1  6441 109 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2  6536  23 TRANSCRIPTIONAL REGULATION OF TYPE-2 METABOTROPIC GLUTAMATE RECEPTORS: AN EPIGENETIC PATH TO NOVEL TREATMENTS FOR CHRONIC PAIN. ACTIVATION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS INHIBITS PAIN TRANSMISSION AT THE SYNAPSES BETWEEN PRIMARY AFFERENT FIBERS AND NEURONS IN THE DORSAL HORN OF THE SPINAL CORD. IN ADDITION, MGLU2 RECEPTORS ARE FOUND IN PERIPHERAL NOCICEPTORS, AND IN PAIN-REGULATORY CENTERS OF THE BRAIN STEM AND FOREBRAIN. MGLU2 RECEPTOR AGONISTS PRODUCE ANALGESIA IN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN, BUT THEIR USE IS LIMITED BY THE DEVELOPMENT OF TOLERANCE. A NEW THERAPEUTIC STRATEGY COULD BE BASED ON THE TRANSCRIPTIONAL REGULATION OF MGLU2 RECEPTORS VIA THE ACETYLATION-PROMOTED ACTIVATION OF THE P65/RELA TRANSCRIPTION FACTOR. "EPIGENETIC" DRUGS THAT INCREASE MGLU2 RECEPTOR EXPRESSION, INCLUDING L-ACETYLCARNITINE AND INHIBITORS OF HISTONE DEACETYLASES, HAVE A DIFFERENT ANALGESIC PROFILE WITH NO TOLERANCE TO THE THERAPEUTIC EFFECT AFTER REPEATED DOSING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3   881  22 CHRONIC CLOZAPINE TREATMENT RESTRAINS VIA HDAC2 THE PERFORMANCE OF MGLU2 RECEPTOR AGONISM IN A RODENT MODEL OF ANTIPSYCHOTIC ACTIVITY. PRECLINICAL FINDINGS IN RODENT MODELS POINTED TOWARD ACTIVATION OF METABOTROPIC GLUTAMATE 2/3 (MGLU2/3) RECEPTORS AS A NEW PHARMACOLOGICAL APPROACH TO TREAT PSYCHOSIS. HOWEVER, MORE RECENT STUDIES FAILED TO SHOW CLINICAL EFFICACY OF MGLU2/3 RECEPTOR AGONISM IN SCHIZOPHRENIA PATIENTS. WE PREVIOUSLY PROPOSED THAT LONG-TERM ANTIPSYCHOTIC MEDICATION RESTRICTED THE THERAPEUTIC EFFECTS OF THESE GLUTAMATERGIC AGENTS. HOWEVER, LITTLE IS KNOWN ABOUT THE MOLECULAR MECHANISM UNDERLYING THE POTENTIAL REPERCUSSION OF PREVIOUS ANTIPSYCHOTIC EXPOSURE ON THE THERAPEUTIC PERFORMANCE OF MGLU2/3 RECEPTOR AGONISTS. HERE WE SHOW THAT THIS MALADAPTIVE EFFECT OF ANTIPSYCHOTIC TREATMENT IS MEDIATED MOSTLY VIA HISTONE DEACETYLASE 2 (HDAC2). CHRONIC TREATMENT WITH THE ANTIPSYCHOTIC CLOZAPINE LED TO A DECREASE IN MOUSE FRONTAL CORTEX MGLU2 MRNA, AN EFFECT THAT REQUIRED EXPRESSION OF BOTH HDAC2 AND THE SEROTONIN 5-HT(2A) RECEPTOR. THIS TRANSCRIPTIONAL ALTERATION OCCURRED IN ASSOCIATION WITH HDAC2-DEPENDENT REPRESSIVE HISTONE MODIFICATIONS AT THE MGLU2 PROMOTER. WE FOUND THAT CHRONIC CLOZAPINE TREATMENT DECREASED VIA HDAC2 THE CAPABILITIES OF THE MGLU2/3 RECEPTOR AGONIST LY379268 TO ACTIVATE G-PROTEINS IN THE FRONTAL CORTEX OF MICE. CHRONIC CLOZAPINE TREATMENT BLUNTED THE ANTIPSYCHOTIC-RELATED BEHAVIORAL EFFECTS OF LY379268, AN EFFECT THAT WAS NOT OBSERVED IN HDAC2 KNOCKOUT MICE. MORE IMPORTANTLY, CO-ADMINISTRATION OF THE CLASS I AND II HDAC INHIBITOR SAHA (VORINOSTAT) PRESERVED THE ANTIPSYCHOTIC PROFILE OF LY379268 AND FRONTAL CORTEX MGLU2/3 RECEPTOR DENSITY IN WILD-TYPE MICE. THESE FINDINGS RAISE CONCERNS ON THE DESIGN OF PREVIOUS CLINICAL STUDIES WITH MGLU2/3 AGONISTS, PROVIDING THE RATIONALE FOR THE DEVELOPMENT OF HDAC2 INHIBITORS AS A NEW EPIGENETIC-BASED APPROACH TO IMPROVE THE CURRENTLY LIMITED RESPONSE TO TREATMENT WITH GLUTAMATERGIC ANTIPSYCHOTICS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  4649  33 NEUROPEPTIDES AND NEUROPEPTIDE RECEPTORS: DRUG TARGETS, AND PEPTIDE AND NON-PEPTIDE LIGANDS: A TRIBUTE TO PROF. DIETER SEEBACH. THE NUMBER OF NEUROPEPTIDES AND THEIR CORRESPONDING RECEPTORS HAS INCREASED STEADILY OVER THE LAST FOURTY YEARS: INITIALLY, PEPTIDES WERE ISOLATED FROM GUT OR BRAIN (E.G., SUBSTANCE P, SOMATOSTATIN), THEN BY TARGETED MINING IN SPECIFIC REGIONS (E.G., CORTISTATIN, OREXIN IN THE BRAIN), OR BY DEORPHANIZATION OF G-PROTEIN-COUPLED RECEPTORS (GPCRS; OREXIN, GHRELIN RECEPTORS) AND THROUGH THE COMPLETION THE HUMAN GENOME PROJECT. NEUROPEPTIDES (AND THEIR RECEPTORS) HAVE REGIONALLY RESTRICTED DISTRIBUTIONS IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. THE NEUROPEPTIDE SIGNALING IS SOMEWHAT MORE DISTINCT SPATIALLY THAN SIGNALING WITH CLASSICAL, LOW-MOLECULAR-WEIGHT NEUROTRANSMITTERS THAT ARE MORE WIDELY EXPRESSED, AND, THEREFORE, ONE ASSUMES THAT DRUGS ACTING AT NEUROPEPTIDE RECEPTORS MAY HAVE MORE SELECTIVE PHARMACOLOGICAL ACTIONS WITH POSSIBLY FEWER SIDE EFFECTS THAN DRUGS ACTING ON GLUTAMATERGIC, GABAERGIC, MONOAMINERGIC, OR CHOLINERGIC SYSTEMS. NEUROPEPTIDE RECEPTORS, WHICH MAY HAVE A FEW OR MULTIPLE SUBTYPES AND SPLICE VARIANTS, BELONG ALMOST EXCLUSIVELY TO THE GPCR FAMILY ALSO KNOWN AS SEVEN-TRANSMEMBRANE RECEPTORS (7TM), A FAVORITE CLASS OF DRUG TARGETS IN THE PHARMACEUTICAL INDUSTRY. MOST NEUROPEPTIDES ARE CO-STORED AND CO-RELEASED WITH CLASSIC NEUROTRANSMITTERS, ALBEIT OFTEN ONLY AT HIGHER FREQUENCIES OF STIMULATION OR AT BURSTING ACTIVITY, THUS RESTRICTING THE NEUROPEPTIDE SIGNALING TO SPECIFIC CIRCUMSTANCES, ANOTHER REASON TO ASSUME THAT NEUROPEPTIDE DRUG MIMICS MAY HAVE LESS SIDE EFFECTS. NEUROPEPTIDES POSSESS A WIDE SPECTRUM OF FUNCTIONS FROM NEUROHORMONE, NEUROTRANSMITTER TO GROWTH FACTOR, BUT ALSO AS KEY INFLAMMATORY MEDIATORS. NEUROPEPTIDES BECOME 'ACTIVE' WHEN THE NERVOUS SYSTEM IS CHALLENGED, E.G., BY STRESS, INJURY, DRUG ABUSE, OR NEUROPSYCHIATRIC DISORDERS WITH GENETIC, EPIGENETIC, AND/OR ENVIRONMENTAL COMPONENTS. THE UNSUSPECTED NUMBER OF TRUE NEUROPEPTIDES AND THEIR COGNATE RECEPTORS PROVIDES OPPORTUNITIES TO IDENTIFY NOVEL TARGETS FOR THE TREATMENT OF BOTH CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS. BOTH, RECEPTOR SUBTYPE-SELECTIVE ANTAGONISTS AND AGONISTS ARE BEING DEVELOPED, AS ILLUSTRATED BY THE SUCCESS OF SOMATOSTATIN AGONISTS, ANGIOTENSIN, AND ENDOTHELIN ANTAGONISTS, AND THE EXPECTED CLINICAL APPLICATIONS OF NK-1/2/3 (SUBSTANCE P) RECEPTOR ANTAGONISTS, CRF, VASOPRESSIN, NPY, NEUROTENSIN, OREXIN ANTAGONISTS, OR NEUROPEPTIDE RECEPTOR MODULATORS; SUCH LIGANDS HAVE EFFICACY IN PRECLINICAL OR CLINICAL MODELS OF PAIN AND NEUROPSYCHIATRIC DISEASES, SUCH AS MIGRAINE, CHRONIC/NEUROPATHIC PAIN, ANXIETY, SLEEP DISORDERS, DEPRESSION, AND SCHIZOPHRENIA. IN ADDITION, BOTH POSITIVE AND NEGATIVE ALLOSTERIC MODULATORS HAVE BEEN DESCRIBED WITH INTERESTING IN VIVO ACTIVITIES (E.G., AT GALANIN RECEPTORS). THE FIELD HAS BECOME MORE COMPLEX NOW THAT AN INCREASING NUMBER OF HETEROMERIC NEUROPEPTIDE RECEPTORS ARE DESCRIBED, E.G., GHRELIN RECEPTORS WITH 5-HT(2C) OR DOPAMINE D(1), D(2) RECEPTORS. AT LONG LAST, STRUCTURE-BASED DRUG DISCOVERY CAN NOW BE ENVISAGED WITH CONFIDENCE, SINCE CRYSTAL OR SOLUTION STRUCTURE OF GPCRS AND GPCR-LIGAND COMPLEXES, INCLUDING PEPTIDE RECEPTORS, ARE PUBLISHED ALMOST ON A MONTHLY BASIS. FINALLY, ALTHOUGH MOST COMPOUNDS ACTING AT PEPTIDE RECEPTORS ARE STILL PEPTIDOMIMETICS, THE LAST DECADE HAS SEEN THE EMERGENCE OF LOW-MOLECULAR-WEIGHT NONPEPTIDE LIGANDS (E.G., FOR OREXIN, GHRELIN, OR NEUROKININ RECEPTORS), AND SURPRISING PROGRESS HAS BEEN MADE WITH BETA- AND GAMMA-PEPTIDES AS VERY STABLE AND POTENT MIMETICS OF, E.G., SOMATOSTATIN (SRIF), WHERE THE NATIVE SRIF HAS A HALF-LIFE LIMITED TO 2-3 MIN. THIS LAST POINT WILL BE ILLUSTRATED MORE SPECIFICALLY, AS WE HAVE HAD A LONG-STANDING COLLABORATION WITH PROF. D. SEEBACH TO WHOM THIS REVIEW IS DEDICATED AT THE OCCASION OF HIS 75TH BIRTHDAY.	2012	

5  1384  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6  5880  24 SYNTHETIC RETINOIDS BEYOND CANCER THERAPY. WHILE THE USES OF RETINOIDS FOR CANCER TREATMENT CONTINUE TO EVOLVE, THIS REVIEW FOCUSES ON OTHER THERAPEUTIC AREAS IN WHICH RETINOIDS [RETINOL (VITAMIN A), ALL-TRANS RETINOIC ACID (RA), AND SYNTHETIC RETINOIC ACID RECEPTOR (RAR)ALPHA-, BETA-, AND GAMMA-SELECTIVE AGONISTS] ARE BEING USED AND ON PROMISING NEW RESEARCH THAT SUGGESTS ADDITIONAL USES FOR RETINOIDS FOR THE TREATMENT OF DISORDERS OF THE KIDNEYS, SKELETAL MUSCLES, HEART, PANCREAS, LIVER, NERVOUS SYSTEM, SKIN, AND OTHER ORGANS. THE MOST MATURE AREA, IN TERMS OF US FOOD AND DRUG ADMINISTRATION-APPROVED, RAR-SELECTIVE AGONISTS, IS FOR TREATMENT OF VARIOUS SKIN DISEASES. SYNTHETIC RETINOID AGONISTS HAVE MAJOR ADVANTAGES OVER ENDOGENOUS RAR AGONISTS SUCH AS RA. BECAUSE THEY ACT THROUGH A SPECIFIC RAR, SIDE EFFECTS MAY BE MINIMIZED, AND SYNTHETIC RETINOIDS OFTEN HAVE BETTER PHARMACEUTICAL PROPERTIES THAN DOES RA. BASED ON OUR INCREASING KNOWLEDGE OF THE MULTIPLE ROLES OF RETINOIDS IN DEVELOPMENT, EPIGENETIC REGULATION, AND TISSUE REPAIR, OTHER EXCITING THERAPEUTIC AREAS ARE EMERGING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  6721  17 VITAMIN D RECEPTOR AGONISTS' ANTI-INFLAMMATORY PROPERTIES. ONE CENTURY AFTER ITS DISCOVERY, VITAMIN D HAS BEEN SHOWN TO BE, IN FACT, A PLEIOTROPIC STEROID HORMONE, WHICH, BESIDES REGULATION OF CALCIUM HOMEOSTASIS AND BONE TURNOVER, HAS ANTIPROLIFERATIVE, PRODIFFERENTIATION, ANTIBACTERIAL, IMMUNOMODULATORY, AND ANTI-INFLAMMATORY PROPERTIES IN VARIOUS CELLS AND TISSUES. D HORMONE (1ALPHA,25(OH)2 D), REGULATED IN AN ENDOCRINE, AUTOCRINE, AND PARACRINE MANNER, MUST BE BOUND TO THE SPECIFIC NUCLEAR VITAMIN D RECEPTOR (VDR) TO EXERT EPIGENETIC AND GENETIC EFFECTS, ACTING AS A CONNECTION BETWEEN EXTRACELLULAR STIMULI AND GENOMIC RESPONSES OF THE CELLS. SINCE ONLY HIGH DOSES OF HORMONE, PROVOKING HYPERCALCEMIA, CAN ACHIEVE IMMUNOMODULATORY EFFECTS, MORE THAN 3000 VDR AGONISTS HAVE BEEN SYNTHESIZED. NUMEROUS EXPERIMENTAL TRIALS HAVE BEEN PERFORMED IN ANIMAL MODELS, EVIDENCING THE PREVENTIVE AND THERAPEUTIC POTENTIAL OF VDR AGONISTS FOR CHRONIC INFLAMMATORY DISEASES AND CANCER. CONSIDERING THE SELECTIVE ANTI-INFLAMMATORY EFFECTS OF VDR AGONISTS COMPARED TO GLUCOCORTICOIDS, SPARING MICROBICIDAL FUNCTIONS, THE FEAR OF HYPERCALCEMIA AS THEIR ONLY FREQUENT SIDE EFFECT BECOMES A QUESTIONABLE REASON FOR THE LACK OF CLINICAL STUDIES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  4207  20 METABOTROPIC GLUTAMATE RECEPTORS AND THE CONTROL OF CHRONIC PAIN. OVER THE PAST TWO DECADES METABOTROPIC GLUTAMATE (MGLU) RECEPTOR LIGANDS HAVE BEEN INVESTIGATED FOR THEIR POTENTIAL THERAPEUTIC EFFECTS IN DIFFERENT DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS), INCLUDING ANXIETY, DEPRESSION, SCHIZOPHRENIA, AND NEURODEGENERATIVE DISEASES. IN ADDITION, IT HAS BEEN WIDELY DEMONSTRATED THAT MGLU RECEPTORS ARE ABLE TO MODULATE PAIN TRANSMISSION BOTH IN INFLAMMATORY AND NEUROPATHIC PAIN MODELS. A LARGE NUMBER OF PRECLINICAL STUDIES COMBINING THE USE OF SELECTIVE LIGANDS WITH THE KNOCKOUT STRATEGY HAVE REVEALED MORE DETAILS ABOUT THE ROLE OF THE DIFFERENT MGLU RECEPTOR SUBTYPES IN THE MODULATION OF PAIN INFORMATION. THIS REVIEW WILL ADDRESS THE ROLE OF MGLU RECEPTORS IN PAIN SENSITIVITY FOCUSING ON DIFFERENT STRATEGIES TO ACHIEVE PAIN CONTROL BY TARGETING SPECIFIC MGLU RECEPTOR SUBTYPES. SPECIFICALLY, PHARMACOLOGICAL INTERVENTIONS AIMED AT INHIBITING GROUP I MGLU RECEPTOR-MEDIATED SIGNALING AND/OR POTENTIATING GROUPS II AND III MGLU RECEPTOR SIGNALING TOGETHER WITH AN EPIGENETIC APPROACH LEADING TO AN INCREASED EXPRESSION OF MGLU2 RECEPTORS WILL BE DISCUSSED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  6648  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10    12  27 2017 CLINICAL TRIALS UPDATE IN NEW TREATMENTS OF BETA-THALASSEMIA. THE UNDERLYING BASIS OF BETA-THALASSEMIA PATHOLOGY IS THE DIMINISHED BETA-GLOBIN SYNTHESIS LEADING TO ALPHA-GLOBIN ACCUMULATION AND PREMATURE APOPTOTIC DESTRUCTION OF ERYTHROBLASTS, CAUSING OXIDATIVE STRESS-INDUCED INEFFECTIVE ERYTHROPOIESIS, BONE MARROW HYPERPLASIA, SPLENOMEGALY, AND INCREASED INTESTINAL IRON ABSORPTION WITH PROGRESSIVE IRON OVERLOAD. BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE LED TO THE RECOGNITION OF NEW TARGETS WITH POTENTIAL THERAPEUTIC UTILITY. AGENTS SUCH AS JAK2 INHIBITORS AND TGF-BETA LIGAND TRAPS THAT REDUCE THE INEFFECTIVE ERYTHROPOIESIS PROCESS ARE ALREADY BEING TESTED IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS THAT AIM TO REDUCE OXIDATIVE STRESS (ACTIVATORS OF FOXO3, HRI-EIF2AP, PRX2, HSP70, AND PK ANTI-OXIDANT SYSTEMS AND INHIBITORS OF HO-1) AND TO DECREASE IRON OVERLOAD (HEPCIDIN AGONISTS, ERYTHROFERRONE INHIBITORS AND EXOGENOUS TRANSFERRIN) ARE ALSO UNDER EXPERIMENTAL INVESTIGATION. SIGNIFICANT PROGRESS HAS ALSO BEEN MADE IN THE AREA OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH SEVERAL ONGOING CLINICAL TRIALS EXAMINING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONOR SELECTION AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS REACHED A CRITICAL POINT AND PHASE 1 CLINICAL TRIALS HAVE RECENTLY BEEN LAUNCHED TO EXAMINE THE EFFECTIVENESS AND ESPECIALLY LONG TERM SAFETY. EPIGENETIC MANIPULATION AND GENOMIC EDITING OF THE GAMMA- OR BETA-GLOBIN GENE ARE NOVEL AND PROMISING EXPERIMENTAL GENE THERAPY APPROACHES FOR BETA-THALASSEMIA GIVING HOPE FOR CURE FOR THIS CHRONIC DISEASE. THIS REVIEW OUTLINES THE KEY POINTS OF THE MOLECULAR MECHANISMS UNDERLYING BETA-THALASSEMIA IN RELATION TO THE DEVELOPMENT OF NEW THERAPIES AND AN UPDATE IS GIVEN BOTH AT THE PRE-CLINICAL AND CLINICAL LEVEL. AM. J. HEMATOL. 91:1135-1145, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  4971  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  5151  34 PPARS IN LIVER DISEASES AND CANCER: EPIGENETIC REGULATION BY MICRORNAS. PEROXISOME-PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) ARE LIGAND-ACTIVATED NUCLEAR RECEPTORS THAT EXERT IN THE LIVER A TRANSCRIPTIONAL ACTIVITY REGULATING A WHOLE SPECTRUM OF PHYSIOLOGICAL FUNCTIONS, INCLUDING CHOLESTEROL AND BILE ACID HOMEOSTASIS, LIPID/GLUCOSE METABOLISM, INFLAMMATORY RESPONSES, REGENERATIVE MECHANISMS, AND CELL DIFFERENTIATION/PROLIFERATION. DYSREGULATIONS OF THE EXPRESSION, OR ACTIVITY, OF SPECIFIC PPAR ISOFORMS IN THE LIVER ARE THEREFORE BELIEVED TO REPRESENT CRITICAL MECHANISMS CONTRIBUTING TO THE DEVELOPMENT OF HEPATIC METABOLIC DISEASES, DISORDERS INDUCED BY HEPATIC VIRAL INFECTIONS, AND HEPATOCELLULAR ADENOMA AND CARCINOMA. IN THIS REGARD, SPECIFIC PPAR AGONISTS HAVE PROVEN TO BE USEFUL TO TREAT THESE METABOLIC DISEASES, BUT FOR CANCER THERAPIES, THE USE OF PPAR AGONISTS IS STILL DEBATED. INTERESTINGLY, IN ADDITION TO PREVIOUSLY DESCRIBED MECHANISMS REGULATING PPARS EXPRESSION AND ACTIVITY, MICRORNAS ARE EMERGING AS NEW IMPORTANT REGULATORS OF PPAR EXPRESSION AND ACTIVITY IN PATHOPHYSIOLOGICAL CONDITIONS AND THEREFORE MAY REPRESENT FUTURE THERAPEUTIC TARGETS TO TREAT HEPATIC METABOLIC DISORDERS AND CANCERS. HERE, WE REVIEWED THE CURRENT KNOWLEDGE ABOUT THE GENERAL ROLES OF THE DIFFERENT PPAR ISOFORMS IN COMMON CHRONIC METABOLIC AND INFECTIOUS LIVER DISEASES, AS WELL AS IN THE DEVELOPMENT OF HEPATIC CANCERS. RECENT WORKS HIGHLIGHTING THE REGULATION OF PPARS BY MICRORNAS IN BOTH PHYSIOLOGICAL AND PATHOLOGICAL SITUATIONS WITH A FOCUS ON THE LIVER ARE ALSO DISCUSSED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13   189  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14   465  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15   842  28 CHEMOKINES IN CHRONIC PAIN: CELLULAR AND MOLECULAR MECHANISMS AND THERAPEUTIC POTENTIAL. CHRONIC PAIN RESULTING FROM NERVE INJURY, TISSUE INFLAMMATION, AND TUMOR INVASION OR TREATMENT, IS A MAJOR HEALTH PROBLEM IMPACTING THE QUALITY OF LIFE AND PRODUCING A SIGNIFICANT ECONOMIC AND SOCIAL BURDEN. HOWEVER, THE CURRENT ANALGESIC DRUGS INCLUDING NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS ARE INADEQUATE TO RELIEVE CHRONIC PAIN DUE TO THE LACK OF EFFICACY OR SEVERE SIDE-EFFECTS. CHEMOKINES ARE A FAMILY OF SMALL SECRETED PROTEINS THAT BIND TO G PROTEIN-COUPLED RECEPTORS TO TRIGGER INTRACELLULAR SIGNALING PATHWAYS AND DIRECT CELL MIGRATION, PROLIFERATION, SURVIVAL, AND INFLAMMATION UNDER HOMEOSTATIC AND PATHOLOGICAL CONDITIONS. ACCUMULATING EVIDENCE SUPPORTS THE IMPORTANT ROLE OF CHEMOKINES AND CHEMOKINE RECEPTORS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM IN MEDIATING CHRONIC PAIN VIA ENHANCING NEUROINFLAMMATION. IN THIS REVIEW, WE FOCUS ON RECENT PROGRESS IN UNDERSTANDING THE COMPREHENSIVE ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN THE GENERATION AND MAINTENANCE OF DIFFERENT TYPES OF CHRONIC PAIN, INCLUDING NEUROPATHIC PAIN, INFLAMMATORY PAIN, CANCER PAIN, AND VISCERAL PAIN. THE CURRENT REVIEW ALSO SUMMARIZES THE UPSTREAM SIGNALING OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION ON THE EXPRESSION OF CHEMOKINES AND CHEMOKINE RECEPTORS AS WELL AS THE DOWNSTREAM SIGNALING OF CHEMOKINE RECEPTORS UNDERLYING CHRONIC PAIN. AS CHRONIC ITCH AND CHRONIC PAIN SHARE SOME COMMON MECHANISMS, WE ALSO DISCUSS THE EMERGING ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN CHRONIC ITCH. TARGETING SPECIFIC CHEMOKINES OR CHEMOKINE RECEPTORS BY SIRNAS, BLOCKING ANTIBODIES, OR SMALL-MOLECULE ANTAGONISTS MAY OFFER NEW THERAPEUTIC POTENTIAL FOR THE MANAGEMENT OF CHRONIC PAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
16  3191  25 HDAC AND HAT INHIBITORS DIFFERENTLY AFFECT ANALGESIA MEDIATED BY GROUP II METABOTROPIC GLUTAMATE RECEPTORS. BACKGROUND: HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYLTRANSFERASES (HATS) ARE KEY PLAYERS IN EPIGENETIC REGULATION OF GENE EXPRESSION. ANALGESIC ACTIVITY BY HDAC INHIBITORS HAS BEEN REPORTED IN DIFFERENT PAIN MODELS INCLUDING INFLAMMATORY AND NEUROPATHIC PAIN. THESE DRUGS INTERFERE WITH GENE EXPRESSION THROUGH DIFFERENT MECHANISMS INCLUDING CHROMATIN REMODELING AND/OR ACTIVATION OF TRANSCRIPTION FACTORS. AMONG OTHER TARGETS, HDAC INHIBITORS REGULATE METABOTROPIC GLUTAMATE RECEPTORS TYPE 2 (MGLU2) EXPRESSION IN CENTRAL AND PERIPHERAL CENTRAL NERVOUS SYSTEM. HOWEVER WHETHER INHIBITION OF HAT ACTIVITY ALSO REGULATES MGLU2 EXPRESSION HAS NOT BEEN REPORTED. FINDINGS: HERE WE REPORT THAT CURCUMIN (CUR), A NATURALLY OCCURRING COMPOUND ENDOWED WITH P300/CREB-BINDING PROTEIN HAT INHIBITORY ACTIVITY, IS ABLE TO INDUCE A DRASTIC DOWN-REGULATION OF THE MGLU2 RECEPTOR IN THE MOUSE SPINAL CORD AFTER SYSTEMIC ADMINISTRATION TOGETHER WITH A MARKED HYPOACETYLATION OF HISTONES H3 AND H4 IN DORSAL ROOT GANGLIA (DRG). FURTHERMORE, THE ANALGESIC ACTIVITY OF THE MGLU2/3 AGONIST, LY379268 IS LOST AFTER A 3-DAY TREATMENT WITH CUR. CONVERSELY THE ANALGESIC ACTIVITY OF LY379268 IS POTENTIATED IN MICE PRETREATED FOR 5 CONSECUTIVE DAYS WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), KNOWN TO INDUCE MGLU2-UPREGULATION. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT SYSTEMICALLY INJECTED CUR IS ABLE TO INHIBIT H3 AND H4 ACETYLATION IN THE DRG AND TO DOWN-REGULATE MGLU2 RECEPTORS IN THE SPINAL CORD. WE ALSO DEMONSTRATE THAT LONG TERM MODIFICATION OF THE MGLU2 EXPRESSION AFFECTS THE ANALGESIC PROPERTIES OF THE ORTHOSTERIC MGLU2/3 AGONIST, LY379268. THESE DATA OPEN UP THE POSSIBILITY THAT EPIGENETIC MODULATORS MIGHT BE GIVEN IN COMBINATION WITH "TRADITIONAL" DRUGS IN A CONTEXT OF A MULTI TARGET APPROACH FOR A BETTER ANALGESIC EFFICACY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  5221  32 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  4753  30 NOVEL THERAPEUTIC ADVANCES IN BETA-THALASSEMIA. THE MAIN CHARACTERISTIC OF THE PATHOPHYSIOLOGY OF BETA-THALASSEMIA IS REDUCED BETA-GLOBIN CHAIN PRODUCTION. THE INEVITABLE IMBALANCE IN THE ALPHA/BETA-GLOBIN RATIO AND ALPHA-GLOBIN ACCUMULATION LEAD TO OXIDATIVE STRESS IN THE ERYTHROID LINEAGE, APOPTOSIS, AND INEFFECTIVE ERYTHROPOIESIS. THE RESULT IS COMPENSATORY HEMATOPOIETIC EXPANSION AND IMPAIRED HEPCIDIN PRODUCTION THAT CAUSES INCREASED INTESTINAL IRON ABSORPTION AND PROGRESSIVE IRON OVERLOAD. CHRONIC HEMOLYSIS AND RED BLOOD CELL TRANSFUSIONS ALSO CONTRIBUTE TO IRON TISSUE DEPOSITION. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS LED TO THE DETECTION OF NEW CURATIVE OR "DISEASE-MODIFYING" THERAPEUTIC OPTIONS. SUBSTANTIAL EVOLVEMENT HAS BEEN MADE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH CURRENT CLINICAL TRIALS INVESTIGATING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONORS AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS ALSO MOVED FORWARD, AND PHASE 2 CLINICAL TRIALS WITH THE USE OF BETA-GLOBIN INSERTION TECHNIQUES HAVE RECENTLY BEEN SUCCESSFULLY COMPLETED LEADING TO APPROVAL FOR USE IN TRANSFUSION-DEPENDENT PATIENTS. GENETIC AND EPIGENETIC MANIPULATION OF THE GAMMA- OR BETA-GLOBIN GENE HAVE ENTERED THE CLINICAL TRIAL SETTING. AGENTS SUCH AS TGF-BETA LIGAND TRAPS AND PYRUVATE KINASE ACTIVATORS, WHICH REDUCE THE INEFFECTIVE ERYTHROPOIESIS, HAVE BEEN TESTED IN CLINICAL TRIALS WITH FAVORABLE RESULTS. ONE TGF-BETA LIGAND TRAP, LUSPATERCEPT, HAS BEEN APPROVED FOR USE IN ADULTS WITH TRANSFUSION-DEPENDENT BETA-THALASSEMIA. THE INDUCTION OF HBF WITH THE PHOSPHODIESTERASE 9 INHIBITOR IMR-687, WHICH INCREASE CYCLIC GUANOSINE MONOPHOSPHATE, IS CURRENTLY BEING TESTED. ANOTHER THERAPEUTIC APPROACH IS TO TARGET THE DYSREGULATION OF IRON HOMEOSTASIS, USING, FOR EXAMPLE, HEPCIDIN AGONISTS (INHIBITORS OF TMPRSS6 AND MINIHEPCIDINS) OR FERROPORTIN INHIBITORS (VIT-2763). THIS REVIEW PROVIDES AN UPDATE ON THE NOVEL THERAPEUTIC OPTIONS THAT ARE PRESENTLY IN DEVELOPMENT AT THE CLINICAL LEVEL IN BETA-THALASSEMIA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  5778  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  4149  18 MECHANISTIC INSIGHT INTO THE EFFECTS OF CURCUMIN ON NEUROINFLAMMATION-DRIVEN CHRONIC PAIN. CHRONIC PAIN IS A PERSISTENT AND UNREMITTING CONDITION THAT HAS IMMENSE EFFECTS ON PATIENTS' QUALITY OF LIFE. STUDIES HAVE SHOWN THAT NEUROINFLAMMATION IS ASSOCIATED WITH THE INDUCTION AND PROGRESSION OF CHRONIC PAIN. THE ACTIVATION OF MICROGLIA AND ASTROCYTES IS THE MAJOR HALLMARK OF SPINAL NEUROINFLAMMATION LEADING TO NEURONAL EXCITABILITY IN THE PROJECTION NEURONS. EXCESSIVE ACTIVATION OF MICROGLIA AND ASTROCYTES IS ONE OF THE MAJOR CONTRIBUTING FACTORS TO THE EXACERBATION OF PAIN. HOWEVER, THE CURRENT CHRONIC PAIN TREATMENTS, MAINLY BY TARGETING THE NEURONAL CELLS, REMAIN INEFFECTIVE AND UNABLE TO MEET THE PATIENTS' NEEDS. CURCUMIN, A NATURAL PLANT PRODUCT FOUND IN THE CURCUMA GENUS, IMPROVES CHRONIC PAIN BY DIMINISHING THE RELEASE OF INFLAMMATORY MEDIATORS FROM THE SPINAL GLIA. THIS REVIEW DETAILS THE ROLE OF CURCUMIN IN MICROGLIA AND ASTROCYTES BOTH IN VITRO AND IN VIVO AND HOW IT IMPROVES PAIN. WE ALSO DESCRIBE THE MECHANISM OF CURCUMIN BY HIGHLIGHTING THE MAJOR GLIA-MEDIATED CASCADES IN PAIN. MOREOVER, THE ROLE OF CURCUMIN ON INFLAMMASOME AND EPIGENETIC REGULATION IS DISCUSSED. FURTHERMORE, WE DISCUSS THE STRATEGIES USED TO IMPROVE THE EFFICACY OF CURCUMIN. THIS REVIEW ILLUSTRATES THAT CURCUMIN MODULATING MICROGLIA AND ASTROCYTES COULD ASSURE THE TREATMENT OF CHRONIC PAIN BY SUPPRESSING SPINAL NEUROINFLAMMATION.	2021