1 4984 132 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 2 4625 34 NEUROBIOLOGY OF VITAMIN C: EXPANDING THE FOCUS FROM ANTIOXIDANT TO ENDOGENOUS NEUROMODULATOR. ASCORBIC ACID (AA) IS A WATER-SOLUBLE VITAMIN (C) FOUND IN ALL BODILY ORGANS. MOST MAMMALS SYNTHESIZE IT, HUMANS ARE REQUIRED TO EAT IT, BUT ALL MAMMALS NEED IT FOR HEALTHY FUNCTIONING. AA REACHES ITS HIGHEST CONCENTRATION IN THE BRAIN WHERE BOTH NEURONS AND GLIA RELY ON TIGHTLY REGULATED UPTAKE FROM BLOOD VIA THE GLUCOSE TRANSPORT SYSTEM AND SODIUM-COUPLED ACTIVE TRANSPORT TO ACCUMULATE AND MAINTAIN AA AT MILLIMOLAR LEVELS. AS A PROTOTYPE ANTIOXIDANT, AA IS NOT ONLY NEUROPROTECTIVE, BUT ALSO FUNCTIONS AS A COFACTOR IN REDOX-COUPLED REACTIONS ESSENTIAL FOR THE SYNTHESIS OF NEUROTRANSMITTERS (E.G., DOPAMINE AND NOREPINEPHRINE) AND PARACRINE LIPID MEDIATORS (E.G., EPOXIECOISATRIENOIC ACIDS) AS WELL AS THE EPIGENETIC REGULATION OF DNA. ALTHOUGH REDOX CAPACITY LED TO THE PROMOTION OF AA IN HIGH DOSES AS POTENTIAL TREATMENT FOR VARIOUS NEUROPATHOLOGICAL AND PSYCHIATRIC CONDITIONS, AMPLE EVIDENCE HAS NOT SUPPORTED THIS THERAPEUTIC STRATEGY. HERE, WE FOCUS ON SOME LONG-NEGLECTED ASPECTS OF AA NEUROBIOLOGY, INCLUDING ITS MODULATORY ROLE IN SYNAPTIC TRANSMISSION AS DEMONSTRATED BY THE LONG-ESTABLISHED LINK BETWEEN RELEASE OF ENDOGENOUS AA IN BRAIN EXTRACELLULAR FLUID AND THE CLEARANCE OF GLUTAMATE, AN EXCITATORY AMINO ACID. EVIDENCE THAT THIS LINK CAN BE DISRUPTED IN ANIMAL MODELS OF HUNTINGTON S DISEASE IS REVEALING OPPORTUNITIES FOR NEW RESEARCH PATHWAYS AND THERAPEUTIC APPLICATIONS (E.G., EPILEPSY AND PAIN MANAGEMENT). IN FACT, WE SUGGEST THAT IMPROVED UNDERSTANDING OF THE REGULATION OF ENDOGENOUS AA AND ITS INTERACTION WITH KEY BRAIN NEUROTRANSMITTER SYSTEMS, RATHER THAN ADMINISTRATION OF AA IN EXCESS, SHOULD BE THE TARGET OF FUTURE BRAIN-BASED THERAPIES. 2019 3 6666 29 UPTAKE OF ASCORBIC ACID BY PANCREATIC ACINAR CELLS IS NEGATIVELY IMPACTED BY CHRONIC ALCOHOL EXPOSURE. VITAMIN C (ASCORBIC ACID, AA) IS INDISPENSABLE FOR NORMAL METABOLISM OF ALL MAMMALIAN CELLS INCLUDING PANCREATIC ACINAR CELLS (PACS). PACS OBTAIN AA FROM THEIR SURROUNDINGS VIA TRANSPORT ACROSS THE CELL MEMBRANE. CHRONIC ALCOHOL EXPOSURE NEGATIVELY AFFECTS BODY AA HOMEOSTASIS; IT ALSO INHIBITS UPTAKE OF OTHER MICRONUTRIENTS INTO PACS, BUT ITS EFFECT ON AA UPTAKE IS NOT CLEAR. WE EXAMINED THIS ISSUE USING BOTH IN VITRO (266-6 CELLS) AND IN VIVO (MICE) MODELS OF CHRONIC ALCOHOL EXPOSURE. FIRST, WE DETERMINED THE RELATIVE EXPRESSION OF THE AA TRANSPORTERS 1 AND 2 [I.E., SODIUM-DEPENDENT VITAMIN C TRANSPORTER-1 (SVCT-1) AND SVCT-2] IN MOUSE AND HUMAN PACS AND FOUND SVCT-2 TO BE THE PREDOMINANT TRANSPORTER. CHRONIC EXPOSURE OF 266-6 CELLS TO ALCOHOL SIGNIFICANTLY INHIBITED AA UPTAKE AND CAUSED A MARKED REDUCTION IN SVCT-2 EXPRESSION AT THE PROTEIN, MRNA, AND HETEROGENEOUS NUCLEAR RNA (HNRNA) LEVELS. SIMILARLY, CHRONIC ALCOHOL FEEDING OF MICE SIGNIFICANTLY INHIBITED AA UPTAKE AND CAUSED A MARKED REDUCTION IN LEVEL OF EXPRESSION OF THE SVCT-2 PROTEIN, MRNA, AND HNRNA. THESE FINDINGS SUGGEST POSSIBLE INVOLVEMENT OF TRANSCRIPTIONAL MECHANISM(S) IN MEDIATING CHRONIC ALCOHOL EFFECT ON AA UPTAKE BY PACS. WE ALSO OBSERVED SIGNIFICANT EPIGENETIC CHANGES (HISTONE MODIFICATIONS) IN THE SLC23A2 GENE (REDUCTION IN H3K4ME3 LEVEL AND AN INCREASE IN H3K27ME3 LEVEL) IN THE ALCOHOL-EXPOSED 266-6 CELLS. THESE FINDINGS SHOW THAT CHRONIC ALCOHOL EXPOSURE INHIBITS PAC AA UPTAKE AND THAT THE EFFECT IS MEDIATED, IN PART, AT THE LEVEL OF TRANSCRIPTION OF THE SLC23A2 GENE AND MAY INVOLVE EPIGENETIC MECHANISM(S). 2016 4 1802 29 EFFECT OF PATERNAL DIET ON SPERMATOGENESIS AND OFFSPRING HEALTH: FOCUS ON EPIGENETICS AND INTERVENTIONS WITH FOOD BIOACTIVE COMPOUNDS. INFERTILITY IS A GROWING PUBLIC HEALTH PROBLEM. CONSUMPTION OF ANTIOXIDANT BIOACTIVE FOOD COMPOUNDS (BFCS) THAT INCLUDE MICRONUTRIENTS AND NON-NUTRIENTS HAS BEEN HIGHLIGHTED AS A POTENTIAL STRATEGY TO PROTECT AGAINST OXIDATIVE AND INFLAMMATORY DAMAGE IN THE MALE REPRODUCTIVE SYSTEM INDUCED BY OBESITY, ALCOHOL, AND TOXICANTS AND, THUS, IMPROVE SPERMATOGENESIS AND THE FERTILITY PARAMETERS. PATERNAL CONSUMPTION OF SUCH DIETARY COMPOUNDS COULD NOT ONLY BENEFIT THE FATHERS BUT THEIR OFFSPRING AS WELL. STUDIES IN THE NEW FIELD OF PATERNAL ORIGINS OF HEALTH AND DISEASE SHOW THAT PATERNAL MALNUTRITION CAN ALTER SPERM EPIGENOME, AND THIS CAN ALTER FETAL DEVELOPMENT AND PROGRAM AN INCREASED RISK OF METABOLIC DISEASES AND BREAST CANCER IN ADULTHOOD. BFCS, SUCH AS ASCORBIC ACID, ALPHA-TOCOPHEROL, POLYUNSATURATED FATTY ACIDS, TRACE ELEMENTS, CARNITINES, N-ACETYLCYSTEINE, AND COENZYME Q10, HAVE BEEN SHOWN TO IMPROVE MALE GAMETOGENESIS, MODULATE EPIGENETICS OF GERM CELLS, AND THE EPIGENETIC SIGNATURE OF THE OFFSPRING, RESTORING OFFSPRING METABOLIC HEALTH INDUCED BY STRESSORS DURING EARLY LIFE. THIS INDICATES THAT, FROM A FATHER'S PERSPECTIVE, PRECONCEPTION IS A VALUABLE WINDOW OF OPPORTUNITY TO START POTENTIAL NUTRITIONAL INTERVENTIONS WITH THESE BFCS TO MAXIMIZE SPERM EPIGENETIC INTEGRITY AND PROMOTE ADEQUATE FETAL GROWTH AND DEVELOPMENT, THUS PREVENTING CHRONIC DISEASE IN ADULTHOOD. 2022 5 871 24 CHRONIC ALCOHOL EXPOSURE AFFECTS PANCREATIC ACINAR MITOCHONDRIAL THIAMIN PYROPHOSPHATE UPTAKE: STUDIES WITH MOUSE 266-6 CELL LINE AND PRIMARY CELLS. THIAMIN IS ESSENTIAL FOR NORMAL METABOLIC ACTIVITY OF ALL MAMMALIAN CELLS, INCLUDING THOSE OF THE PANCREAS. CELLS OBTAIN THIAMIN FROM THEIR SURROUNDINGS AND ENZYMATICALLY CONVERT IT INTO THIAMIN PYROPHOSPHATE (TPP) IN THE CYTOPLASM; TPP IS THEN TAKEN UP BY MITOCHONDRIA VIA A SPECIFIC CARRIER THE MITOCHONDRIAL TPP TRANSPORTER (MTPPT; PRODUCT OF THE SLC25A19 GENE). CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS THE HEALTH OF PANCREATIC ACINAR CELLS (PAC), BUT ITS EFFECT ON PHYSIOLOGICAL/MOLECULAR PARAMETERS OF MTPPT IS NOT KNOWN. WE ADDRESSED THIS ISSUE USING MOUSE PANCREATIC ACINAR TUMOR CELL LINE 266-6 AND PRIMARY PAC OF WILD-TYPE AND TRANSGENIC MICE CARRYING THE SLC25A19 PROMOTER THAT WERE FED ALCOHOL CHRONICALLY. CHRONIC ALCOHOL EXPOSURE OF 266-6 CELLS (BUT NOT TO ITS NONOXIDATIVE METABOLITES ETHYL PALMITATE AND ETHYL OLEATE) LED TO A SIGNIFICANT INHIBITION IN MITOCHONDRIAL TPP UPTAKE, WHICH WAS ASSOCIATED WITH A DECREASED EXPRESSION OF MTPPT PROTEIN, MRNA, AND ACTIVITY OF THE SLC25A19 PROMOTER. SIMILARLY, CHRONIC ALCOHOL FEEDING OF MICE LED TO A SIGNIFICANT INHIBITION IN EXPRESSION OF MTPPT PROTEIN, MRNA, HETEROGENEOUS NUCLEAR RNA, AS WELL AS IN ACTIVITY OF SLC25A19 PROMOTER IN PAC. WHILE CHRONIC ALCOHOL EXPOSURE DID NOT AFFECT DNA METHYLATION OF THE SLC25A19 PROMOTER, A SIGNIFICANT DECREASE IN HISTONE H3 EUCHROMATIN MARKERS AND AN INCREASE IN H3 HETEROCHROMATIN MARKER WERE OBSERVED. THESE FINDINGS SHOW, FOR THE FIRST TIME, THAT CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS PANCREATIC MTPPT, AND THAT THIS EFFECT IS EXERTED, AT LEAST IN PART, AT THE LEVEL OF SLC25A19 TRANSCRIPTION AND APPEARS TO INVOLVE EPIGENETIC MECHANISM(S). 2015 6 1787 29 EFFECT OF CHRONIC ALCOHOL EXPOSURE ON GUT VITAMIN B7 UPTAKE: INVOLVEMENT OF EPIGENETIC MECHANISMS AND EFFECT OF ALCOHOL METABOLITES. VITAMIN B7 (BIOTIN) IS ESSENTIAL FOR NORMAL HEALTH AND ITS DEFICIENCY/SUBOPTIMAL LEVELS OCCUR IN A VARIETY OF CONDITIONS INCLUDING CHRONIC ALCOHOLISM. MAMMALS, INCLUDING HUMANS, OBTAIN BIOTIN FROM DIET AND GUT-MICROBIOTA VIA ABSORPTION ALONG THE INTESTINAL TRACT. THE ABSORPTION PROCESS IS CARRIER MEDIATED AND INVOLVES THE SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT; SLC5A6). WE HAVE PREVIOUSLY SHOWN THAT CHRONIC ALCOHOL EXPOSURE SIGNIFICANTLY INHIBITS INTESTINAL/COLONIC BIOTIN UPTAKE VIA SUPPRESSION OF SLC5A6 TRANSCRIPTION IN ANIMAL AND CELL LINE MODELS. HOWEVER, LITTLE IS KNOWN ABOUT THE TRANSCRIPTIONAL/EPIGENETIC FACTORS THAT MEDIATE THIS SUPPRESSION. IN ADDITION, THE EFFECT OF ALCOHOL METABOLITES (GENERATED VIA ALCOHOL METABOLISM BY GUT MICROBIOTA AND HOST TISSUES) ON BIOTIN UPTAKE IS STILL UNKNOWN. TO ADDRESS THESE QUESTIONS, WE FIRST DEMONSTRATED THAT CHRONIC ALCOHOL EXPOSURE INHIBITS SMALL INTESTINAL AND COLONIC BIOTIN UPTAKE AND SMVT EXPRESSION IN HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS. WE THEN SHOWED THAT CHRONIC ALCOHOL EXPOSURES OF BOTH, CACO-2 CELLS AND MICE, ARE ASSOCIATED WITH A SIGNIFICANT SUPPRESSION IN EXPRESSION OF THE NUCLEAR FACTOR KLF-4 (NEEDED FOR SLC5A6 PROMOTER ACTIVITY), AS WELL AS WITH EPIGENETIC ALTERATIONS (HISTONE MODIFICATIONS). WE ALSO FOUND THAT CHRONIC EXPOSURE OF NCM460 HUMAN COLONIC EPITHELIAL CELLS AS WELL AS HUMAN DIFFERENTIATED COLONOID MONOLAYERS, TO ALCOHOL METABOLITES (ACETALDEHYDE, ETHYL PALMITATE, ETHYL OLEATE) SIGNIFICANTLY INHIBITED BIOTIN UPTAKE AND SMVT EXPRESSION. THESE FINDINGS SHED LIGHT ONTO THE MOLECULAR/EPIGENETIC MECHANISMS THAT MEDIATE THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON INTESTINAL BIOTIN UPTAKE. THEY FURTHER SHOW THAT ALCOHOL METABOLITES ARE ALSO CAPABLE OF INHIBITING BIOTIN UPTAKE IN THE GUT.NEW & NOTEWORTHY USING COMPLEMENTARY MODELS, INCLUDING HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS, THIS STUDY SHOWS THE INVOLVEMENT OF MOLECULAR AND EPIGENETIC MECHANISMS IN MEDIATING THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON BIOTIN UPTAKE ALONG THE INTESTINAL TRACT. THE STUDY ALSO SHOWS THAT ALCOHOL METABOLITES (GENERATED BY GUT MICROBIOTA AND HOST TISSUES) CAUSE INHIBITION IN GUT BIOTIN UPTAKE. 2021 7 873 26 CHRONIC ALCOHOL EXPOSURE INHIBITS BIOTIN UPTAKE BY PANCREATIC ACINAR CELLS: POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS. CHRONIC EXPOSURE TO ALCOHOL AFFECTS DIFFERENT PHYSIOLOGICAL ASPECTS OF PANCREATIC ACINAR CELLS (PAC), BUT ITS EFFECT ON THE UPTAKE PROCESS OF BIOTIN IS NOT KNOWN. WE ADDRESSED THIS ISSUE USING MOUSE-DERIVED PANCREATIC ACINAR 266-6 CELLS CHRONICALLY EXPOSED TO ALCOHOL AND WILD-TYPE AND TRANSGENIC MICE (CARRYING THE HUMAN SLC5A6 5'-PROMOTER) FED ALCOHOL CHRONICALLY. FIRST WE ESTABLISHED THAT BIOTIN UPTAKE BY PAC IS NA(+) DEPENDENT AND CARRIER MEDIATED AND INVOLVES SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT). CHRONIC EXPOSURE OF 266-6 CELLS TO ALCOHOL LED TO A SIGNIFICANT INHIBITION IN BIOTIN UPTAKE, EXPRESSION OF SMVT PROTEIN, AND MRNA AS WELL AS IN THE ACTIVITY OF THE SLC5A6 PROMOTER. SIMILARLY, CHRONIC ALCOHOL FEEDING OF WILD-TYPE AND TRANSGENIC MICE CARRYING THE SLC5A6 PROMOTER LED TO A SIGNIFICANT INHIBITION IN BIOTIN UPTAKE BY PAC, AS WELL AS IN THE EXPRESSION OF SMVT PROTEIN AND MRNA AND THE ACTIVITY OF THE SLC5A6 PROMOTERS EXPRESSED IN THE TRANSGENIC MICE. WE ALSO FOUND THAT CHRONIC ALCOHOL FEEDING OF MICE IS ASSOCIATED WITH A SIGNIFICANT INCREASE IN THE METHYLATION STATUS OF CPG ISLANDS PREDICTED TO BE IN THE MOUSE SLC5A6 PROMOTERS AND A DECREASE IN THE LEVEL OF EXPRESSION OF TRANSCRIPTION FACTOR KLF-4, WHICH PLAYS AN IMPORTANT ROLE IN REGULATING SLC5A6 PROMOTER ACTIVITY. THESE RESULTS DEMONSTRATE, FOR THE FIRST TIME, THAT CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS BIOTIN UPTAKE IN PAC AND THAT THIS EFFECT IS EXERTED (AT LEAST IN PART) AT THE LEVEL OF TRANSCRIPTION OF THE SLC5A6 GENE AND MAY INVOLVE EPIGENETIC/MOLECULAR MECHANISMS. 2014 8 6290 34 THE POTENTIAL ROLE OF NUTRITIONAL GENOMICS TOOLS IN VALIDATING HIGH HEALTH FOODS FOR CANCER CONTROL: BROCCOLI AS EXAMPLE. NUTRITIONAL GENOMICS REFLECTS GENE/NUTRIENT INTERACTIONS, UTILISING HIGH-THROUGHPUT GENOMIC TOOLS IN NUTRITION RESEARCH. THE FIELD ALSO CONSIDERS THE CONTRIBUTION OF INDIVIDUAL GENOTYPES TO WELLNESS AND THE RISK OF CHRONIC DISEASE (NUTRIGENETICS), AND HOW SUCH GENETIC PREDISPOSITION MAY BE MODIFIED BY APPROPRIATE DIETS. FOR EXAMPLE, HIGH CONSUMPTION OF BRASSICACEOUS VEGETABLES, INCLUDING BROCCOLI, HAS REGULARLY ASSOCIATED WITH LOW CANCER RISK. BIOACTIVE CHEMICALS IN BROCCOLI INCLUDE GLUCOSINOLATES, PLANT PIGMENTS INCLUDING KAEMPFEROL, QUERCETIN, LUTEIN AND CAROTENOIDS, VARIOUS VITAMINS, MINERALS AND AMINO ACIDS. CANCER PREVENTION IS HYPOTHESISED TO ACT THROUGH VARIOUS MECHANISMS INCLUDING MODULATION OF XENOBIOTIC METABOLISING ENZYMES, NF-E2 P45-RELATED FACTOR-2 (NRF2)-MEDIATED STRESS-RESPONSE MECHANISMS, AND PROTECTION AGAINST GENOMIC INSTABILITY. BROCCOLI AND BROCCOLI EXTRACTS ALSO REGULATE THE PROGRESSION OF CANCER THROUGH ANTI-INFLAMMATORY EFFECTS, EFFECTS ON SIGNAL TRANSDUCTION, EPIGENETIC EFFECTS AND MODULATION OF THE COLONIC MICROFLORA. HUMAN INTERVENTION STUDIES WITH BROCCOLI AND RELATED FOODS, USING STANDARD BIOMARKER METHODOLOGIES, REVEAL PART OF A COMPLEX PICTURE. NUTRIGENOMIC APPROACHES, ESPECIALLY TRANSCRIPTOMICS, ENABLE SIMULTANEOUS STUDY OF VARIOUS SIGNALLING PATHWAYS AND NETWORKS. PHENOTYPIC, GENETIC AND/OR METABOLIC STRATIFICATION MAY IDENTIFY INDIVIDUALS MOST LIKELY TO RESPOND POSITIVELY TO FOODS OR DIETS. JOINTLY, THESE TECHNOLOGIES CAN PROVIDE PROOF OF HUMAN EFFICACY, AND MAY BE ESSENTIAL TO ENSURE EFFECTIVE MARKET TRANSFER AND UPTAKE OF BROCCOLI AND RELATED FOODS. 2012 9 1460 29 DISORDERS OF CONSCIOUSNESS AND PHARMACEUTICALS THAT ACT ON OXYGEN BASED AMINO ACID AND MONOAMINE NEUROTRANSMITTER PATHWAYS OF THE BRAIN. OXYGEN BASED NEUROTRANSMITTERS IN THE SYNAPSES OF THE BRAIN ARE PROPOSED TO PLAY AN IMPORTANT ROLE IN THE GENERATION OF CONSCIOUSNESS. THEY INCLUDE THE AMINO ACIDS GLUTAMATE AND GABA WHICH USE KREBS CYCLE PRECURSORS FOR THEIR SYNTHESIS, AND THE MONOAMINES DOPAMINE, NORADRENALIN, ADRENALIN AND SEROTONIN, WHICH ARE DERIVED FROM TYROSINE AND TRYPTOPHAN. DURING ISCHEMIA AFTER AN ACUTE BRAIN INJURY, A GABA SURGE OFTEN INITIATES BRAIN SUPPRESSION. IT HAS BEEN PROPOSED THAT WITH CHRONIC ISCHEMIA, A SECONDARY, POSSIBLY EPIGENETIC RESPONSE OCCURS WHEN NEUROTRANSMITTERS DEPLETE, A GLUCOSE AND OXYGEN SAVING MECHANISM TERMED NEURODORMANCY THAT MAY INVOKE ALTERNATIVE LONG TERM LOW ENERGY METABOLIC PATHWAYS IN THE BRAIN, ENCOUNTERED IN DISORDERS OF CONSCIOUSNESS. SOME MEDICATIONS CAN REVERSE DISORDERS OF CONSCIOUSNESS IN SOME PATIENTS. VIRTUALLY ALL OF THEM ACT ON NEUROTRANSMITTER SYSTEMS THAT USE OXYGEN AS A BUILDING BLOCK OR AS AN ENERGY SOURCE WITHIN THE BRAIN. PHARMACEUTICALS THAT ACT IN THE OXYGEN BASED AMINO ACID SYSTEMS OF THE BRAIN INCLUDE THE GABAERGIC MEDICATIONS ZOLPIDEM AND BACLOFEN, WHILE THOSE THAT ACT IN THE MONOAMINE AXES INCLUDE THE DOPAMINERGIC MEDICATIONS L DOPA, AMANTADINE, BROMOCRIPTINE, APOMORPHINE AND METHYLPHENIDATE, AND THE NORADRENERGIC AND SEROTONERGIC MEDICATIONS DESIPRAMINE, AMITRIPTYLINE, PROTRIPTYLINE AND FLUOXETINE. ANOTHER GROUP ARE THE CHOLINESTERASE INHIBITORS, RESPONSIBLE FOR INCREASING ACETYLCHOLINE, WHICH IS SYNTHESIZED FROM THE KREBS CYCLE INITIATOR, ACETYL COA. IT APPEARS THAT PHARMACEUTICALS THAT ARE ACTIVE IN THE OXYGEN BASED NEUROTRANSMITTER PATHWAYS OF THE BRAIN ARE SUCCESSFUL TO AROUSE TO CONSCIOUSNESS PATIENTS THAT SUFFER FROM ITS DISORDERS. RESEARCH NEEDS TO BE SUPPORTED AS FOUNDATION TO UNDERSTAND THE BIOCHEMICAL MECHANISMS THAT ARE INVOLVED IN CONSCIOUSNESS DISORDERS AND TO EXPLORE FURTHER THE PHARMACOLOGICAL TREATMENT POSSIBILITIES FOR THESE DEVASTATING NEUROLOGICAL CONDITIONS. 2014 10 1066 36 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 11 5010 33 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID. 1994 12 4652 25 NEUROPROTECTION WITH NATURAL ANTIOXIDANTS AND NUTRACEUTICALS IN THE CONTEXT OF BRAIN CELL DEGENERATION: THE EPIGENETIC CONNECTION. BIOACTIVE ANTIOXIDANT AGENTS PRESENT IN SELECTED PLANTS ARE KNOWN TO PROVIDE THE FIRST LINE OF BIOLOGICAL DEFENSE AGAINST OXIDATIVE STRESS. IN PARTICULAR, SOLUBLE VITAMIN C, E, CAROTENOIDS AND PHENOLIC COMPOUNDS HAVE DEMONSTRATED CRUCIAL BIOLOGICAL EFFECTS IN CELLS AGAINST OXIDATIVE DAMAGE, PREVENTING PREVALENT CHRONIC DISEASES, SUCH AS DIABETES, CANCER AND CARDIOVASCULAR DISEASE. THE REPORTED WIDE RANGE OF EFFECTS THAT INCLUDED ANTI-AGING, ANTI-ATHEROSCLEROSIS, ANTI-INFLAMMATORY AND ANTICANCER ACTIVITY WERE STUDIED AGAINST DEGENERATIVE PATHOLOGIES OF THE BRAIN. VITAMINS AND DIFFERENT PHYTOCHEMICALS ARE IMPORTANT EPIGENETIC MODIFIERS THAT PREVENT NEURODEGENERATION. IN ORDER TO EXPLORE THE POTENTIAL ANTIOXIDANT SOURCES IN FUNCTIONAL FOODS AND NUTRACEUTICALS AGAINST NEURODEGENERATION, THE PRESENT PAPER AIMS TO SHOW A COMPREHENSIVE ASSESSMENT OF ANTIOXIDANT ACTIVITY AT CHEMICAL AND CELLULAR LEVELS. THE EFFECTS OF THE DIFFERENT BIOACTIVE COMPOUNDS AVAILABLE AND THEIR ANTIOXIDANT ACTIVITY THROUGH AN EPIGENETIC POINT OF VIEW ARE ALSO DISCUSSED. 2019 13 4977 36 PATHOPHYSIOLOGY AND EVOLUTIONARY ASPECTS OF DIETARY FATS AND LONG-CHAIN POLYUNSATURATED FATTY ACIDS ACROSS THE LIFE CYCLE. DIETARY FAT IS OUR SECOND MOST IMPORTANT ENERGY-PRODUCING MACRONUTRIENT. IT ALSO CONTAINS FATTY ACIDS AND VITAMINS ESSENTIAL FOR GROWTH, DEVELOPMENT, AND MAINTENANCE OF GOOD HEALTH. DIETARY FAT QUANTITY AND QUALITY HAVE BEEN SUBJECT TO TREMENDOUS CHANGE OVER THE PAST 10,000 YEARS. THIS HAS, TOGETHER WITH OTHER MAN-MADE CHANGES IN OUR ENVIRONMENT, CAUSED A CONFLICT WITH OUR SLOWLY ADAPTING GENOME THAT IS IMPLICATED IN "TYPICALLY WESTERN" DISEASES. RATHER THAN REDUCING OUR LIFE EXPECTANCY, THESE DISEASES NOTABLY DIMINISH OUR NUMBER OF YEARS IN HEALTH. IMPORTANT CHANGES IN DIETARY FAT QUALITY ARE THE INCREASED INTAKES OF CERTAIN SATURATED FATTY ACIDS (SAFA) AND LINOLEIC ACID (LA), INTRODUCTION OF INDUSTRIALLY PRODUCED TRANS FATTY ACIDS, AND REDUCED INTAKES OF OMEGA3 FATTY ACIDS, NOTABLY ALPHA-LINOLENIC ACID (ALA) FROM VEGETABLE SOURCES AND EICOSAPENTAENOIC ACID (EPA) AND DOCOSAHEXAENOIC ACID (DHA) FROM FISH. THE PATHOPHYSIOLOGICAL EFFECTS OF THESE CHANGES ARE DIVERSE, BUT ARE INCREASINGLY ASCRIBED TO INDUCTION OF A PROINFLAMMATORY STATE THAT PROGRESSES EASILY TO CHRONIC LOW-GRADE INFLAMMATION. THE LATTER MIGHT AFFECT VIRTUALLY ALL ORGANS AND SYSTEMS, POSSIBLY BEGINNING AT CONCEPTION, AND POSSIBLY EVEN PRIOR TO GAMETOGENESIS THROUGH EPIGENETIC ALTERATIONS. LOW-GRADE INFLAMMATION MIGHT BE A COMMON DENOMINATOR OF THE METABOLIC SYNDROME AND ITS SEQUELAE (E.G., CORONARY ARTERY DISEASE (CAD), DIABETES MELLITUS TYPE 2, SOME TYPES OF CANCER, AND PREGNANCY COMPLICATIONS), SOME PSYCHIATRIC DISEASES (E.G., MAJOR AND POSTPARTUM DEPRESSION, SCHIZOPHRENIA, AND AUTISM), AND NEURODEGENERATIVE DISEASES (E.G., ALZHEIMER'S DISEASE, PARKINSON'S DISEASE). THE LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LCPUFA) ARACHIDONIC ACID (AA), EPA, AND DHA ARE INTIMATELY RELATED TO THE INITIATION AND RESOLUTION OF INFLAMMATORY RESPONSES. THE CURRENT BALANCE BETWEEN AA AND EPA + DHA IS HOWEVER DISTURBED BY THE DOMINANCE OF AA, WHICH ORIGINATES FROM THE DIET OR SYNTHESIS FROM LA. LCPUFA ARE TOGETHER WITH THEIR HIGHLY POTENT METABOLITES (PROSTAGLANDINS, THROMBOXANES, LEUKOTRIENES, RESOLVINS, AND (NEURO)PROTECTINS) INVOLVED IN THE FUNCTIONING OF MEMBRANE-BOUND RECEPTORS, TRANSPORTERS, ION CHANNELS, AND ENZYMES, AND ALSO IN SIGNAL TRANSDUCTION AND GENE EXPRESSION. AMONG THEIR MANY TARGETS ARE NUCLEAR RECEPTORS WHICH, UPON LIGATION WITH LCPUFA AND THEIR METABOLITES, FUNCTION AS TRANSCRIPTION FACTORS OF A VARIETY OF GENES FUNCTIONING IN MANY PATHWAYS. FOR INSTANCE, THE TARGETED PEROXISOME PROLIFERATORS-ACTIVATED RECEPTORS (PPARS) ARE STRATEGIC INTERMEDIATES IN THE COORDINATED EXPRESSION OF PROTEINS WITH FUNCTIONS IN, FOR EXAMPLE, LIPID AND GLUCOSE HOMEOSTASIS AND INFLAMMATORY REACTIONS. MANY INTERVENTIONS HAVE BEEN CONDUCTED WITH LCPUFA, ESPECIALLY EPA AND DHA, AIMING AT PRIMARY AND SECONDARY CAD PREVENTIONS, IMPROVEMENT OF FETAL AND NEWBORN (BRAIN) DEVELOPMENT BY SUPPLEMENTATION DURING PREGNANCY OR EARLY POSTNATAL LIFE, AND IN PSYCHIATRIC DISEASES. CONSENSUS HAS BEEN REACHED THAT THOSE IN CAD AND DEPRESSION ARE POSITIVE, ALTHOUGH MORE LARGE-SCALE TRIALS ARE NEEDED. MANY RECOMMENDATIONS FOR THE INTAKES OF SATURATED FAT, TRANS FAT AND EPA + DHA HAVE BEEN ISSUED, NOTABLY FOR CAD PREVENTION, AND ALSO FOR EPA + DHA INTAKES BY PREGNANT WOMEN AND FOR AA, EPA, AND DHA INTAKES BY NEWBORNS. THE ULTIMATE GOAL MIGHT, HOWEVER, BE TO RETURN TO THE FAT QUALITY OF OUR ANCIENT DIET ON WHICH OUR GENES HAVE EVOLVED DURING THE PAST MILLION YEARS OF EVOLUTION, WHILE THIS ACTUALLY APPLIES FOR OUR ENTIRE DIETARY COMPOSITION AND LIFESTYLE, AS TRANSLATED TO THE CULTURE OF THE CURRENT SOCIETY. 2010 14 617 28 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 15 4271 37 MICROBIAL DYSBIOSIS-INDUCED OBESITY: ROLE OF GUT MICROBIOTA IN HOMOEOSTASIS OF ENERGY METABOLISM. THE GLOBAL OBESITY EPIDEMIC HAS NECESSITATED THE SEARCH FOR BETTER INTERVENTION STRATEGIES INCLUDING THE EXPLOITATION OF THE HEALTH BENEFITS OF SOME GUT MICROBIOTA AND THEIR METABOLIC PRODUCTS. THEREFORE, WE EXAMINED THE GUT MICROBIAL COMPOSITION AND MECHANISMS OF INTERACTION WITH THE HOST IN RELATION TO HOMOEOSTATIC ENERGY METABOLISM AND PATHOPHYSIOLOGY OF DYSBIOSIS-INDUCED METABOLIC INFLAMMATION AND OBESITY. WE ALSO DISCUSSED THE EUBIOTIC, HEALTH-PROMOTING EFFECTS OF PROBIOTICS AND PREBIOTICS AS WELL AS EPIGENETIC MODIFICATIONS ASSOCIATED WITH GUT MICROBIAL DYSBIOSIS AND RISK OF OBESITY. HIGH-FAT/CARBOHYDRATE DIET PROGRAMMES THE GUT MICROBIOTA TO ONE PREDOMINATED BY FIRMICUTES (CLOSTRIDIUM), PREVOTELLA AND METHANOBREVIBACTER BUT DEFICIENT IN BENEFICIAL GENERA/SPECIES SUCH AS BACTEROIDES, BIFIDOBACTERIUM, LACTOBACILLUS AND AKKERMANSIA. ALTERED GUT MICROBIOTA IS ASSOCIATED WITH DECREASED EXPRESSION OF SCFA THAT MAINTAIN INTESTINAL EPITHELIAL BARRIER INTEGRITY, REDUCE BACTERIAL TRANSLOCATION AND INFLAMMATION AND INCREASE EXPRESSION OF HUNGER-SUPPRESSING HORMONES. REDUCED AMOUNTS OF BENEFICIAL MICRO-ORGANISMS ALSO INHIBIT FASTING-INDUCED ADIPOCYTE FACTOR EXPRESSION LEADING TO DYSLIPIDAEMIA. A LOW-GRADE CHRONIC INFLAMMATION (METABOLIC ENDOTOXAEMIA) ENSUES WHICH CULMINATES IN OBESITY AND ITS CO-MORBIDITIES. THE SYNERGY OF HIGH-FAT DIET AND DYSBIOTIC GUT MICROBIOTA INITIATES A RECIPE THAT EPIGENETICALLY PROGRAMMES THE HOST FOR INCREASED ADIPOSITY AND POOR GLYCAEMIC CONTROL. INTERESTINGLY, THESE OBESOGENIC MECHANISTIC PATHWAYS THAT ARE TRANSMITTABLE FROM ONE GENERATION TO ANOTHER CAN BE MODULATED THROUGH THE ADMINISTRATION OF PROBIOTICS, PREBIOTICS AND SYNBIOTICS. THOUGH THE INFLUENCE OF GUT MICROBIOTA ON THE RISK OF OBESITY AND SEVERAL INTERVENTION STRATEGIES HAVE BEEN EXTENSIVELY DEMONSTRATED IN ANIMAL MODELS, APPLICATION IN HUMANS STILL REQUIRES FURTHER ROBUST INVESTIGATION. 2020 16 1395 36 DIET AND MICROBIOME IN THE BEGINNING OF THE SEQUENCE OF GUT INFLAMMATION. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT DUE, AT LEAST PARTIALLY, TO AN ABERRANT AND EXCESSIVE MUCOSAL IMMUNE RESPONSE TO GUT BACTERIA IN GENETICALLY-PREDISPOSED INDIVIDUALS UNDER CERTAIN ENVIRONMENTAL FACTORS. THE INCIDENCE OF IBD IS RISING IN WESTERN AND NEWLY INDUSTRIALIZED COUNTRIES, PARALLELING THE INCREASE OF WESTERNIZED DIETARY PATTERNS, THROUGH NEW ANTIGENS, EPITHELIAL FUNCTION AND PERMEABILITY, EPIGENETIC MECHANISMS (E.G., DNA METHYLATION), AND ALTERATION OF THE GUT MICROBIOME. ALTERATION IN THE COMPOSITION AND FUNCTIONALITY OF THE GUT MICROBIOME (INCLUDING BACTERIA, VIRUSES AND FUNGI) SEEMS TO BE A NUCLEAR PATHOGENIC FACTOR. THE MICROBIOME ITSELF IS DYNAMIC, AND THE CHANGES IN FOOD QUALITY, DIETARY HABITS, LIVING CONDITIONS AND HYGIENE OF THESE WESTERN SOCIETIES, COULD INTERACT IN A COMPLEX MANNER AS MODULATORS OF DYSBIOSIS, THEREBY INFLUENCING THE ACTIVATION OF IMMUNE CELLS' PROMOTING INFLAMMATION. THE MICROBIOME PRODUCES DIVERSE SMALL MOLECULES VIA SEVERAL METABOLIC WAYS, WITH THE FIBER-DERIVED SHORT-CHAIN FATTY ACIDS (I.E., BUTYRATE) AS MAIN ELEMENTS AND HAVING ANTI-INFLAMMATORY EFFECTS. THESE METABOLITES AND SOME MICRONUTRIENTS OF THE DIET (I.E., VITAMINS, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS) ARE REGULATORS OF INNATE AND ADAPTIVE INTESTINAL IMMUNE HOMEOSTASIS. AN EXCESSIVE AND UNHEALTHY CONSUMPTION OF SUGAR, ANIMAL FAT AND A LOW-VEGETABLE AND -FIBER DIET ARE RISK FACTORS FOR IBD APPEARANCE. FURTHERMORE, METABOLISM OF NUTRIENTS IN INTESTINAL EPITHELIUM AND IN GUT MICROBIOTA IS ALTERED BY INFLAMMATION, CHANGING THE DEMAND FOR NUTRIENTS NEEDED FOR HOMEOSTASIS. THIS ROLE OF FOOD AND A REDUCED GUT MICROBIAL DIVERSITY IN CAUSING IBD MIGHT ALSO HAVE A PROPHYLACTIC OR THERAPEUTIC ROLE FOR IBD. THE RELATIONSHIP BETWEEN DIETARY INTAKE, SYMPTOMS, AND BOWEL INFLAMMATION COULD LEAD TO DIETARY AND LIFESTYLE RECOMMENDATIONS, INCLUDING DIETS WITH ABUNDANT FRUITS, VEGETABLES, OLIVE OIL AND OILY FISH, WHICH HAVE ANTI-INFLAMMATORY EFFECTS AND COULD PREVENT DYSBIOSIS AND IBD. DIETARY MODULATION AND APPROPRIATE EXCLUSION DIETS MIGHT BE A NEW COMPLEMENTARY MANAGEMENT FOR TREATMENT AT DISEASE FLARES AND IN REFRACTORY PATIENTS, EVEN REDUCING COMPLICATIONS, HOSPITALIZATIONS AND SURGERY, THROUGH MODIFYING THE LUMINAL INTESTINAL ENVIRONMENT. 2021 17 6872 26 [POLYPHENOLS AS PROMISING BIOACTIVE COMPOUNDS]. POLYPHENOLS ARE DIVERSE AND WIDESPREAD BIOACTIVE PLANT-BASED COMPOUNDS. THESE COMPOUNDS ARE FOUND IN VARIOUS FOODS SUCH AS BERRIES, FRUITS, VEGETABLES, CEREALS, NUTS, COFFEE, CACAO, SPICES, SEEDS. THEY ARE DIVIDED INTO PHENOLIC ACIDS, STILBENES, FLAVONOIDS, LIGNANS DEPENDING ON THEIR MOLECULAR STRUCTURE. THEY ATTRACT THE ATTENTION OF RESEARCHERS DUE TO WIDE RANGE OF BIOLOGICAL EFFECTS ON HUMAN BODY. THE PURPOSE OF THIS WORK WAS TO ANALYZE MODERN SCIENTIFIC PUBLICATIONS ON THE BIOLOGICAL EFFECTS OF POLYPHENOLS. MATERIAL AND METHODS. THE REVIEW IS BASED ON PUBLICATIONS PRESENTED IN THE PUBMED, GOOGLE SCHOLAR, RESEARCHGATE, ELSEVIER, ELIBRARY, CYBERLENINKA DATABASES USING "POLYPHENOLS", "FLAVONOIDS", "RESVERATROL", "QUERCETIN", "CATECHINS" AS KEY WORDS. PREFERENCE WAS GIVEN TO ORIGINAL RESEARCHES OVER THE PAST 10 YEARS PUBLISHED IN REFEREED JOURNALS. RESULTS. OXIDATIVE STRESS, CHRONIC INFLAMMATION, MICROBIOME DISORDERS, INSULIN RESISTANCE, EXCESSIVE PROTEIN GLYCATION, AND GENOTOXIC EFFECTS ARE AT THE HEART OF THE PATHOGENESIS OF MANY DISEASES, INCLUDING THOSE ASSOCIATED WITH AGE. A LARGE AMOUNT OF MATERIAL HAS BEEN ACCUMULATED ON THE ANTIOXIDANT, ANTICARCINOGENIC, EPIGENETIC, METABOLIC, GEROPROTECTIVE, ANTI-INFLAMMATORY AND ANTIVIRAL EFFECTS OF POLYPHENOLS. THIS GIVES REASONS TO CONSIDER POLYPHENOLS AS VERY PROMISING MICRONUTRIENTS, WHICH INCLUSION IN THE DIET CAN REDUCE THE RISK OF DEVELOPING CARDIOVASCULAR, ONCOLOGICAL, NEURODEGENERATIVE DISEASES, DIABETES MELLITUS, OBESITY, METABOLIC SYNDROME, PREMATURE AGING, THAT IS, THE MAIN CAUSES OF DEATH, A DECREASE IN THE DURATION AND QUALITY OF LIFE OF A MODERN PERSON. CONCLUSION. EXPANDING THE RANGE OF PRODUCTS ENRICHED WITH POLYPHENOLS WITH THEIR HIGH BIOAVAILABILITY IS A PROMISING AREA OF SCIENTIFIC RESEARCH AND DEVELOPMENT OF PRODUCTION IN ORDER TO PREVENT SOCIALLY SIGNIFICANT AGE-ASSOCIATED DISEASES. 2023 18 6166 30 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 19 440 25 ANTIOXIDATIVE EFFECTS OF RHODIOLA GENUS: PHYTOCHEMISTRY AND PHARMACOLOGICAL MECHANISMS AGAINST THE DISEASES. RHODIOLA AS ONE OF TRADITIONAL MEDICINES HAS BEEN USED FOR CLINICAL TREATMENTS DUE TO ITS STRONG ANTIOXIDANT PROPERTIES. PHYTOCHEMICAL ANALYSIS REVEALED THE PRESENCE OF FLAVONOIDS, PHENYLPROPANOIDS, PHENYLETHANOL/BENZYL ALCOHOL DERIVATIVES, CYANOGENIC GLYCOSIDES AND TERPENOIDS. THE BIOACTIVE COMPOUNDS HAD BEEN DEMONSTRATED TO BE EFFECTIVE AT SCAVENGING REACTIVE OXYGEN SPECIES (ROS). THE STRUCTURES CONTAIN PHENOLIC HYDROXYL GROUPS AND UNSATURATED BONDS. THIS ARTICLE REVIEWS ANTIOXIDANT CAPACITIES OF THE EXTRACTS AND BIOACTIVE COMPONENTS DERIVED FROM RHODIOLA PLANTS. AS THE MAJOR PHARMACOLOGICAL INGREDIENT, SALIDROSIDE IS RIGOROUSLY INVESTIGATED AND USED IN SCIENTIFIC RESEARCHES AND CLINICAL PRACTICES. ACCUMULATED EVIDENCES INDICATED THAT EXTRACTS OF RHODIOLA PLANTS OR SALIDROSIDE COULD BE ABLE TO REVERSE DNA DAMAGE AND ALTER EXPRESSION OF CYTOKINES AND ANTIOXIDATIVE ENZYMES INDUCED BY ROS. THE UNDERLYING MECHANISMS FOR THE ANTIOXIDATIVE EFFECTS OF THE HERB HAVE BEEN INVESTIGATED IN THE LAST TWO DECADES. WE SUMMARIZE THE POSSIBLE EFFECTS AND ACTING PATHWAYS FOR THE HERB INVOLVED IN SEVERAL CHRONIC DISEASES IN CARDIOVASCULAR, RESPIRATORY, AND NERVOUS SYSTEMS, AS WELL AS POTENTIAL EPIGENETIC INFLUENCES. THE INFORMATION GENERATED FROM EXPERIMENTAL AND CLINICAL STUDIES OFFERED VALUABLE INSIGHTS FOR FURTHER INVESTIGATIONS OF MEDICAL POTENTIALS OF RHODIOLA PLANTS. 2017 20 5149 29 PPAR AND FUNCTIONAL FOODS: RATIONALE FOR NATURAL NEUROSTEROID-BASED INTERVENTIONS FOR POSTPARTUM DEPRESSION. ALLOPREGNANOLONE, A GABAERGIC NEUROSTEROID AND PROGESTERONE DERIVATIVE, WAS RECENTLY APPROVED BY THE FOOD AND DRUG ADMINISTRATION FOR THE TREATMENT OF POSTPARTUM DEPRESSION (PPD). SEVERAL MECHANISMS APPEAR TO BE INVOLVED IN THE PATHOGENESIS OF PPD, INCLUDING NEUROENDOCRINE DYSFUNCTION, NEUROINFLAMMATION, NEUROTRANSMITTER ALTERATIONS, GENETIC AND EPIGENETIC MODIFICATIONS. RECENT EVIDENCE HIGHLIGHTS THE HIGHER RISK FOR INCIDENCE OF PPD IN MOTHERS EXPOSED TO UNHEALTHY DIETS THAT NEGATIVELY IMPACT THE MICROBIOME COMPOSITION AND INCREASE INFLAMMATION, ALL EFFECTS THAT ARE STRONGLY CORRELATED WITH MOOD DISORDERS. CONVERSELY, HEALTHY DIETS HAVE CONSISTENTLY BEEN REPORTED TO DECREASE THE RISK OF PERIPARTUM DEPRESSION AND TO PROTECT THE BODY AND BRAIN AGAINST LOW-GRADE SYSTEMIC CHRONIC INFLAMMATION. SEVERAL BIOACTIVE MICRONUTRIENTS FOUND IN THE SO-CALLED FUNCTIONAL FOODS HAVE BEEN SHOWN TO PLAY A RELEVANT ROLE IN PREVENTING NEUROINFLAMMATION AND DEPRESSION, SUCH AS VITAMINS, MINERALS, OMEGA-3 FATTY ACIDS AND FLAVONOIDS. AN INTRIGUING MOLECULAR SUBSTRATE LINKING FUNCTIONAL FOODS WITH IMPROVEMENT OF MOOD DISORDERS MAY BE REPRESENTED BY THE PEROXISOME-PROLIFERATOR ACTIVATED RECEPTOR (PPAR) PATHWAY, WHICH CAN REGULATE ALLOPREGNANOLONE BIOSYNTHESIS AND BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) AND THEREBY MAY REDUCE INFLAMMATION AND ELEVATE MOOD. HEREIN, WE DISCUSS THE POTENTIAL CONNECTION BETWEEN FUNCTIONAL FOODS AND PPAR AND THEIR ROLE IN PREVENTING NEUROINFLAMMATION AND SYMPTOMS OF PPD THROUGH NEUROSTEROID REGULATION. WE SUGGEST THAT HEALTHY DIETS BY TARGETING THE PPAR-NEUROSTEROID AXIS AND THEREBY DECREASING INFLAMMATION MAY OFFER A SUITABLE FUNCTIONAL STRATEGY TO PREVENT AND SAFELY ALLEVIATE MOOD SYMPTOMS DURING THE PERINATAL PERIOD. 2020