1 6721 108 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 2 1103 23 COMBINED DUAL EFFECT OF MODULATION OF HUMAN NEUTROPHILS' OXIDATIVE BURST AND INHIBITION OF COLON CANCER CELLS PROLIFERATION BY HYDROXYCINNAMIC ACID DERIVATIVES. COLON CANCER IS ONE OF THE MOST INCIDENT CANCERS IN THE WESTERN WORLD. WHILE BOTH GENETIC AND EPIGENETIC FACTORS MAY CONTRIBUTE TO THE DEVELOPMENT OF COLON CANCER, IT IS KNOWN THAT CHRONIC INFLAMMATION ASSOCIATED TO EXCESSIVE PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES BY PHAGOCYTES MAY ULTIMATELY INITIATE THE MULTISTEP PROCESS OF COLON CANCER DEVELOPMENT. PHENOLIC COMPOUNDS, WHICH REVEAL ANTIOXIDANT AND ANTIPROLIFERATIVE ACTIVITIES IN COLON CANCER CELLS, CAN BE A GOOD APPROACH TO SURPASS THIS PROBLEM. IN THIS WORK, HYDROXYCINNAMIC AMIDES AND THE RESPECTIVE ACID PRECURSORS WERE TESTED IN VITRO FOR THEIR CAPACITY TO MODULATE HUMAN NEUTROPHILS' OXIDATIVE BURST AND SIMULTANEOUSLY TO INHIBIT GROWTH OF COLON CANCER CELLS. A PHENOLIC AMIDE DERIVATIVE, CAFFEIC ACID HEXYLAMIDE (CAHA) (4) WAS FOUND TO BE THE MOST ACTIVE COMPOUND IN BOTH ASSAYS, INHIBITING HUMAN NEUTROPHILS' OXIDATIVE BURST, RESTRAINING THE INFLAMMATORY PROCESS, INHIBITING GROWTH OF COLON CANCER CELLS AND TRIGGERING MITOCHONDRIAL DYSFUNCTION THAT LEADS CANCER CELLS TO APOPTOSIS. ALTOGETHER, THESE ACHIEVEMENTS CAN CONTRIBUTE TO THE UNDERSTANDING OF THE RELATIONSHIP BETWEEN ANTIOXIDANT AND ANTICANCER ACTIVITIES AND BASED ON THE STRUCTURE-ACTIVITY RELATIONSHIPS (SAR) ESTABLISHED CAN BE THE STARTING POINT TO FIND MORE EFFECTIVE PHENOLIC COMPOUNDS AS ANTICANCER AGENTS. 2016 3 426 25 ANTI-DIABETIC FUNCTIONS OF SOY ISOFLAVONE GENISTEIN: MECHANISMS UNDERLYING ITS EFFECTS ON PANCREATIC BETA-CELL FUNCTION. TYPE 2 DIABETES IS A RESULT OF CHRONIC INSULIN RESISTANCE AND LOSS OF FUNCTIONAL PANCREATIC BETA-CELL MASS. STRATEGIES TO PRESERVE BETA-CELL MASS AND A GREATER UNDERSTANDING OF THE MECHANISMS UNDERLYING BETA-CELL TURNOVER ARE NEEDED TO PREVENT AND TREAT THIS DEVASTATING DISEASE. GENISTEIN, A NATURALLY OCCURRING SOY ISOFLAVONE, IS REPORTED TO HAVE NUMEROUS HEALTH BENEFITS ATTRIBUTED TO MULTIPLE BIOLOGICAL FUNCTIONS. OVER THE PAST 10 YEARS, NUMEROUS STUDIES HAVE DEMONSTRATED THAT GENISTEIN HAS ANTI-DIABETIC EFFECTS, IN PARTICULAR, DIRECT EFFECTS ON BETA-CELL PROLIFERATION, GLUCOSE-STIMULATED INSULIN SECRETION AND PROTECTION AGAINST APOPTOSIS, INDEPENDENT OF ITS FUNCTIONS AS AN ESTROGEN RECEPTOR AGONIST, ANTIOXIDANT, OR TYROSINE KINASE INHIBITOR. EFFECTS ARE STRUCTURE-SPECIFIC AND NOT COMMON TO ALL FLAVONOIDS. WHILE THERE ARE LIMITED DATA ON THE EFFECTS OF GENISTEIN CONSUMPTION IN HUMANS WITH DIABETES, THERE ARE A PLETHORA OF ANIMAL AND CELL-CULTURE STUDIES THAT DEMONSTRATE A DIRECT EFFECT OF GENISTEIN ON BETA-CELLS AT PHYSIOLOGICALLY RELEVANT CONCENTRATIONS (<10 MUM). THE EFFECTS APPEAR TO INVOLVE CAMP/PKA SIGNALING AND THERE ARE SOME STUDIES THAT SUGGEST AN EFFECT ON EPIGENETIC REGULATION OF GENE EXPRESSION. THIS REVIEW FOCUSES ON THE ANTI-DIABETIC EFFECTS OF GENISTEIN IN BOTH IN VITRO AND IN VIVO MODELS AND POTENTIAL MECHANISMS UNDERLYING ITS DIRECT EFFECTS ON BETA-CELLS. 2013 4 4044 24 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 5 1339 22 DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION, AND STRUCTURAL CHARACTERIZATION OF POTENT HISTONE DEACETYLASE INHIBITORS BASED ON CYCLIC ALPHA/BETA-TETRAPEPTIDE ARCHITECTURES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF ENZYMES FOUND IN BACTERIA, FUNGI, PLANTS, AND ANIMALS THAT PROFOUNDLY AFFECT CELLULAR FUNCTION BY CATALYZING THE REMOVAL OF ACETYL GROUPS FROM -N-ACETYLATED LYSINE RESIDUES OF VARIOUS PROTEIN SUBSTRATES INCLUDING HISTONES, TRANSCRIPTION FACTORS, ALPHA-TUBULIN, AND NUCLEAR IMPORTERS. ALTHOUGH THE PRECISE ROLES OF HDAC ISOFORMS IN CELLULAR FUNCTION ARE NOT YET COMPLETELY UNDERSTOOD, INHIBITION OF HDAC ACTIVITY HAS EMERGED AS A PROMISING APPROACH FOR REVERSING THE ABERRANT EPIGENETIC STATES ASSOCIATED WITH CANCER AND OTHER CHRONIC DISEASES. POTENT NEW ISOFORM-SELECTIVE HDAC INHIBITORS WOULD THEREFORE HELP EXPAND OUR UNDERSTANDING OF THE HDAC ENZYMES AND REPRESENT ATTRACTIVE LEAD COMPOUNDS FOR DRUG DESIGN, ESPECIALLY IF COMBINED WITH HIGH-RESOLUTION STRUCTURAL ANALYSES OF SUCH INHIBITORS TO SHED LIGHT ON THE THREE-DIMENSIONAL PHARMACOPHORIC FEATURES NECESSARY FOR THE FUTURE DESIGN OF MORE POTENT AND SELECTIVE COMPOUNDS. HERE WE PRESENT STRUCTURAL AND FUNCTIONAL ANALYSES OF A SERIES OF BETA-AMINO-ACID-CONTAINING HDAC INHIBITORS INSPIRED BY CYCLIC TETRAPEPTIDE NATURAL PRODUCTS. TO SURVEY A DIVERSE ENSEMBLE OF PHARMACOPHORIC CONFIGURATIONS, WE SYSTEMATICALLY VARIED THE POSITION OF THE BETA-AMINO ACID, AMINO ACID CHIRALITY, FUNCTIONALIZATION OF THE ZN(2+)-COORDINATING AMINO ACID SIDE CHAIN, AND ALKYLATION OF THE BACKBONE AMIDE NITROGEN ATOMS AROUND THE MACROCYCLE. IN MANY CASES, THE COMPOUNDS WERE A SINGLE CONFORMATION IN SOLUTION AND EXHIBITED POTENT ACTIVITIES AGAINST A NUMBER OF HDAC ISOFORMS AS WELL AS EFFECTIVE ANTIPROLIFERATIVE AND CYTOTOXIC ACTIVITIES AGAINST HUMAN TUMOR CELLS. HIGH-RESOLUTION NMR SOLUTION STRUCTURES WERE DETERMINED FOR A SELECTION OF THE INHIBITORS, PROVIDING A USEFUL MEANS OF CORRELATING DETAILED STRUCTURAL INFORMATION WITH POTENCY. THE STRUCTURE-BASED APPROACH DESCRIBED HERE IS EXPECTED TO FURNISH VALUABLE INSIGHTS TOWARD THE FUTURE DESIGN OF MORE SELECTIVE HDAC INHIBITORS. 2009 6 3335 32 HISTONE DEACETYLASE INHIBITORS FOR CARDIOVASCULAR CONDITIONS AND HEALTHY LONGEVITY. HISTONE DEACETYLASE INHIBITORS (HDACI) REGULATE GENE EXPRESSION VIA EPIGENETIC MECHANISMS. ACCUMULATING EVIDENCE SUGGESTS THAT HDACI EXERT ANTIPROLIFERATIVE, ANTIOXIDANT, ANTINEOPLASTIC, AND PROAPOPTOTIC EFFECTS THROUGH EPIGENETIC MECHANISMS. FURTHERMORE, HDACI ALSO EXERT ANTITHROMBOTIC AND ANTIFIBROTIC EFFECTS THROUGH REGULATION OF THROMBOTIC AND FIBROTIC TRANSDUCTION MECHANISMS. ONE OF THE OLDEST HDACI IS VALPROIC ACID, WHICH WAS FIRST SYNTHESISED IN 1882. AFTER THE DISCOVERY OF ITS ANTICONVULSANT PROPERTIES FOR THE TREATMENT OF EPILEPSY, THE USE OF VALPROIC ACID WAS EXTENDED TO OTHER CONDITIONS, SUCH AS BIPOLAR DISORDER AND MIGRAINE. GIVEN THE ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF HDACI IN THE TREATMENT OF MULTIPLE MEDICAL CONDITIONS BEYOND EPILEPSY, THE INTEREST IN NOVEL POTENTIAL INDICATIONS FOR HDACI HAS BEEN RENEWED. CONSIDERING THE PLEOTROPIC EPIGENETIC EFFECTS OF HDACI, FUTURE STUDIES COULD ASSESS THEIR EFFICACY AND SAFETY FOR CARDIOVASCULAR DISEASE PREVENTION AND TREATMENT; TREATMENT OF VENOUS THROMBOSIS, ALZHEIMER'S DISEASE, AUTOIMMUNE AND PROINFLAMMATORY CONDITIONS, CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION, AND PULMONARY ARTERIAL HYPERTENSION; AND AS A COADJUVANT THERAPY FOR CANCER. ADEQUATELY DESIGNED AND POWERED CLINICAL TRIALS ARE REQUIRED TO ASSESS THE EFFICACY AND SAFETY OF HDACI BEFORE THEIR CLINICAL REPURPOSING. 2021 7 4211 28 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 8 4582 20 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 9 2732 25 EXPLORING THE EPIGENETIC REGULATED MODULATION OF FIBROBLAST GROWTH FACTOR 21 INVOLVEMENT IN HIGH-FAT DIET ASSOCIATED PARKINSON'S DISEASE IN RATS. IMBALANCE IN BRAIN GLUCOSE METABOLISM AND EPIGENETIC MODULATION DURING THE DISEASE COURSE OF INSULIN RESISTANCE (IR) ASSOCIATED WITH PARKINSON'S DISEASE (PD) RISK REMAINS A PRIME CONCERN. FIBROBLAST GROWTH FACTOR 21 (FGF21), THE METABOLIC HORMONE, IMPROVES INSULIN SENSITIVITY AND ELICITS ANTI-DIABETIC PROPERTIES. CHRONIC STRESS DURING BRAIN IR MAY MODULATE THE FGF21 EXPRESSION AND ITS DYNAMIC RELEASE VIA EPIGENETIC MODIFICATIONS. METFORMIN REGULATES AND INCREASES THE EXPRESSION OF FGF21 WHICH CAN BE MODULATING IN OBESITY, DIABETES, AND IR. HENCE, THIS STUDY WAS DESIGNED TO INVESTIGATE THE FGF21 EXPRESSION MODULATION VIA AN EPIGENETIC MECHANISM IN PD AND WHETHER METFORMIN (MF), AN AUTOPHAGY ACTIVATOR, AND SODIUM BUTYRATE (NAB), A PAN HISTONE DEACETYLASE INHIBITOR, ALONE AND IN COMBINATION, EXERT ANY THERAPEUTIC BENEFIT IN PD PATHOLOGY EXACERBATED BY HIGH-FAT DIET (HFD). OUR RESULTS PORTRAY THAT THE COMBINATION TREATMENT WITH MF AND NAB POTENTIALLY ATTENUATED THE ABNORMAL LIPID PROFILE AND INCREASED MOTOR PERFORMANCE FOR THE RATS FED WITH HFD FOR 8 WEEKS FOLLOWED BY INTRASTRIATAL 6-HYDROXY DOPAMINE ADMINISTRATION. THE ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) ESTIMATIONS OF C-REACTIVE PROTEIN, TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN-1 BETA AND 6, AND FGF21 EXHIBITED EXTENSIVE DOWNREGULATION AFTER TREATMENT WITH THE COMBINATION. LASTLY, MRNA, WESTERN BLOT, HISTOLOGICAL, AND CRESYL VIOLET STAINING DEPICTED THAT THE COMBINATION TREATMENT CAN RESTORE DEGENERATED NEURONAL DENSITY AND INCREASE THE PROTEIN LEVEL COMPARED TO THE DISEASE GROUP. THE FINDINGS FROM THE STUDY EFFECTIVELY CONCLUDE THAT THE EPIGENETIC MECHANISM INVOLVED IN FGF21 MEDIATED FUNCTIONAL ABNORMALITIES IN IR-LINKED PD PATHOLOGY. HENCE, COMBINED TREATMENT WITH MF AND NAB MAY PROVE TO BE A NOVEL COMBINATION IN AMELIORATING IR-ASSOCIATED PD IN RATS, PROBABLY VIA THE UPREGULATION OF FGF21 EXPRESSION. 2023 10 6166 23 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 11 3601 32 IMPORTANCE OF PROBIOTICS IN THE PREVENTION AND TREATMENT OF COLORECTAL CANCER. COLORECTAL CANCER (CRC) REMAINS ONE OF THE MOST COMMON AND DEADLY CANCERS. INTESTINAL GUT MICROFLORA IS IMPORTANT TO MAINTAIN AND CONTRIBUTES TO SEVERAL INTESTINAL FUNCTIONS, INCLUDING THE DEVELOPMENT OF THE MUCOSAL IMMUNE SYSTEM, ABSORPTION OF COMPLEX MACROMOLECULES, SYNTHESIS OF AMINO ACIDS/VITAMINS AND THE PROTECTION AGAINST PATHOGENIC MICROORGANISMS. IT IS WELL KNOWN THAT THE GUT MICROBIOTA CHANGES OR DYSBIOSIS MAY HAVE AN ESSENTIAL IMPACT IN THE INITIATION AND PROMOTION OF CHRONIC INFLAMMATORY PATHWAYS AND ALSO HAVE A PROFOUND DIFFERENT GENETIC AND EPIGENETIC ALTERATIONS LEADING TO DYSPLASIA, CLONAL EXPANSION, AND MALIGNANT TRANSFORMATION. PROBIOTIC BACTERIA HAS ANTITUMOR ACTIVITY WITH VARIOUS MECHANISMS SUCH AS NONSPECIFIC PHYSIOLOGICAL AND IMMUNOLOGICAL MECHANISMS. THIS REVIEW EVALUATES THE EFFECTS OF MICROBIOTA AND PROBIOTICS IN CLINICAL TRIALS, IN VITRO AND ANIMAL MODEL STUDIES THAT HAVE EXPLORED HOW PROBIOTIC AGAINST CANCER DEVELOPMENT AND ALSO DISCUSSES THE POSSIBLE IMMUNOMODULATORY MECHANISMS. SEVERAL MECHANISMS ALTERATION OF THE INTESTINAL MICROFLORA; INACTIVATION OF CANCEROGENIC COMPOUNDS; COMPETITION WITH PUTREFACTIVE AND PATHOGENIC MICROBIOTA; IMPROVEMENT OF THE HOST'S IMMUNE RESPONSE; ANTIPROLIFERATIVE EFFECTS VIA REGULATION OF APOPTOSIS AND CELL DIFFERENTIATION; FERMENTATION OF UNDIGESTED FOOD; INHIBITION OF TYROSINE KINASE; REDUCES THE ENTEROPATHOGENIC COMPLICATIONS BEFORE AND AFTER COLON CANCER SURGERY AND IMPROVE DIARRHEA AND IT'S HAVE BEEN ABLE TO CREATE THE INTEGRITY OF GUT MUCOSAL AND HAVE STIMULATORY EFFECTS ON THE SYSTEMIC IMMUNE SYSTEM AND PREVENT THE CRC METASTASIS. RESEARCH IN CLINICAL TRIALS ENCOURAGING FINDINGS THAT SUPPORT A ROLE OF PROBIOTICS IN CRC PREVENTION AND IMPROVE THE SAFETY AND EFFECTIVENESS OF CANCER THERAPY EVEN THOUGH ADDITIONAL CLINICAL RESEARCH IS STILL NECESSARY. 2019 12 4891 23 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 13 5296 20 PROTECTIVE ROLE OF SODIUM BUTYRATE, A HDAC INHIBITOR ON BETA-CELL PROLIFERATION, FUNCTION AND GLUCOSE HOMEOSTASIS THROUGH MODULATION OF P38/ERK MAPK AND APOPTOTIC PATHWAYS: STUDY IN JUVENILE DIABETIC RAT. TYPE 1 DIABETES (T1D) ALSO KNOWN AS JUVENILE DIABETES IS A CHRONIC AUTOIMMUNE DISORDER THAT PRECIPITATES IN GENETICALLY SUSCEPTIBLE INDIVIDUALS BY ENVIRONMENTAL FACTORS PARTICULARLY DURING EARLY AGE. BOTH GENETIC AND EPIGENETIC FACTORS ARE IMPLICATED IN THE BETA-CELL DEVELOPMENT, PROLIFERATION, DIFFERENTIATION AND FUNCTION. RECENT EVIDENCES SUGGESTED THAT THERE IS A LINK BETWEEN DIABETES AND HISTONE DEACETYLASES (HDACS), BECAUSE HDAC INHIBITORS PROMOTE BETA-CELL DEVELOPMENT, PROLIFERATION AND FUNCTION AS WELL AS IMPROVE GLUCOSE HOMEOSTASIS. SODIUM BUTYRATE (NAB) IS A SHORT CHAIN FATTY ACID HAVING HDAC INHIBITION ACTIVITY. THE PRESENT STUDY WAS AIMED TO INVESTIGATE THE PROTECTIVE ROLE OF NAB TREATMENT ON THE BETA-CELL PROLIFERATION, FUNCTION AND GLUCOSE HOMEOSTASIS AS WELL AS APOPTOSIS IN JUVENILE DIABETIC RAT. DIABETES WAS INDUCED BY SINGLE INJECTION OF STZ (60 MG/KG, I.P.) IN CHILLED CITRATE BUFFER, WHILE NAB (500 MG/KG/DAY) WAS ADMINISTRATED BY I.P. ROUTE FOR 21 DAYS AS PRE- AND POST-TREATMENT SCHEDULE. PLASMA GLUCOSE AND INSULIN LEVELS, HBA1C, GLUCOSE TOLERANCE, APOPTOSIS, AND EXPRESSION OF PROLIFERATING CELL NUCLEAR ANTIGEN (PCNA), P38, P53, CASPASE-3, EXTRACELLULAR SIGNAL-REGULATED KINASE-1/2 (ERK-1/2), FORKHEAD BOX PROTEIN O1 (FOXO1) AND INSULIN RECEPTOR SUBSTRATE-1 (IRS-1) AS WELL AS HISTONE ACETYLATION WERE EVALUATED. NAB TREATMENT DECREASED PLASMA GLUCOSE, HBA1C, BETA-CELL APOPTOSIS AND IMPROVED PLASMA INSULIN LEVEL AND GLUCOSE HOMEOSTASIS THROUGH HDAC INHIBITION AND HISTONE ACETYLATION IN DIABETIC ANIMAL AS COMPARED TO CONTROL. NAB TREATMENT IMPROVED THE BETA-CELL PROLIFERATION, FUNCTION AND GLUCOSE HOMEOSTASIS AS WELL AS REDUCED BETA-CELL APOPTOSIS IN JUVENILE DIABETIC RAT BY THE MODULATION OF P38/ERK MAPK AND APOPTOTIC PATHWAY. 2014 14 898 24 CHRONIC EXPOSURE OF MICE TO BISPHENOL-A ALTERS UTERINE FIBROBLAST GROWTH FACTOR SIGNALING AND LEADS TO ABERRANT EPITHELIAL PROLIFERATION. UTERINE EPITHELIAL PROLIFERATION IS REGULATED IN A PARACRINE MANNER BY A COMPLEX INTERPLAY BETWEEN ESTROGEN (E) AND PROGESTERONE (P) SIGNALING, IN WHICH E STIMULATES PROLIFERATION AND P INHIBITS IT. PERTURBATION OF STEROID HORMONE SIGNALING WITHIN THE UTERINE MILIEU COULD CONTRIBUTE TO THE DEVELOPMENT OF ENDOMETRIAL HYPERPLASIA AND CANCER. IT IS WELL ESTABLISHED THAT BISPHENOL-A (BPA) IS AN ENDOCRINE-DISRUPTING CHEMICAL WITH WEAK ESTROGENIC EFFECTS, ALTHOUGH LITTLE IS KNOWN ABOUT HOW IT AFFECTS STEROID HORMONE SIGNALING IN THE ADULT UTERUS. BECAUSE BPA ACTS AS A WEAK E, WE HYPOTHESIZED THAT CHRONIC EXPOSURE TO BPA WOULD CREATE AN IMBALANCE BETWEEN E AND P SIGNALING AND CAUSE CHANGES IN THE UTERUS, SUCH AS ABERRANT EPITHELIAL PROLIFERATION. INDEED, EXPOSURE TO AN ENVIRONMENTALLY RELEVANT DOSE OF BPA HAD A UTEROTROPHIC AFFECT. BPA-TREATED MICE SHOWED INCREASED PROLIFERATION, NOTABLY IN THE GLANDULAR EPITHELIUM, WHICH ARE SITES OF ORIGIN FOR ENDOMETRIAL HYPERPLASIA AND CANCER. INCREASED PROLIFERATION APPEARED TO BE MEDIATED THROUGH A SIMILAR MECHANISM AS E-INDUCED PROLIFERATION, VIA ACTIVATION OF THE FIBROBLAST GROWTH FACTOR RECEPTOR PATHWAY AND PHOSPHORYLATION OF THE ERK1/2 MITOGEN-ACTIVATED PROTEIN KINASES IN THE EPITHELIUM. INTERESTINGLY, BPA REDUCED EXPRESSION OF HEART AND NEURAL CREST DERIVATIVES EXPRESSED 2 (HAND2), A KNOWN MEDIATOR OF THE ANTIPROLIFERATIVE EFFECTS OF P. BPA ALSO INCREASED METHYLATION OF A CPG ISLAND IN THE HAND2 GENE PROMOTER, SUGGESTING THAT BPA MAY PROMOTE EPITHELIAL PROLIFERATION THROUGH EPIGENETIC SILENCING OF ANTIPROLIFERATIVE FACTORS LIKE HAND2. COLLECTIVELY, THESE FINDINGS ESTABLISH THAT CHRONIC EXPOSURE TO BPA IMPAIRS STEROID HORMONE SIGNALING IN THE MOUSE UTERUS, AND MAY CONTRIBUTE TO THE PATHOGENESIS OF UTERINE HYPERPLASIA AND CANCER. 2019 15 3688 25 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 16 799 20 CELLULAR SIGNALING AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. DYSFUNCTION AND DEATH OF MICROVASCULAR CELLS AND IMBALANCE BETWEEN THE PRODUCTION AND THE DEGRADATION OF EXTRACELLULAR MATRIX (ECM) PROTEINS ARE A CHARACTERISTIC FEATURE OF DIABETIC RETINOPATHY (DR). GLUCOSE-INDUCED BIOCHEMICAL ALTERATIONS IN THE VASCULAR ENDOTHELIAL CELLS MAY ACTIVATE A CASCADE OF SIGNALING PATHWAYS LEADING TO INCREASED PRODUCTION OF ECM PROTEINS AND CELLULAR DYSFUNCTION/DEATH. CHRONIC DIABETES LEADS TO THE ACTIVATION OF A NUMBER OF SIGNALING PROTEINS INCLUDING PROTEIN KINASE C, PROTEIN KINASE B, AND MITOGEN-ACTIVATED PROTEIN KINASES. THESE SIGNALING CASCADES ARE ACTIVATED IN RESPONSE TO HYPERGLYCEMIA-INDUCED OXIDATIVE STRESS, POLYOL PATHWAY, AND ADVANCED GLYCATION END PRODUCT FORMATION AMONG OTHERS. THE ABERRANT SIGNALING PATHWAYS ULTIMATELY LEAD TO ACTIVATION OF TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR-KAPPAB AND ACTIVATING PROTEIN-1. THE ACTIVITY OF THESE TRANSCRIPTION FACTORS IS ALSO REGULATED BY EPIGENETIC MECHANISMS THROUGH TRANSCRIPTIONAL COACTIVATOR P300. THESE COMPLEX SIGNALING PATHWAYS MAY BE INVOLVED IN GLUCOSE-INDUCED ALTERATIONS OF ENDOTHELIAL CELL PHENOTYPE LEADING TO THE PRODUCTION OF INCREASED ECM PROTEINS AND VASOACTIVE EFFECTOR MOLECULES CAUSING FUNCTIONAL AND STRUCTURAL CHANGES IN THE MICROVASCULATURE. UNDERSTANDING OF SUCH MECHANISTIC PATHWAYS WILL HELP TO DEVELOP FUTURE ADJUVANT THERAPIES FOR DIABETIC RETINOPATHY. 2007 17 6796 24 [ENDOMETRIOSIS: A NEW APPROACH TO ETIOLOGY AND PATHOGENESIS (REVIEW)]. ENDOMETRIOSIS IS A DYSHORMONAL IMMUNE-DEPENDENT GENETICALLY DETERMINED DISEASE, WHICH APPEARS AS AN ENDOMETRIOID TISSUE THAT GROWS OUTSIDE THE UTERINE. ENDOMETRIOSIS IS ONE OF THE MOST URGENT PROBLEMS OF MEDICINE. TO DATE, NEW CONCEPTS OF THE ENDOMETRIOSIS ETIOLOGY AND PATHOGENESIS HAVE BEEN DEVELOPED, BUT, DESPITE THEIR ABUNDANCE, THERE IS NO UNIFIED THEORY. GENETIC AND EPIGENETIC FACTORS RESULT IN CHANGES IN AN EXPRESSION OF AROMATASE, STEROIDOGENIC FACTOR 1, AND ESTROGEN RECEPTORS ARE SUGGESTED TO BE THE MAIN CAUSE OF ENDOMETRIOSIS. THESE CHANGES LEAD TO AN ACTIVE SYNTHESIS OF VARIOUS PRO-INFLAMMATORY AGENTS AND A NERVE GROWTH FACTOR, THAT ARE IMPORTANT IN THE DEVELOPMENT OF PAIN SYNDROME. ALSO, CHANGES IN THE PROGESTERONE RECEPTOR FUNCTIONING AND THE LOCAL PROGESTERONE RESISTANCE DEVELOPMENT DECREASE THE ANTIPROLIFERATIVE ACTIVITY, APOPTOSIS, AND THE ANTI-INFLAMMATORY SUBSTANCES LEVEL, AS WELL AS INCREASE THE PROSTAGLANDIN, METALLOPROTEINASE ACTIVITY, AND LEVEL OF HYPOXIA FACTORS. IN ADDITION, THERE ARE SHREDS OF EVIDENCE THAT ENDOMETRIOSIS IS ASSOCIATED WITH THE RISK OF MALIGNANT TUMORS DEVELOPMENT, SO NEW CONCEPTS FOR UNDERSTANDING THESE MECHANISMS ARE ACTIVELY DEVELOPING. SOME OF THESE MECHANISMS ARE DISCUSSED IN THIS REVIEW. 2017 18 616 27 BIOACTIVE COMPOUNDS IN OXIDATIVE STRESS-MEDIATED DISEASES: TARGETING THE NRF2/ARE SIGNALING PATHWAY AND EPIGENETIC REGULATION. OXIDATIVE STRESS IS A PATHOLOGICAL CONDITION OCCURRING DUE TO AN IMBALANCE BETWEEN THE OXIDANTS AND ANTIOXIDANT DEFENSE SYSTEMS IN THE BODY. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2), ENCODED BY THE GENE NFE2L2, IS THE MASTER REGULATOR OF PHASE II ANTIOXIDANT ENZYMES THAT PROTECT AGAINST OXIDATIVE STRESS AND INFLAMMATION. NRF2/ARE SIGNALING HAS BEEN CONSIDERED AS A PROMISING TARGET AGAINST OXIDATIVE STRESS-MEDIATED DISEASES LIKE DIABETES, FIBROSIS, NEUROTOXICITY, AND CANCER. THE CONSUMPTION OF DIETARY PHYTOCHEMICALS ACTS AS AN EFFECTIVE MODULATOR OF NRF2/ARE IN VARIOUS ACUTE AND CHRONIC DISEASES. IN THE PRESENT REVIEW, WE DISCUSSED THE ROLE OF NRF2 IN DIABETES, ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), CANCER, AND ATHEROSCLEROSIS. ADDITIONALLY, WE DISCUSSED THE PHYTOCHEMICALS LIKE CURCUMIN, QUERCETIN, RESVERATROL, EPIGALLOCATECHIN GALLATE, APIGENIN, SULFORAPHANE, AND URSOLIC ACID THAT HAVE EFFECTIVELY MODIFIED NRF2 SIGNALING AND PREVENTED VARIOUS DISEASES IN BOTH IN VITRO AND IN VIVO MODELS. BASED ON THE LITERATURE, IT IS CLEAR THAT DIETARY PHYTOCHEMICALS CAN PREVENT DISEASES BY (1) BLOCKING OXIDATIVE STRESS-INHIBITING INFLAMMATORY MEDIATORS THROUGH INHIBITING KEAP1 OR ACTIVATING NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS IN THE NUCLEUS, INCLUDING HO-1, SOD, AND CAT; (2) REGULATING NRF2 SIGNALING BY VARIOUS KINASES LIKE GSK3BETA, PI3/AKT, AND MAPK; AND (3) MODIFYING EPIGENETIC MODULATION, SUCH AS METHYLATION, AT THE NRF2 PROMOTER REGION; HOWEVER, FURTHER INVESTIGATION INTO OTHER UPSTREAM SIGNALING MOLECULES LIKE NRF2 AND THE EFFECT OF PHYTOCHEMICALS ON THEM STILL NEED TO BE INVESTIGATED IN THE NEAR FUTURE. 2021 19 6022 23 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 20 5993 22 TGFBETA PROMOTES FIBROSIS BY MYST1-DEPENDENT EPIGENETIC REGULATION OF AUTOPHAGY. ACTIVATION OF FIBROBLASTS IS ESSENTIAL FOR PHYSIOLOGICAL TISSUE REPAIR. UNCONTROLLED ACTIVATION OF FIBROBLASTS, HOWEVER, MAY LEAD TO TISSUE FIBROSIS WITH ORGAN DYSFUNCTION. ALTHOUGH SEVERAL PATHWAYS CAPABLE OF PROMOTING FIBROBLAST ACTIVATION AND TISSUE REPAIR HAVE BEEN IDENTIFIED, THEIR INTERPLAY IN THE CONTEXT OF CHRONIC FIBROTIC DISEASES REMAINS INCOMPLETELY UNDERSTOOD. HERE, WE PROVIDE EVIDENCE THAT TRANSFORMING GROWTH FACTOR-BETA (TGFBETA) ACTIVATES AUTOPHAGY BY AN EPIGENETIC MECHANISM TO AMPLIFY ITS PROFIBROTIC EFFECTS. TGFBETA INDUCES AUTOPHAGY IN FIBROTIC DISEASES BY SMAD3-DEPENDENT DOWNREGULATION OF THE H4K16 HISTONE ACETYLTRANSFERASE MYST1, WHICH REGULATES THE EXPRESSION OF CORE COMPONENTS OF THE AUTOPHAGY MACHINERY SUCH AS ATG7 AND BECLIN1. ACTIVATION OF AUTOPHAGY IN FIBROBLASTS PROMOTES COLLAGEN RELEASE AND IS BOTH, SUFFICIENT AND REQUIRED, TO INDUCE TISSUE FIBROSIS. FORCED EXPRESSION OF MYST1 ABROGATES THE STIMULATORY EFFECTS OF TGFBETA ON AUTOPHAGY AND RE-ESTABLISHES THE EPIGENETIC CONTROL OF AUTOPHAGY IN FIBROTIC CONDITIONS. INTERFERENCE WITH THE ABERRANT ACTIVATION OF AUTOPHAGY INHIBITS TGFBETA-INDUCED FIBROBLAST ACTIVATION AND AMELIORATES EXPERIMENTAL DERMAL AND PULMONARY FIBROSIS. THESE FINDINGS LINK UNCONTROLLED TGFBETA SIGNALING TO ABERRANT AUTOPHAGY AND DEREGULATED EPIGENETICS IN FIBROTIC DISEASES AND MAY CONTRIBUTE TO THE DEVELOPMENT OF THERAPEUTIC INTERVENTIONS IN FIBROTIC DISEASES. 2021