1 3164 140 GREEN TEA PREVENTS NAFLD BY MODULATION OF MIR-34A AND MIR-194 EXPRESSION IN A HIGH-FAT DIET MOUSE MODEL. BACKGROUND/AIMS: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS CONSIDERED THE HEPATIC MANIFESTATION OF METABOLIC SYNDROME. IT IS CURRENTLY THE MOST COMMON CHRONIC LIVER DISEASE WITH COMPLEX PATHOGENESIS AND CHALLENGING TREATMENT. HERE, WE INVESTIGATED THE HEPATOPROTECTIVE ROLE OF GREEN TEA (GT) AND DETERMINED THE INVOLVEMENT OF MIRNAS AND ITS MECHANISM OF ACTION. METHODS: MALE C57BL/6 MICE WERE FED WITH A HIGH-FAT DIET FOR 4 WEEKS. AFTER THIS PERIOD, THE ANIMALS RECEIVED GAVAGE WITH GT (500 MG/KG BODY WEIGHT) OVER 12 WEEKS (5 DAYS/WEEK). HEPG2 CELL LINES WERE TRANSFECTED WITH MIR-34A OR MIR-194 MIMETICS AND INHIBITORS TO VALIDATE THE IN VIVO RESULTS OR WERE TREATED WITH TNF-ALPHA TO EVALUATE MIRNA REGULATION. RESULTS: GT SUPPLEMENTATION PROTECTS AGAINST NAFLD DEVELOPMENT BY ALTERING LIPID METABOLISM, INCREASING GENE EXPRESSION INVOLVED IN TRIGLYCERIDES AND FATTY ACID CATABOLISM, AND DECREASING UPTAKE AND LIPID ACCUMULATION. THIS PHENOTYPE WAS ACCOMPANIED BY MIR-34A DOWNREGULATION AND AN INCREASE IN THEIR MRNA TARGETS SIRT1, PPARALPHA, AND INSIG2. GT UPREGULATED HEPATIC MIR-194 BY INHIBITING TNF-ALPHA ACTION LEADING TO A DECREASE IN MIR-194 TARGET GENES HMGCS/APOA5. CONCLUSION: OUR STUDY IDENTIFIED FOR THE FIRST TIME THAT THE BENEFICIAL EFFECTS OF GT IN THE LIVER CAN BE DUE TO THE MODULATION OF MIRNAS, OPENING NEW PERSPECTIVES FOR THE TREATMENT OF NAFLD FOCUSING ON EPIGENETIC REGULATION OF MIR-34A AND MIR-194 AS GREEN TEA TARGETS. 2019 2 4649 36 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 3 4526 32 MULTIFUNCTIONAL TARGETS OF DIETARY POLYPHENOLS IN DISEASE: A CASE FOR THE CHEMOKINE NETWORK AND ENERGY METABOLISM. CHRONIC, NON-ACUTE INFLAMMATION IS BEHIND CONDITIONS THAT REPRESENT MOST OF THE DISEASE BURDEN IN HUMANS AND IS CLEARLY LINKED TO IMMUNE AND METABOLIC MECHANISMS. THE CONVERGENCE OF PATHWAYS INVOLVING THE IMMUNE RESPONSE, OXIDATIVE STRESS, INCREASED CIRCULATING LIPIDS AND ABERRANT INSULIN SIGNALING RESULTS IN CCL2-ASSOCIATED MACROPHAGE RECRUITMENT AND ALTERED ENERGY METABOLISM. THE CCL2/CCR2 PATHWAY AND THE ENERGY SENSOR AMP-ACTIVATED PROTEIN KINASE (AMPK) ARE ATTRACTIVE THERAPEUTIC TARGETS AS A PART OF PREVENTIVE MANAGEMENT OF DISEASE. SEVERAL EFFECTS OF POLYPHENOLS ARE USEFUL IN THIS SCENARIO, INCLUDING A REDUCTION IN THE ACTIVITIES OF CYTOKINES AND MODULATION OF CELLULAR METABOLISM THROUGH HISTONE DEACETYLASE INHIBITORS, AMPK ACTIVATORS, CALORIE-RESTRICTION MIMETICS OR EPIGENETIC REGULATORS. RESEARCH IS CURRENTLY UNDERWAY TO DEVELOP ORALLY ACTIVE DRUGS WITH THESE EFFECTS, BUT IT IS CONVENIENT TO EXAMINE MORE CLOSELY WHAT WE ARE EATING. IF A LACK OF RELEVANCE IN TERMS OF TOXICITY AND SUBSTANTIAL EFFECTIVENESS ARE CONFIRMED, PLANT-DERIVED COMPONENTS MAY PROVIDE USEFUL DRUGGABLE COMPONENTS AND DIETARY SUPPLEMENTS. WE CONSIDER THERAPEUTIC ACTIONS AS A COMBINATION OF SYNERGISTIC AND/OR ANTAGONISTIC INTERACTIONS IN A MULTI-TARGET STRATEGY. HENCE, IMPROVEMENT IN FOOD THROUGH ENRICHMENT WITH POLYPHENOLS WITH DEMONSTRATED ACTIVITY MAY REPRESENT A MAJOR ADVANCE IN THE DESIGN OF DIETS WITH BOTH INDUSTRIAL AND SANITARY VALUE. 2013 4 1394 32 DIET AND AGING. NUTRITION HAS IMPORTANT LONG-TERM CONSEQUENCES FOR HEALTH THAT ARE NOT ONLY LIMITED TO THE INDIVIDUAL BUT CAN BE PASSED ON TO THE NEXT GENERATION. IT CAN CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF CHRONIC DISEASES THUS EFFECTING LIFE SPAN. CALORIC RESTRICTION (CR) CAN EXTEND THE AVERAGE AND MAXIMUM LIFE SPAN AND DELAY THE ONSET OF AGE-ASSOCIATED CHANGES IN MANY ORGANISMS. CR ELICITS COORDINATED AND ADAPTIVE STRESS RESPONSES AT THE CELLULAR AND WHOLE-ORGANISM LEVEL BY MODULATING EPIGENETIC MECHANISMS (E.G., DNA METHYLATION, POSTTRANSLATIONAL HISTONE MODIFICATIONS), SIGNALING PATHWAYS THAT REGULATE CELL GROWTH AND AGING (E.G., TOR, AMPK, P53, AND FOXO), AND CELL-TO-CELL SIGNALING MOLECULES (E.G., ADIPONECTIN). THE OVERALL EFFECT OF THESE ADAPTIVE STRESS RESPONSES IS AN INCREASED RESISTANCE TO SUBSEQUENT STRESS, THUS DELAYING AGE-RELATED CHANGES AND PROMOTING LONGEVITY. IN HUMAN, CR COULD DELAY MANY DISEASES ASSOCIATED WITH AGING INCLUDING CANCER, DIABETES, ATHEROSCLEROSIS, CARDIOVASCULAR DISEASE, AND NEURODEGENERATIVE DISEASES. AS AN ALTERNATIVE TO CR, SEVERAL CR MIMETICS HAVE BEEN TESTED ON ANIMALS AND HUMANS. AT PRESENT, THE MOST PROMISING ALTERNATIVES TO THE USE OF CR IN HUMANS SEEM TO BE EXERCISE, ALONE OR IN COMBINATION WITH REDUCED CALORIE INTAKE, AND THE USE OF PLANT-DERIVED POLYPHENOL RESVERATROL AS A FOOD SUPPLEMENT. 2012 5 5050 31 PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION ELICITS EPIGENETIC REPROGRAMMING OF DIFFERENTIATED CELLS TO STEM-LIKE SELF-RENEWAL STATES. NETWORKS OF ONCOGENES AND TUMOR SUPPRESSOR GENES THAT CONTROL CANCER CELL PROLIFERATION ALSO REGULATE STEM CELL RENEWAL AND POSSIBLY STEM CELL AGING. BECAUSE (DE)DIFFERENTIATION PROCESSES MIGHT DICTATE TUMOR CELLS TO RETROGRESS TO A MORE STEM-LIKE STATE IN RESPONSE TO AGING-RELEVANT EPIGENETIC AND/OR ENVIRONMENTAL PLAYERS, WE RECENTLY ENVISIONED THAT CULTURED HUMAN CANCER CELLS MIGHT BE USED AS RELIABLE MODELS TO TEST THE ABILITY OF ANTIAGING INTERVENTIONS FOR PROMOTING THE INITIATION AND MAINTENANCE OF SELF-RENEWING DIVISIONS. CANCER CELL LINES NATURALLY BEARING UNDETECTABLE AMOUNTS OF STEM/PROGENITOR-LIKE CELL POPULATIONS WERE CONTINUOUSLY CULTURED IN THE PRESENCE OF THE CALORIC RESTRICTION MIMETIC METFORMIN FOR SEVERAL MONTHS. MICROARRAY TECHNOLOGY WAS EMPLOYED TO PROFILE EXPRESSION OF GENES RELATED TO THE IDENTIFICATION, GROWTH, AND DIFFERENTIATION OF STEM CELLS. DETECTION OF FUNCTIONALLY RELATED GENE GROUPS USING A PATHWAY ANALYSIS PACKAGE PROVIDED ANNOTATED GENETIC SIGNATURES OVER- AND UNDEREXPRESSED IN RESPONSE TO PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION. BY FOLLOWING THIS METHODOLOGICAL APPROACH, WE RECENTLY OBTAINED DATA FITTING A MODEL IN WHICH, IN RESPONSE TO CHRONIC IMPAIRMENT OF CELLULAR BIOENERGETICS IMPOSED BY METFORMIN-INDUCED MITOCHONDRIAL UNCOUPLING AS ASSESSED BY THE PHOSPHORYLATION STATE OF CAMP-RESPONSE ELEMENT BINDING PROTEIN (CREB), TUMOR CELLS CAN RETROGRESS FROM A DIFFERENTIATED STATE TO A MORE CD44(+) STEM-LIKE PRIMITIVE STATE EPIGENETICALLY GOVERNED BY THE POLYCOMB-GROUP SUPPRESSOR BMI1-A CRUCIAL "STEMNESS" GENE INVOLVED IN THE EPIGENETIC MAINTENANCE OF ADULT STEM CELLS. THESE FINDINGS MIGHT PROVIDE A NOVEL MOLECULAR AVENUE TO INVESTIGATE IF ANTIAGING BENEFITS FROM CALORIC RESTRICTION MIMETICS MIGHT RELATE TO THEIR ABILITY TO EPIGENETICALLY REPROGRAM STEMNESS WHILE PROLONGING THE CAPACITY OF STEM-LIKE CELL STATES TO PROLIFERATE, DIFFERENTIATE, AND REPLACE MATURE CELLS IN ADULT AGING TISSUES. 2010 6 4597 22 NATURAL PRODUCTS WITH ANTI-AGING POTENTIAL: AFFECTED TARGETS AND MOLECULAR MECHANISMS. IN RECENT YEARS, THERE HAS BEEN A GREAT DEAL OF ATTENTION TOWARD THE MOLECULAR MACHINERY RELEVANT TO AGE-RELATED PROGRESSION CONTROLLED THROUGH THE EXTERNAL INTERVENTION OF POLYPHENOLS- AN EPIGENETIC-MODULATING DIET. NATURAL PRODUCTS MODULATE CELLULAR LONGEVITY THROUGH HISTONE POST-TRANSLATIONAL MODIFICATION AND CAN ALSO INDUCE THE UPREGULATION OF AUTOPHAGY, THUS REDUCING THE LEVEL OF ACETYL COENZYME A (ACCOA). IN ADDITION, THE EFFECT OF CALORIC RESTRICTION (CR) ON CANCER-RELATED CHRONIC INFLAMMATION IS OF GREAT SIGNIFICANCE IN AGING. IN LINE WITH THIS, SIRT1 PROTEIN LEVELS ARE EXPANDED IN RESPONSE TO CALORIE RESTRICTION MIMETICS (CRM), IN THIS WAY ACTING AS AUTOPHAGY INDUCERS RELEVANT TO CANCER PREVENTION. 2018 7 4860 27 OREXIN SIGNALING MEDIATES THE ANTIDEPRESSANT-LIKE EFFECT OF CALORIE RESTRICTION. DURING PERIODS OF REDUCED FOOD AVAILABILITY, ANIMALS MUST RESPOND WITH BEHAVIORAL ADAPTATIONS THAT PROMOTE SURVIVAL. DESPITE THE FACT THAT MANY PSYCHIATRIC SYNDROMES INCLUDE DISORDERED EATING PATTERNS AS A COMPONENT OF THE ILLNESS, LITTLE IS KNOWN ABOUT THE NEUROBIOLOGY UNDERLYING BEHAVIORAL CHANGES INDUCED BY SHORT-TERM CALORIE RESTRICTION. PRESENTLY, WE DEMONSTRATE THAT 10 D OF CALORIE RESTRICTION, CORRESPONDING TO A 20-25% WEIGHT LOSS, CAUSES A MARKED ANTIDEPRESSANT-LIKE RESPONSE IN TWO RODENT MODELS OF DEPRESSION AND THAT THIS RESPONSE IS DEPENDENT ON THE HYPOTHALAMIC NEUROPEPTIDE OREXIN (HYPOCRETIN). WILD-TYPE MICE, BUT NOT MICE LACKING OREXIN, SHOW LONGER LATENCY TO IMMOBILITY AND LESS TOTAL IMMOBILITY IN THE FORCED SWIM TEST AFTER CALORIE RESTRICTION. IN THE SOCIAL DEFEAT MODEL OF CHRONIC STRESS, CALORIE RESTRICTION REVERSES THE BEHAVIORAL DEFICITS SEEN IN WILD-TYPE MICE BUT NOT IN OREXIN KNOCK-OUT MICE. ADDITIONALLY, CHRONIC SOCIAL DEFEAT STRESS INDUCES A PROLONGED REDUCTION IN THE EXPRESSION OF PREPRO-OREXIN MRNA VIA EPIGENETIC MODIFICATION OF THE OREXIN GENE PROMOTER, WHEREAS CALORIE RESTRICTION ENHANCES THE ACTIVATION OF OREXIN CELLS AFTER SOCIAL DEFEAT. TOGETHER, THESE DATA INDICATE THAT OREXIN PLAYS AN ESSENTIAL ROLE IN MEDIATING REDUCED DEPRESSION-LIKE SYMPTOMS INDUCED BY CALORIE RESTRICTION. 2008 8 719 42 CALORIE RESTRICTION-REGULATED MOLECULAR PATHWAYS AND ITS IMPACT ON VARIOUS AGE GROUPS: AN OVERVIEW. CALORIE RESTRICTION (CR) IF PLANNED PROPERLY WITH REGULAR EXERCISE AT DIFFERENT AGES CAN RESULT IN HEALTHY WEIGHT LOSS. CR CAN ALSO HAVE DIFFERENT BENEFICIAL EFFECTS ON IMPROVING LIFESPAN AND DECREASING THE AGE-ASSOCIATED DISEASES BY REGULATING PHYSIOLOGICAL, BIOCHEMICAL, AND MOLECULAR MARKERS. THE DIFFERENT PATHWAYS REGULATED BY CR INCLUDE:(1) AMP-ACTIVATED PROTEIN KINASE (AMPK), WHICH INVOLVES PGC-1ALPHA, SIRT1, AND SIRT3. AMPK ALSO EFFECTS MYOCYTE ENHANCER FACTOR 2 (MEF2), PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DELTA, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA, WHICH ARE INVOLVED IN MITOCHONDRIAL BIOGENESIS AND LIPID OXIDATION; (2) FORKHEAD BOX TRANSCRIPTION FACTOR'S SIGNALING IS RELATED TO THE DNA REPAIR, LIPID METABOLISM, PROTECTION OF PROTEIN STRUCTURE, AUTOPHAGY, AND RESISTANCE TO OXIDATIVE STRESS; (3) MAMMALIAN TARGET OF RAPAMYCIN (MTOR) SIGNALING, WHICH INVOLVES KEY FACTORS, SUCH AS S6 PROTEIN KINASE-1 (S6K1), MTOR COMPLEX-1 (MTORC1), AND 4E-BINDING PROTEIN (4E-BP). UNDER CR CONDITIONS, AMPK ACTIVATION AND MTOR INHIBITION HELPS IN THE ACTIVATION OF ULK1 COMPLEX ALONG WITH THE ACETYLTRANSFERASE MEC-17, WHICH IS NECESSARY FOR AUTOPHAGY; (4) INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) PATHWAY DOWNREGULATION PROTECTS AGAINST CANCER AND SLOWS THE AGING PROCESS; (5) NUCLEAR FACTOR KAPPA B PATHWAY DOWNREGULATION DECREASES THE INFLAMMATION; AND (6) C-JUN N-TERMINAL KINASE AND P38 KINASE REGULATION AS A RESPONSE TO THE STRESS. THE ACUTE AND CHRONIC CR BOTH SHOWS ANTIDEPRESSION AND ANXIOLYTIC ACTION BY EFFECTING GHRELIN/GHS-R1A SIGNALING. CR ALSO REGULATES GSK3BETA KINASE AND PROTECTS AGAINST AGE-RELATED BRAIN ATROPHY. CR AT YOUNG AGE MAY SHOW MANY DELETERIOUS EFFECTS BY EFFECTING DIFFERENT MECHANISMS. PARENTAL CR BEFORE OR DURING CONCEPTION WILL ALSO AFFECT THE HEALTH AND DEVELOPMENT OF THE OFFSPRING BY CAUSING MANY EPIGENETIC MODIFICATIONS THAT SHOW TRANSGENERATIONAL TRANSMISSION. MATERNAL CR IS ASSOCIATED WITH INTRAUTERINE GROWTH RETARDATION EFFECTING THE OFFSPRING IN THEIR ADULTHOOD BY DEVELOPING DIFFERENT METABOLIC SYNDROMES. THE EPIGENETIC CHANGES WITH RESPONSE TO PATERNAL FOOD SUPPLY ALSO LINKED TO OFFSPRING HEALTH. CR AT MIDDLE AND OLD AGE PROVIDES A SIGNIFICANT PREVENTIVE IMPACT AGAINST THE DEVELOPMENT OF AGE-ASSOCIATED DISEASES. 2022 9 4211 36 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 10 4117 34 MECHANISMS OF AUTOPHAGIC RESPONSES TO ALTERED NUTRITIONAL STATUS. AUTOPHAGY IS A DYNAMIC PROCESS AND CRITICAL FOR CELLULAR REMODELING AND ORGANELLE QUALITY CONTROL. IN RESPONSE TO ALTERED NUTRITIONAL STATUS (E.G., FASTING AND FEEDING), AUTOPHAGIC ACTIVITY IS FINELY TUNED BY TRANSCRIPTIONAL, POSTTRANSLATIONAL, AND EPIGENETIC REGULATIONS VIA VARIOUS SIGNALING PATHWAYS, INCLUDING ENERGY SENSORS (E.G., MECHANISTIC TARGET OF RAPAMYCIN (MTOR)/ AMP-ACTIVATED PROTEIN KINASE - UNC-51 LIKE AUTOPHAGY ACTIVATING KINASE 1, MTORC1- WD REPEAT DOMAIN, PHOSPHOINOSITIDE INTERACTING 2, MTORC1- TRANSCRIPTION FACTOR EB, PERILIPIN 5- SIRTUIN 1, AND SIRTUIN 1-MEDIATED DEACETYLATION OF AUTOPHAGY PROTEINS), FASTING OR FEEDING INDUCED HORMONES (E.G., FIBROBLAST GROWTH FACTOR [FGF21]- PROTEIN KINASE A - JUMONJI DOMAIN-CONTAINING PROTEIN D3, FGF21- DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR - E3 LIGASE MIDLINE-1- TRANSCRIPTION FACTOR EB, FGF19-SHP- LYSINE-SPECIFIC DEMETHYLASE, INSULIN- INSULIN RECEPTOR SUBSTRATE - PROTEIN KINASE B - FORKHEAD BOX O, GLUCAGON- PROTEIN KINASE A - CAMP RESPONSE BINDING PROTEIN), AND LYSOSOMAL ENZYMES (E.G., CATHEPSIN B AND CATHEPSIN L). IN CONTRAST TO FASTING THAT INDUCES AUTOPHAGY AND HEALTH BENEFITS, NUTRIENT OVERSUPPLY (OVERFEEDING OR FEEDING ON HIGH ENERGY DIETS) DYSREGULATES AUTOPHAGY, WHICH HAS BEEN INCREASINGLY OBSERVED IN ANIMAL MODELS OF HUMAN CHRONIC DISEASES SUCH AS OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CARDIOVASCULAR DISEASE. STUDIES HAVE REVEALED MULTIFACETED EFFECTS OF HIGH ENERGY DIETS ON AUTOPHAGY, BEING EITHER AN INHIBITOR OR ENHANCER OF AUTOPHAGY. THE CONUNDRUM MAY ARISE FROM THE VARIATIONS IN METHODS FOR AUTOPHAGY ANALYSIS, COMPONENTS OF HIGH ENERGY DIETS AND CONTROL DIETS FOR TREATMENTS, TREATMENT DURATIONS, AND THE AGES OF GENETIC BACKGROUNDS OF LABORATORY ANIMALS. IN THIS ARTICLE, WE REVIEWED THE EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES, PRESENTING THE MOLECULAR MECHANISM OF AUTOPHAGIC RESPONSE TO ALTERED NUTRITIONAL STATUS AND DISCUSSING THE CONTRIBUTING FACTORS OF AND POSSIBLE SOLUTION TO THE CURRENT CONUNDRUM CONCERNING THE EXACT ROLE OF HIGH ENERGY DIETS IN AUTOPHAGIC REGULATION. 2022 11 6441 37 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 12 4647 46 NEUROPEPTIDE AND SMALL TRANSMITTER COEXISTENCE: FUNDAMENTAL STUDIES AND RELEVANCE TO MENTAL ILLNESS. NEUROPEPTIDES ARE AUXILIARY MESSENGER MOLECULES THAT ALWAYS CO-EXIST IN NERVE CELLS WITH ONE OR MORE SMALL MOLECULE (CLASSIC) NEUROTRANSMITTERS. NEUROPEPTIDES ACT BOTH AS TRANSMITTERS AND TROPHIC FACTORS, AND PLAY A ROLE PARTICULARLY WHEN THE NERVOUS SYSTEM IS CHALLENGED, AS BY INJURY, PAIN OR STRESS. HERE NEUROPEPTIDES AND COEXISTENCE IN MAMMALS ARE REVIEWED, BUT WITH SPECIAL FOCUS ON THE 29/30 AMINO ACID GALANIN AND ITS THREE RECEPTORS GALR1, -R2 AND -R3. IN PARTICULAR, GALANIN'S ROLE AS A CO-TRANSMITTER IN BOTH RODENT AND HUMAN NORADRENERGIC LOCUS COERULEUS (LC) NEURONS IS ADDRESSED. EXTENSIVE EXPERIMENTAL ANIMAL DATA STRONGLY SUGGEST A ROLE FOR THE GALANIN SYSTEM IN DEPRESSION-LIKE BEHAVIOR. THE TRANSLATIONAL POTENTIAL OF THESE RESULTS WAS TESTED BY STUDYING THE GALANIN SYSTEM IN POSTMORTEM HUMAN BRAINS, FIRST IN NORMAL BRAINS, AND THEN IN A COMPARISON OF FIVE REGIONS OF BRAINS OBTAINED FROM DEPRESSED PEOPLE WHO COMMITTED SUICIDE, AND FROM MATCHED CONTROLS. THE DISTRIBUTION OF GALANIN AND THE FOUR GALANIN SYSTEM TRANSCRIPTS IN THE NORMAL HUMAN BRAIN WAS DETERMINED, AND SELECTIVE AND PARALLEL CHANGES IN LEVELS OF TRANSCRIPTS AND DNA METHYLATION FOR GALANIN AND ITS THREE RECEPTORS WERE ASSESSED IN DEPRESSED PATIENTS WHO COMMITTED SUICIDE: UPREGULATION OF TRANSCRIPTS, E.G., FOR GALANIN AND GALR3 IN LC, PARALLELED BY A DECREASE IN DNA METHYLATION, SUGGESTING INVOLVEMENT OF EPIGENETIC MECHANISMS. IT IS HYPOTHESIZED THAT, WHEN EXPOSED TO SEVERE STRESS, THE NORADRENERGIC LC NEURONS FIRE IN BURSTS AND RELEASE GALANIN FROM THEIR SOMA/DENDRITES. GALANIN THEN ACTS ON SOMATO-DENDRITIC, INHIBITORY GALANIN AUTORECEPTORS, OPENING POTASSIUM CHANNELS AND INHIBITING FIRING. THE PURPOSE OF THESE AUTORECEPTORS IS TO ACT AS A 'BRAKE' TO PREVENT OVEREXCITATION, A BRAKE THAT IS ALSO PART OF RESILIENCE TO STRESS THAT PROTECTS AGAINST DEPRESSION. DEPRESSION THEN ARISES WHEN THE INHIBITION IS TOO STRONG AND LONG LASTING - A MALADAPTION, ALLOSTATIC LOAD, LEADING TO DEPLETION OF NA LEVELS IN THE FOREBRAIN. IT IS SUGGESTED THAT DISINHIBITION BY A GALANIN ANTAGONIST MAY HAVE ANTIDEPRESSANT ACTIVITY BY RESTORING FOREBRAIN NA LEVELS. A ROLE OF GALANIN IN DEPRESSION IS ALSO SUPPORTED BY A RECENT CANDIDATE GENE STUDY, SHOWING THAT VARIANTS IN GENES FOR GALANIN AND ITS THREE RECEPTORS CONFER INCREASED RISK OF DEPRESSION AND ANXIETY IN PEOPLE WHO EXPERIENCED CHILDHOOD ADVERSITY OR RECENT NEGATIVE LIFE EVENTS. IN SUMMARY, GALANIN, A NEUROPEPTIDE COEXISTING IN LC NEURONS, MAY PARTICIPATE IN THE MECHANISM UNDERLYING RESILIENCE AGAINST A SERIOUS AND COMMON DISORDER, MDD. EXISTING AND FURTHER RESULTS MAY LEAD TO AN INCREASED UNDERSTANDING OF HOW THIS ILLNESS DEVELOPS, WHICH IN TURN COULD PROVIDE A BASIS FOR ITS TREATMENT. 2018 13 2100 26 EPIGENETIC EFFECTS OF NATURAL POLYPHENOLS: A FOCUS ON SIRT1-MEDIATED MECHANISMS. POLYPHENOLS ARE A CLASS OF NATURAL COMPOUNDS WIDELY DISTRIBUTED IN FRUITS, VEGETABLES, AND PLANTS. THEY HAVE BEEN REPORTED TO POSSESS A WIDE RANGE OF ACTIVITIES IN PREVENTION AND ALLEVIATION OF VARIOUS DISEASES LIKE CANCER, NEUROINFLAMMATION, DIABETES, AND AGING. POLYPHENOLS ARE EFFECTIVE AGAINST CHRONIC DISEASES AND RECENT REPORTS INDICATED STRONG EPIGENETIC EFFECTS OF POLYPHENOLS. MOST OF THE STUDIES INVESTIGATING EPIGENETIC EFFECTS OF NATURAL POLYPHENOLS HAVE FOCUSED ON THEIR BENEFICIAL EFFECTS IN CANCER TREATMENT. HOWEVER, EPIGENETIC DEFECTS HAVE BEEN DEMONSTRATED IN MANY OTHER DISEASES AS WELL, AND APPLICATION OF POLYPHENOLS TO MODULATE THE EPIGENOME IS BECOMING AN INTERESTING FIELD OF RESEARCH. THIS REVIEW SUMMARIZES THE EFFECTS OF NATURAL POLYPHENOLS IN MODULATING EPIGENETIC-RELATED ENZYMES AS WELL AS THEIR EFFECT IN PREVENTION AND TREATMENT OF CHRONIC DISEASES WITH A FOCUS ON SIRT1 MODULATION. WE HAVE ALSO DISCUSSED THE RELATION BETWEEN THE STRUCTURE AND FUNCTION OF EPIGENETIC-MODIFYING POLYPHENOLS. 2014 14 5868 29 SUPPRESSIVE EFFECTS OF METFORMIN ON T-HELPER 1-RELATED CHEMOKINES EXPRESSION IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. PURPOSE OF THE STUDY: TYPE 1 AND TYPE 2 DIABETES MELLITUS (DM) ARE CHRONIC T-CELL-MEDIATED INFLAMMATORY DISEASES. METFORMIN IS A WIDELY USED DRUG FOR TYPE 2 DM THAT REDUCES THE NEED FOR INSULIN IN TYPE 1 DM. HOWEVER, WHETHER METFORMIN HAS AN ANTI-INFLAMMATORY EFFECT FOR TREATING DM IS UNKNOWN. WE INVESTIGATED THE ANTI-INFLAMMATORY MECHANISM OF METFORMIN IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. MATERIALS AND METHODS: THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1 WAS PRETREATED WITH METFORMIN AND STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE PRODUCTION OF T-HELPER (TH)-1-RELATED CHEMOKINES INCLUDING INTERFERON-GAMMA-INDUCED PROTEIN-10 (IP-10) AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE, AND THE PROINFLAMMATORY CHEMOKINE TUMOR NECROSIS FACTOR-ALPHA WAS MEASURED USING ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE INVESTIGATED USING WESTERN BLOT ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: METFORMIN SUPPRESSED LPS-INDUCED IP-10 AND MCP-1 PRODUCTION AS WELL AS LPS-INDUCED PHOSPHORYLATION OF C-JUN N-TERMINAL KINASE (JNK), P38, EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB). MOREOVER, METFORMIN SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 AND H4 AT THE IP-10 PROMOTER. CONCLUSIONS: METFORMIN SUPPRESSED THE PRODUCTION OF TH1-RELATED CHEMOKINES IP-10 AND MCP-1 IN THP-1 CELLS. SUPPRESSIVE EFFECTS OF METFORMIN ON IP-10 PRODUCTION MIGHT BE ATTRIBUTED AT LEAST PARTIALLY TO THE JNK, P38, ERK, AND NF-KAPPAB PATHWAYS AS WELL AS TO EPIGENETIC REGULATION THROUGH THE ACETYLATION OF HISTONES H3 AND H4. THESE RESULTS INDICATED THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF METFORMIN. 2018 15 2862 42 FRUCTOSE-MEDIATED EFFECTS ON GENE EXPRESSION AND EPIGENETIC MECHANISMS ASSOCIATED WITH NAFLD PATHOGENESIS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A CHRONIC, FREQUENTLY PROGRESSIVE CONDITION THAT DEVELOPS IN RESPONSE TO EXCESSIVE HEPATOCYTE FAT ACCUMULATION (I.E., STEATOSIS) IN THE ABSENCE OF SIGNIFICANT ALCOHOL CONSUMPTION. LIVER STEATOSIS DEVELOPS AS A RESULT OF IMBALANCED LIPID METABOLISM, DRIVEN LARGELY BY INCREASED RATES OF DE NOVO LIPOGENESIS AND HEPATIC FATTY ACID UPTAKE AND REDUCED FATTY ACID OXIDATION AND/OR DISPOSAL TO THE CIRCULATION. FRUCTOSE IS A NATURALLY OCCURRING SIMPLE SUGAR, WHICH IS MOST COMMONLY CONSUMED IN MODERN DIETS IN THE FORM OF SUCROSE, A DISACCHARIDE COMPRISED OF ONE MOLECULE OF FRUCTOSE COVALENTLY BONDED WITH ONE MOLECULE OF GLUCOSE. A NUMBER OF OBSERVATIONAL AND EXPERIMENTAL STUDIES HAVE DEMONSTRATED DETRIMENTAL EFFECTS OF DIETARY FRUCTOSE CONSUMPTION NOT ONLY ON DIVERSE METABOLIC OUTCOMES SUCH AS INSULIN RESISTANCE AND OBESITY, BUT ALSO ON HEPATIC STEATOSIS AND NAFLD-RELATED FIBROSIS. DESPITE THE COMPELLING EVIDENCE THAT EXCESSIVE FRUCTOSE CONSUMPTION IS ASSOCIATED WITH THE PRESENCE OF NAFLD AND MAY EVEN PROMOTE THE DEVELOPMENT AND PROGRESSION OF NAFLD TO MORE CLINICALLY SEVERE PHENOTYPES, THE MOLECULAR MECHANISMS BY WHICH FRUCTOSE ELICITS EFFECTS ON DYSREGULATED LIVER METABOLISM REMAIN UNCLEAR. EMERGING DATA SUGGEST THAT DIETARY FRUCTOSE MAY DIRECTLY ALTER THE EXPRESSION OF GENES INVOLVED IN LIPID METABOLISM, INCLUDING THOSE THAT INCREASE HEPATIC FAT ACCUMULATION OR REDUCE HEPATIC FAT REMOVAL. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE CURRENT RESEARCH SUPPORTING A ROLE FOR DIETARY FRUCTOSE INTAKE IN THE MODULATION OF TRANSCRIPTOMIC AND EPIGENETIC MECHANISMS UNDERLYING THE PATHOGENESIS OF NAFLD. 2020 16 5074 38 PHYSIOLOGIC AND EPIGENETIC EFFECTS OF NUTRIENTS ON DISEASE PATHWAYS. BACKGROUND/OBJECTIVES: EPIGENETIC REGULATION BY NUTRIENTS CAN INFLUENCE THE DEVELOPMENT OF SPECIFIC DISEASES. THIS STUDY SOUGHT TO EXAMINE THE EFFECT OF INDIVIDUAL NUTRIENTS AND NUTRIENT FAMILIES IN THE CONTEXT OF PREVENTING CHRONIC METABOLIC DISEASES VIA EPIGENETIC REGULATION. THE INHIBITION OF LIPID ACCUMULATION AND INFLAMMATION BY NUTRIENTS INCLUDING PROTEINS, LIPIDS, VITAMINS, AND MINERALS WERE OBSERVED, AND HISTONE ACETYLATION BY HISTONE ACETYLTRANSFERASE (HAT) WAS MEASURED. CORRELATIVE ANALYSES WERE ALSO PERFORMED. MATERIALS/METHODS: NUTRIENTS WERE SELECTED ACCORDING TO INFORMATION FROM THE KOREAN MINISTRY OF FOOD AND DRUG SAFETY. SELECTED NUTRIENT FUNCTIONALITIES, INCLUDING THE ATTENUATION OF FATTY ACID-INDUCED LIPID ACCUMULATION AND LIPOPOLYSACCHARIDE-MEDIATED ACUTE INFLAMMATION WERE EVALUATED IN MOUSE MACROPHAGE RAW264.7 AND MOUSE HEPATOCYTE AML-12 CELLS. EFFECTS OF THE SELECTED NUTRIENTS ON IN VITRO HAT INHIBITION WERE ALSO EVALUATED. RESULTS: NITRIC OXIDE (NO) PRODUCTION CORRELATED WITH HAT ACTIVITY, WHICH WAS REGULATED BY THE AMINO ACIDS GROUP, SUGGESTING THAT AMINO ACIDS POTENTIALLY CONTRIBUTE TO THE ATTENUATION OF NO PRODUCTION VIA THE INHIBITION OF HAT ACTIVITY. UNSATURATED FATTY ACIDS TENDED TO ATTENUATE INFLAMMATION BY INHIBITING NO PRODUCTION, WHICH MAY BE ATTRIBUTABLE TO THE INHIBITION OF IN VITRO HAT ACTIVITY. IN CONTRAST TO WATER-SOLUBLE VITAMINS, THE LIPID-SOLUBLE VITAMINS SIGNIFICANTLY DECREASED NO PRODUCTION. WATER- AND LIPID-SOLUBLE VITAMINS BOTH EXHIBITED SIGNIFICANT INHIBITORY ACTIVITIES AGAINST HAT. IN ADDITION, CALCIUM AND MANGANESE SIGNIFICANTLY INHIBITED LIPID ACCUMULATION, NO PRODUCTION, AND HAT ACTIVITY. CONCLUSIONS: SEVERAL CANDIDATE NUTRIENTS AND THEIR FAMILY MEMBERS MAY HAVE ROLES IN THE PREVENTION OF DISEASES, INCLUDING HEPATIC STEATOSIS AND INFLAMMATION-RELATED DISEASES (I.E., NONALCOHOLIC STEATOHEPATITIS) VIA EPIGENETIC REGULATION. FURTHER STUDIES ARE WARRANTED TO DETERMINE WHICH SPECIFIC AMINO ACIDS, UNSATURATED FATTY ACIDS AND LIPID-SOLUBLE VITAMINS OR SPECIFIC MINERALS INFLUENCE THE DEVELOPMENT OF STEATOSIS AND INFLAMMATORY-RELATED DISEASES. 2023 17 617 34 BIOACTIVE FOOD COMPOUNDS, EPIGENETICS AND CHRONIC DISEASE PREVENTION: FOCUS ON EARLY-LIFE INTERVENTIONS WITH POLYPHENOLS. CONSUMPTION OF BIOACTIVE COMPOUNDS SUCH AS POLYPHENOLS, ISOTHIOCYANATES, SULFUR-CONTAINING COMPOUNDS AND TERPENOIDS, FOUND IN FRUITS AND VEGETABLES, IS ASSOCIATED WITH PREVENTION OF CHRONIC DISEASE. THESE BIOACTIVE FOOD COMPOUNDS ELICIT THEIR PROTECTIVE EFFECTS THROUGH COMPLEX MECHANISMS AT THE CELLULAR AND MOLECULAR, INCLUDING EPIGENETIC LEVELS. ACCORDING TO THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) PARADIGM, IN UTERO EXPOSURE TO STRESSORS SUCH AS MALNUTRITION THROUGH MATERNAL DIET WOULD IMPAIR FETAL DEVELOPMENT AND EPIGENETICALLY PROGRAM INCREASED RISK OF METABOLIC DISEASES AND SOME CANCERS IN ADULT LIFE. IN ADDITION, A ROLE FOR FATHERS DIET DURING PRECONCEPTION ON THEIR OFFSPRING HEALTH AND CHRONIC DISEASE SUSCEPTIBILITY HAS ALSO EMERGED. THIS HIGHLIGHTS EARLY LIFE AS A PROMISING WINDOW OF OPPORTUNITY FOR STARTING DIETARY INTERVENTIONS FOCUSING ON PREVENTING CHRONIC DISEASES. HOWEVER, KNOWLEDGE ON THE POTENTIAL BENEFICIAL IMPACT OF EARLY LIFE EXPOSURE TO BIOACTIVE FOOD COMPOUNDS IS LIMITED. AMONG THE STUDIES THAT HAVE INVESTIGATED BIOACTIVE FOOD COMPOUNDS IN THE CONTEXT OF DOHAD, MOST HAVE FOCUSED ON THE IMPACT OF DIETARY POLYPHENOLS. THUS, IN THIS REVIEW WE DISCUSS EXPERIMENTAL EVIDENCE SUPPORTING A ROLE FOR THE DIETARY POLYPHENOLS RESVERATROL, GENISTEIN, EPIGALLOCATECHIN-3-GALLATE AND ANTHOCYANINS IN CHRONIC DISEASE PREVENTION CONSIDERING A PERSPECTIVE FROM EARLY-LIFE INTERVENTIONS THROUGH MATERNAL AND PATERNAL DIETS AND FOCUSING ON EPIGENETICS AS A POTENTIAL UNDERLYING MECHANISM. 2019 18 5858 41 SULFORAPHANE AND EPIGALLOCATECHIN GALLATE RESTORE ESTROGEN RECEPTOR EXPRESSION BY MODULATING EPIGENETIC EVENTS IN THE BREAST CANCER CELL LINE MDA-MB-231: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND/AIMS: EPIGENETICS REFERS TO MODIFICATIONS IN GENE ACTIVITY AND EXPRESSION WITHOUT ALTERATION AT THE DNA SEQUENCE. ENVIRONMENT AND DIET COULD INFLUENCE GENE EXPRESSION. DIET MODIFICATIONS MAY BE MEANINGFUL IN PREVENTING AND TREATING CHRONIC DISEASES, CANCER INCLUDED. DIETARY BIOACTIVE COMPOUNDS, SUCH AS POLYPHENOLS (E.G., CURCUMIN, RESVERATROL, OR EPIGALLOCATECHIN GALLATE [EGCG]) OR ISOTHIOCYANATE (E.G., SULFORAPHANE [SFN]), CAN REGULATE HISTONE ACETYLATION. THE AIM OF THIS SYSTEMATIC REVIEW AND META-ANALYSIS WAS TO EVALUATE THE EFFECT OF SFN AND EGCG ON BREAST CANCER (BC) CELLS CULTURED IN VITRO. METHODS: DUE TO THE ENORMOUS VARIABILITY OBSERVED IN STUDY PROTOCOLS AND THE INNUMERABLE GENES INVOLVED, ONLY STUDIES ANALYZING THE NUMBER OF APOPTOTIC CELLS IN THE MDA-MB-231 CELL LINE WERE EVALUATED. THE EFFECT SIZE (ES) WAS COMPUTED AS THE RATIO OF MEANS. RESULTS: WE IDENTIFIED 7 STUDIES, 4 REGARDING THE EFFECT OF 10 MICROM SFN ON MDA-MB-231 CELLS (ES = 4.59, 95% CONFIDENCE INTERVAL 4.05-5.20) AND 3 FOCUSING ON THE IMPACT OF 20 MICROM EGCG (ES = 2.84, 95% CONFIDENCE INTERVAL 2.60-3.10). CONCLUSION: THE FINDINGS SUGGEST BENEFICIAL EFFECTS OF DIETARY BIOACTIVE COMPOUNDS SUCH AS SFN AND EGCG AND THEIR EFFECT ON BC CELLS BY RESTORING ESTROGEN RECEPTOR GENE EXPRESSION, MODULATING EPIGENETIC CHANGES AND EVENTS, AND INTERFERING WITH TUMOR GROWTH RATE. PUBLICATION BIAS LIMITS THE GENERALIZABILITY OF THE CONCLUSIONS. HIGH-QUALITY STUDIES ARE NEEDED. 2017 19 4044 26 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 20 2732 42 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