE OF ALC IN PATIENTS WITH CHRONIC PAIN, AND COGNITIVE AND MOOD DISORDERS, AND INVESTIGATE THE RATIONALE UNDERLYING ITS USE IN PATIENTS WITH FIBROMYALGIA SYNDROME, WHICH IS CHARACTERISED BY NOCIPLASTIC CHANGES THAT INCREASE THE SENSITIVITY OF THE NERVOUS SYSTEM TO PAIN. 2021 19 2795 27 FATTY LIVER AND CHRONIC KIDNEY DISEASE: NOVEL MECHANISTIC INSIGHTS AND THERAPEUTIC OPPORTUNITIES. CHRONIC KIDNEY DISEASE (CKD) IS A RISK FACTOR FOR END-STAGE RENAL DISEASE (ESRD) AND CARDIOVASCULAR DISEASE (CVD). ESRD OR CVD DEVELOP IN A SUBSTANTIAL PROPORTION OF PATIENTS WITH CKD RECEIVING STANDARD-OF-CARE THERAPY, AND MORTALITY IN CKD REMAINS UNCHANGED. THESE DATA SUGGEST THAT KEY PATHOGENETIC MECHANISMS UNDERLYING CKD PROGRESSION GO UNAFFECTED BY CURRENT TREATMENTS. GROWING EVIDENCE SUGGESTS THAT NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND CKD SHARE COMMON PATHOGENETIC MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS. COMMON NUTRITIONAL CONDITIONS PREDISPOSING TO BOTH NAFLD AND CKD INCLUDE EXCESSIVE FRUCTOSE INTAKE AND VITAMIN D DEFICIENCY. MODULATION OF NUCLEAR TRANSCRIPTION FACTORS REGULATING KEY PATHWAYS OF LIPID METABOLISM, INFLAMMATION, AND FIBROSIS, INCLUDING PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AND FARNESOID X RECEPTOR, IS ADVANCING TO STAGE III CLINICAL DEVELOPMENT. THE RELEVANCE OF EPIGENETIC REGULATION IN THE PATHOGENESIS OF NAFLD AND CKD IS ALSO EMERGING, AND MODULATION OF MICRORNA21 IS A PROMISING THERAPEUTIC TARGET. ALTHOUGH SINGLE ANTIOXIDANT SUPPLEMENTATION HAS YIELDED VARIABLE RESULTS, MODULATION OF KEY EFFECTORS OF REDOX REGULATION AND MOLECULAR SENSORS OF INTRACELLULAR ENERGY, NUTRIENT, OR OXYGEN STATUS SHOW PROMISING PRECLINICAL RESULTS. OTHER EMERGING THERAPEUTIC APPROACHES TARGET KEY MEDIATORS OF INFLAMMATION, SUCH AS CHEMOKINES; FIBROGENESIS, SUCH AS GALECTIN-3; OR GUT DYSFUNCTION THROUGH GUT MICROBIOTA MANIPULATION AND INCRETIN-BASED THERAPIES. FURTHERMORE, NAFLD PER SE AFFECTS CKD THROUGH LIPOPROTEIN METABOLISM AND HEPATOKINE SECRETION, AND CONVERSELY, TARGETING THE RENAL TUBULE BY SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS CAN IMPROVE BOTH CKD AND NAFLD. IMPLICATIONS FOR THE TREATMENT OF NAFLD AND CKD ARE DISCUSSED IN LIGHT OF THIS NEW THERAPEUTIC ARMAMENTARIUM. 2016 20 4777 20 NUTRACEUTICALS AND NETWORK PHARMACOLOGY APPROACH FOR ACUTE KIDNEY INJURY: A REVIEW FROM THE DRUG DISCOVERY ASPECT. ACUTE KIDNEY INJURY (AKI) HAS BECOME A GLOBAL HEALTH ISSUE, WITH APPROXIMATELY 12 MILLION REPORTS YEARLY, RESULTING IN A PERSISTENT INCREASE IN MORBIDITY AND MORTALITY RATES. AKI PATHOPHYSIOLOGY IS MULTIFACTORIAL INVOLVING OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC MODIFICATIONS, INFLAMMATION, AND EVENTUALLY, CELL DEATH. HENCE, THERAPIES ABLE TO TARGET MULTIPLE PATHOMECHANISMS CAN AID IN AKI MANAGEMENT. TO CHANGE THE DRUG DISCOVERY FRAMEWORK FROM "ONE DRUG, ONE TARGET" TO "MULTICOMPONENT, MULTITARGET," NETWORK PHARMACOLOGY IS EVOLVING AS A NEXT-GENERATION RESEARCH APPROACH. RESEARCHERS HAVE USED THE NETWORK PHARMACOLOGY APPROACH TO PREDICT THE ROLE OF NUTRACEUTICALS AGAINST DIFFERENT AILMENTS INCLUDING AKI. NUTRACEUTICALS (HERBAL PRODUCTS, ISOLATED NUTRIENTS, AND DIETARY SUPPLEMENTS) BELONG TO THE PIONEERING CATEGORY OF NATURAL PRODUCTS AND HAVE SHOWN PROTECTIVE ACTION AGAINST AKI. NUTRACEUTICALS HAVE RECENTLY DRAWN ATTENTION BECAUSE OF THEIR ABILITY TO PROVIDE PHYSIOLOGICAL BENEFITS WITH LESS TOXIC EFFECTS. THIS REVIEW EMPHASIZES THE NUTRACEUTICALS THAT EXHIBITED RENOPROTECTION AGAINST AKI AND CAN BE USED EITHER AS MONOTHERAPY OR ADJUVANT WITH CONVENTIONAL THERAPIES TO BOOST THEIR EFFECTIVENESS AND LESSEN THE ADVERSE EFFECTS. ADDITIONALLY, THE STUDY SHEDS LIGHT ON THE APPLICATION OF NETWORK PHARMACOLOGY AS A COST-EFFECTIVE AND TIME-SAVING APPROACH FOR THE THERAPEUTIC TARGET PREDICTION OF NUTRACEUTICALS AGAINST AKI. 2023