1 6406 167 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 2 1066 35 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 3 4786 33 NUTRITION AND HEALTH DURING MID-LIFE: SEARCHING FOR SOLUTIONS AND MEETING CHALLENGES FOR THE AGING POPULATION. INTERACTIONS BETWEEN GENETIC (GENOME) AND ENVIRONMENTAL FACTORS (EPIGENOME) OPERATE DURING A PERSON'S ENTIRE LIFESPAN. THE AGING PROCESS IS ASSOCIATED WITH SEVERAL CELLULAR AND ORGANIC FUNCTIONAL ALTERATIONS THAT, AT THE END, CAUSE MULTI-ORGANIC CELL FAILURE. EPIGENETIC MECHANISMS OF AGING ARE MODIFIABLE BY APPROPRIATE PREVENTIVE ACTIONS MEDIATED BY SIRTUINS, CALORIC INPUT, DIET COMPONENTS, ADIPOSE TISSUE-RELATED INFLAMMATORY REACTIONS, AND PHYSICAL ACTIVITY. THE MEDITERRANEAN LIFESTYLE HAS BEEN FOR MANY MILLENNIA A DAILY HABIT FOR PEOPLE IN WESTERN CIVILIZATIONS LIVING AROUND THE MEDITERRANEAN SEA WHO WORKED INTENSIVELY AND SURVIVED WITH VERY FEW SEASONAL FOODS. A HIGH ADHERENCE TO THE TRADITIONAL MEDITERRANEAN DIET IS ASSOCIATED WITH LOW MORTALITY (HIGHER LONGEVITY) AND REDUCED RISK OF DEVELOPING CHRONIC DISEASES, INCLUDING CANCER, THE METABOLIC SYNDROME, DEPRESSION AND CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. REPORTS INDICATE THAT SOME DIETARY COMPONENTS, SUCH AS OLIVE OIL, ANTIOXIDANTS, OMEGA-3 AND -6 POLYUNSATURATED ACIDS, POLYPHENOLS AND FLAVONOIDS, MEDIATE BENEFICIAL ANTI-AGING EFFECTS (ANTI-CHRONIC DISEASES AND INCREASED LONGEVITY). EQUALLY, PHYSICAL ACTIVITY DISPLAYS A POSITIVE EFFECT, PRODUCING CALORIC CONSUMPTION AND REGULATION OF ADIPOSE AND PANCREATIC FUNCTION. THE PREDICTIVE STRENGTH OF SOME FOOD PATTERNS MAY BE A WAY OF DEVELOPING RECOMMENDATIONS FOR FOOD AND HEALTH POLICIES. THIS PAPER WILL DISCUSS SEVERAL WAYS OF IMPROVING HEALTH DURING MID-LIFE, FOCUSING ON CERTAIN GROUPS OF FUNCTIONAL FOODS AND HEALTHY HABITS WHICH MAY REDUCE OR PREVENT AGE-RELATED CHRONIC DISEASES. 2013 4 4796 32 NUTRITIONAL INTERVENTION AS AN ESSENTIAL PART OF MULTIPLE SCLEROSIS TREATMENT? MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. IN ADDITION TO THE GENETIC, EPIGENETIC AND IMMUNOLOGICAL COMPONENTS, VARIOUS OTHER FACTORS, E.G. UNHEALTHY DIETARY HABITS, PLAY A ROLE IN THE MS PATHOGENESIS. DIETARY INTERVENTION IS A HIGHLY APPEALING APPROACH, AS IT PRESENTS A SIMPLE AND RELATIVELY LOW RISK METHOD TO POTENTIALLY IMPROVE OUTCOMES IN PATIENTS WITH BRAIN DISORDERS IN ORDER TO ACHIEVE REMISSION AND IMPROVEMENT OF CLINICAL STATUS, WELL-BEING AND LIFE EXPECTANCY OF PATIENTS WITH MS. THE IMPORTANCE OF SATURATED FAT INTAKE RESTRICTION FOR THE CLINICAL STATUS IMPROVEMENT OF MS PATIENTS WAS POINTED FOR THE FIRST TIME IN 1950S. RECENTLY, DECREASED RISK OF FIRST CLINICAL DIAGNOSIS OF CNS DEMYELINATION ASSOCIATED WITH HIGHER INTAKE OF OMEGA-3 POLYUNSATURATED FATTY ACIDS PARTICULARLY ORIGINATING FROM FISH WAS REPORTED. ONLY FEW CLINICAL TRIALS HAVE BEEN PERFORMED TO ADDRESS THE QUESTION OF THE ROLE OF DIETARY INTERVENTION, SUCH IS E.G. LOW SATURATED FAT DIET IN MS TREATMENT. THIS REVIEW SUMMARIZES CURRENT KNOWLEDGE ABOUT THE EFFECT OF DIFFERENT DIETARY APPROACHES (DIETS LOW IN SATURATED FAT AND DIETARY SUPPLEMENTS SUCH AS FISH OIL, LIPOIC ACID, OMEGA-3 POLYUNSATURATED FATTY ACIDS, SEEDS OILS, HIGH FIBER DIET, VITAMIN D, ETC.) ON NEUROLOGICAL SIGNS, PATIENT'S WELL-BEING, PHYSICAL AND INFLAMMATORY STATUS. SO FAR THE RESULTS ARE NOT CONCLUSIVE, THEREFORE MUCH MORE RESEARCH IS NEEDED TO CONFIRM AND TO UNDERSTAND THE EFFECTIVENESS OF THESE DIETARY INTERVENTIONS IN THE LONG TERM AND WELL DEFINED STUDIES. 2018 5 4625 32 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 6 4652 19 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 7 4977 39 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 8 5033 28 PESTICIDES AND HUMAN CHRONIC DISEASES: EVIDENCES, MECHANISMS, AND PERSPECTIVES. ALONG WITH THE WIDE USE OF PESTICIDES IN THE WORLD, THE CONCERNS OVER THEIR HEALTH IMPACTS ARE RAPIDLY GROWING. THERE IS A HUGE BODY OF EVIDENCE ON THE RELATION BETWEEN EXPOSURE TO PESTICIDES AND ELEVATED RATE OF CHRONIC DISEASES SUCH AS DIFFERENT TYPES OF CANCERS, DIABETES, NEURODEGENERATIVE DISORDERS LIKE PARKINSON, ALZHEIMER, AND AMYOTROPHIC LATERAL SCLEROSIS (ALS), BIRTH DEFECTS, AND REPRODUCTIVE DISORDERS. THERE IS ALSO CIRCUMSTANTIAL EVIDENCE ON THE ASSOCIATION OF EXPOSURE TO PESTICIDES WITH SOME OTHER CHRONIC DISEASES LIKE RESPIRATORY PROBLEMS, PARTICULARLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CARDIOVASCULAR DISEASE SUCH AS ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE, CHRONIC NEPHROPATHIES, AUTOIMMUNE DISEASES LIKE SYSTEMIC LUPUS ERYTHEMATOUS AND RHEUMATOID ARTHRITIS, CHRONIC FATIGUE SYNDROME, AND AGING. THE COMMON FEATURE OF CHRONIC DISORDERS IS A DISTURBANCE IN CELLULAR HOMEOSTASIS, WHICH CAN BE INDUCED VIA PESTICIDES' PRIMARY ACTION LIKE PERTURBATION OF ION CHANNELS, ENZYMES, RECEPTORS, ETC., OR CAN AS WELL BE MEDIATED VIA PATHWAYS OTHER THAN THE MAIN MECHANISM. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCE ON THE ASSOCIATION OF PESTICIDE'S EXPOSURE WITH THE INCIDENCE OF CHRONIC DISEASES AND INTRODUCE GENETIC DAMAGES, EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS AND UNFOLDED PROTEIN RESPONSE (UPR), IMPAIRMENT OF UBIQUITIN PROTEASOME SYSTEM, AND DEFECTIVE AUTOPHAGY AS THE EFFECTIVE MECHANISMS OF ACTION. 2013 9 6038 49 THE CHEMICAL DEFENSIVE SYSTEM IN THE PATHOBIOLOGY OF IDIOPATHIC ENVIRONMENT-ASSOCIATED DISEASES. CHEMICAL DEFENSIVE SYSTEM CONSISTING OF BIO-SENSORING, TRANSMITTING, AND RESPONSIVE ELEMENTS HAS BEEN EVOLVED TO PROTECT MULTI-CELLULAR ORGANISMS AGAINST ENVIRONMENTAL CHEMICAL INSULTS (XENOBIOTICS) AND TO MAINTAIN HOMEOSTASIS OF ENDOGENOUS LOW MOLECULAR WEIGHT METABOLITES (ENDOBIOTICS). BOTH GENETIC AND EPIGENETIC DEFECTS OF THE SYSTEM IN ASSOCIATION WITH CARCINOGENESIS AND INDIVIDUAL SENSITIVITY TO ANTI-TUMOR THERAPIES HAVE BEEN INTENSELY STUDIED. RECENTLY, SEVERAL NON-TUMOR HUMAN PATHOLOGIES WITH EVIDENT ENVIRONMENTAL COMPONENTS SUCH AS RATHER RARE FUNCTIONAL SYNDROMES (MULTIPLE CHEMICAL SENSITIVITY, CHRONIC FATIGUE, PERSIAN GULF, AND FIBROMYALGIA NOW COLLECTIVELY LABELED AS IDIOPATHIC ENVIRONMENTAL INTOLERANCES) AND COMMON DISEASES (VITILIGO AND SYSTEMIC LUPUS ERYTHEMATOSUS) HAVE BECOME SUBJECTS OF THE RESEARCH ON THE IMPAIRED METABOLISM AND DETOXIFICATION OF XENOBIOTICS AND ENDOGENOUS TOXINS. HERE, WE COLLECTED AND CRITICALLY REVIEWED EPIDEMIOLOGICAL, GENETIC, AND BIOCHEMICAL DATA ON THE INVOLVEMENT AND POSSIBLE ROLE OF CYTOCHROME P450 SUPER FAMILY ENZYMES, GLUTATHIONE-S-TRANSFERASE ISOZYMES, CATECHOL-O-METHYL-TRANSFERASE, UDP-GLUCURONOSYL TRANSFERASES, AND PROTEINS DETOXIFYING INORGANIC AND ORGANIC PEROXIDES (CATALASE, GLUTATHIONE PEROXIDASE, AND PEROXIREDOXIN) IN THE ABOVE PATHOLOGIES. GENETIC PREDISPOSITION ASSESSED MAINLY BY SINGLE NUCLEOTIDE POLYMORPHISM AND GENE EXPRESSION ANALYSES REVEALED CORRELATIONS BETWEEN DEFECTS IN GENES ENCODING XENOBIOTIC-METABOLIZING AND/OR DETOXIFYING ENZYMES AND RISK/SEVERITY OF THESE SYNDROMES/DISEASES. PROTEOME ANALYSIS IDENTIFIED ABNORMAL EXPRESSION OF THE ENZYMES. THEIR FUNCTIONS WERE AFFECTED EPIGENETICALLY LEADING TO METABOLIC IMPAIRMENT AND, AS A CONSEQUENCE, TO THE NEGATIVE HEALTH OUTCOMES SHARED BY SOME OF THESE PATHOLOGIES. DATA OBTAINED SO FAR SUGGEST THAT DISTINCT COMPONENTS OF THE CHEMICAL DEFENSIVE SYSTEM COULD BE SUITABLE MOLECULAR TARGETS FOR FUTURE PATHOGENIC THERAPIES. 2009 10 4683 33 NEW PERSPECTIVES ON FOLATE TRANSPORT IN RELATION TO ALCOHOLISM-INDUCED FOLATE MALABSORPTION--ASSOCIATION WITH EPIGENOME STABILITY AND CANCER DEVELOPMENT. FOLATES ARE MEMBERS OF THE B-CLASS OF VITAMINS, WHICH ARE REQUIRED FOR THE SYNTHESIS OF PURINES AND PYRIMIDINES, AND FOR THE METHYLATION OF ESSENTIAL BIOLOGICAL SUBSTANCES, INCLUDING PHOSPHOLIPIDS, DNA, AND NEUROTRANSMITTERS. FOLATES CANNOT BE SYNTHESIZED DE NOVO BY MAMMALS; HENCE, AN EFFICIENT INTESTINAL ABSORPTION PROCESS IS REQUIRED. INTESTINAL FOLATE TRANSPORT IS CARRIER-MEDIATED, PH-DEPENDENT AND ELECTRONEUTRAL, WITH SIMILAR AFFINITY FOR OXIDIZED AND REDUCED FOLIC ACID DERIVATIVES. THE VARIOUS TRANSPORTERS, I.E. REDUCED FOLATE CARRIER, PROTON-COUPLED FOLATE TRANSPORTER, FOLATE-BINDING PROTEIN, AND ORGANIC ANION TRANSPORTERS, ARE INVOLVED IN THE FOLATE TRANSPORT PROCESS IN VARIOUS TISSUES. ANY IMPAIRMENT IN UPTAKE OF FOLATE CAN LEAD TO A STATE OF FOLATE DEFICIENCY, THE MOST PREVALENT VITAMIN DEFICIENCY IN WORLD, AFFECTING 10% OF THE POPULATION IN THE USA. SUCH IMPAIRMENTS IN FOLATE TRANSPORT OCCUR IN A VARIETY OF CONDITIONS, INCLUDING CHRONIC USE OF ETHANOL, SOME INBORN HEREDITARY DISORDERS, AND CERTAIN DISEASES. AMONG THESE, ETHANOL INGESTION HAS BEEN THE MAJOR CONTRIBUTOR TO FOLATE DEFICIENCY. ETHANOL-ASSOCIATED FOLATE DEFICIENCY CAN DEVELOP BECAUSE OF DIETARY INADEQUACY, INTESTINAL MALABSORPTION, ALTERED HEPATOBILIARY METABOLISM, ENHANCED COLONIC METABOLISM, AND INCREASED RENAL EXCRETION. ETHANOL REDUCES THE INTESTINAL AND RENAL UPTAKE OF FOLATE BY ALTERING THE BINDING AND TRANSPORT KINETICS OF FOLATE TRANSPORT SYSTEMS. ALSO, ETHANOL REDUCES THE EXPRESSION OF FOLATE TRANSPORTERS IN BOTH INTESTINE AND KIDNEY, AND THIS MIGHT BE A CONTRIBUTING FACTOR FOR FOLATE MALABSORPTION, LEADING TO FOLATE DEFICIENCY. THE MAINTENANCE OF INTRACELLULAR FOLATE HOMEOSTASIS IS ESSENTIAL FOR THE ONE-CARBON TRANSFER REACTIONS NECESSARY FOR DNA SYNTHESIS AND BIOLOGICAL METHYLATION REACTIONS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC DETERMINANT IN GENE EXPRESSION, IN THE MAINTENANCE OF DNA INTEGRITY AND STABILITY, IN CHROMOSOMAL MODIFICATIONS, AND IN THE DEVELOPMENT OF MUTATIONS. ETHANOL, A TOXIN THAT IS CONSUMED REGULARLY, HAS BEEN FOUND TO AFFECT THE METHYLATION OF DNA. IN ADDITION TO ITS EFFECT ON DNA METHYLATION DUE TO FOLATE DEFICIENCY, ETHANOL COULD DIRECTLY EXERT ITS EFFECT THROUGH ITS INTERACTION WITH ONE-CARBON METABOLISM, IMPAIRMENT OF METHYL GROUP SYNTHESIS, AND AFFECTING THE ENZYMES REGULATING THE SYNTHESIS OF S-ADENOSYLMETHIONINE, THE PRIMARY METHYL GROUP DONOR FOR MOST BIOLOGICAL METHYLATION REACTIONS. THUS, ETHANOL PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL DISEASES THROUGH ITS POTENTIAL ABILITY TO MODULATE THE METHYLATION OF BIOLOGICAL MOLECULES. THIS REVIEW DISCUSSES THE UNDERLYING MECHANISM OF FOLATE MALABSORPTION IN ALCOHOLISM, THE MECHANISM OF METHYLATION-ASSOCIATED SILENCING OF GENES, AND HOW THE INTERACTION BETWEEN ETHANOL AND FOLATE DEFICIENCY AFFECTS THE METHYLATION OF GENES, THEREBY MODULATING EPIGENOME STABILITY AND THE RISK OF CANCER. 2009 11 558 28 B-VITAMIN DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. CONVINCING EVIDENCE LINKS ABERRANT B-VITAMIN DEPENDENT HEPATIC METHIONINE METABOLISM TO THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). THIS REVIEW FOCUSES ON THE ESSENTIAL ROLES OF FOLATE AND VITAMINS B6 AND B12 IN HEPATIC METHIONINE METABOLISM, THE CAUSES OF THEIR DEFICIENCIES AMONG CHRONIC ALCOHOLIC PERSONS, AND HOW THEIR DEFICIENCIES TOGETHER WITH CHRONIC ALCOHOL EXPOSURE IMPACT ON ABERRANT METHIONINE METABOLISM IN THE PATHOGENESIS OF ALD. FOLATE IS THE DIETARY TRANSMETHYLATION DONOR FOR THE PRODUCTION OF S-ADENOSYLMETHIONINE (SAM), WHICH IS THE SUBSTRATE FOR ALL METHYLTRANSFERASES THAT REGULATE GENE EXPRESSIONS IN PATHWAYS OF LIVER INJURY, AS WELL AS A REGULATOR OF THE TRANSSULFURATION PATHWAY THAT IS ESSENTIAL FOR PRODUCTION OF GLUTATHIONE (GSH), THE PRINCIPAL ANTIOXIDANT FOR DEFENSE AGAINST OXIDATIVE LIVER INJURY. VITAMIN B12 REGULATES TRANSMETHYLATION REACTIONS FOR SAM PRODUCTION AND VITAMIN B6 REGULATES TRANSSULFURATION REACTIONS FOR GSH PRODUCTION. FOLATE DEFICIENCY ACCELERATES THE EXPERIMENTAL DEVELOPMENT OF ALD IN ETHANOL-FED ANIMALS WHILE REDUCING LIVER SAM LEVELS WITH RESULTANT ABNORMAL GENE EXPRESSION AND DECREASED PRODUCTION OF ANTIOXIDANT GSH. THROUGH ITS EFFECTS ON FOLATE METABOLISM, REDUCED SAM ALSO IMPAIRS NUCLEOTIDE BALANCE WITH RESULTANT INCREASED DNA STRAND BREAKS, OXIDATION, HEPATOCELLULAR APOPTOSIS, AND RISK OF CARCINOGENESIS. THE REVIEW ENCOMPASSES REFERENCED STUDIES ON MECHANISMS FOR PERTURBATIONS OF METHIONINE METABOLISM IN ALD, EVIDENCE FOR ALTERED GENE EXPRESSIONS AND THEIR EPIGENETIC REGULATION IN THE PATHOGENESIS OF ALD, AND CLINICAL STUDIES ON POTENTIAL PREVENTION AND TREATMENT OF ALD BY CORRECTION OF METHIONINE METABOLISM WITH SAM. 2013 12 5587 32 ROLE OF S-ADENOSYLHOMOCYSTEINE IN CARDIOVASCULAR DISEASE AND ITS POTENTIAL EPIGENETIC MECHANISM. TRANSMETHYLATION REACTIONS UTILIZE S-ADENOSYLMETHIONINE (SAM) AS A METHYL DONOR AND ARE CENTRAL TO THE REGULATION OF MANY BIOLOGICAL PROCESSES: MORE THAN FIFTY SAM-DEPENDENT METHYLTRANSFERASES METHYLATE A BROAD SPECTRUM OF CELLULAR COMPOUNDS INCLUDING DNA, HISTONES, PHOSPHOLIPIDS AND OTHER SMALL MOLECULES. COMMON TO ALL SAM-DEPENDENT TRANSMETHYLATION REACTIONS IS THE RELEASE OF THE POTENT INHIBITOR S-ADENOSYLHOMOCYSTEINE (SAH) AS A BY-PRODUCT. SAH IS REVERSIBLY HYDROLYZED TO ADENOSINE AND HOMOCYSTEINE BY SAH HYDROLASE. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. HOWEVER, A MAJOR UNANSWERED QUESTION IS IF HOMOCYSTEINE IS CAUSALLY INVOLVED IN DISEASE PATHOGENESIS OR SIMPLY A PASSIVE AND INDIRECT INDICATOR OF A MORE COMPLEX MECHANISM. A CHRONIC ELEVATION IN HOMOCYSTEINE LEVELS RESULTS IN A PARALLEL INCREASE IN INTRACELLULAR OR PLASMA SAH, WHICH IS A MORE SENSITIVE BIOMARKER OF CARDIOVASCULAR DISEASE THAN HOMOCYSTEINE AND SUGGESTS THAT SAH IS A CRITICAL PATHOLOGICAL FACTOR IN HOMOCYSTEINE-ASSOCIATED DISORDERS. PREVIOUS REPORTS INDICATE THAT SUPPLEMENTATION WITH FOLATE AND B VITAMINS EFFICIENTLY LOWERS HOMOCYSTEINE LEVELS BUT NOT PLASMA SAH LEVELS, WHICH POSSIBLY EXPLAINS THE FAILURE OF HOMOCYSTEINE-LOWERING VITAMINS TO REDUCE VASCULAR EVENTS IN SEVERAL RECENT CLINICAL INTERVENTION STUDIES. FURTHERMORE, MORE STUDIES ARE FOCUSING ON THE ROLE AND MECHANISMS OF SAH IN DIFFERENT CHRONIC DISEASES RELATED TO HYPERHOMOCYSTEINEMIA, SUCH AS CARDIOVASCULAR DISEASE, KIDNEY DISEASE, DIABETES, AND OBESITY. THIS REVIEW SUMMARIZES THE CURRENT ROLE OF SAH IN CARDIOVASCULAR DISEASE AND ITS EFFECT ON SEVERAL RELATED RISK FACTORS. IT ALSO EXPLORES POSSIBLE THE MECHANISMS, SUCH AS EPIGENETICS AND OXIDATIVE STRESS, OF SAH. THIS ARTICLE IS PART OF A DIRECTED ISSUE ENTITLED: EPIGENETIC DYNAMICS IN DEVELOPMENT AND DISEASE. 2015 13 6205 29 THE INFLUENCE OF PLANT EXTRACTS AND PHYTOCONSTITUENTS ON ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION IN THE PREVENTION AND TREATMENT OF IMPAIRED GLUCOSE HOMEOSTASIS AND DIABETES COMPLICATIONS. DIABETES IS A COMPLEX METABOLIC DISORDER RESULTING EITHER FROM INSULIN RESISTANCE OR AN IMPAIRED INSULIN SECRETION. PROLONGED ELEVATED BLOOD GLUCOSE CONCENTRATION, THE KEY CLINICAL SIGN OF DIABETES, INITIATES AN ENHANCEMENT OF REACTIVE OXYGEN SPECIES DERIVED FROM GLUCOSE AUTOXIDATION AND GLYCOSYLATION OF PROTEINS. CONSEQUENTLY, CHRONIC OXIDATIVE STRESS OVERWHELMS CELLULAR ENDOGENOUS ANTIOXIDANT DEFENSES AND LEADS TO THE ACUTE AND LONG-STANDING STRUCTURAL AND FUNCTIONAL CHANGES OF MACROMOLECULES RESULTING IN IMPAIRED CELLULAR FUNCTIONING, CELL DEATH AND ORGAN DYSFUNCTION. THE OXIDATIVE STRESS PROVOKED CHAIN OF PATHOLOGICAL EVENTS OVER TIME CAUSE DIABETIC COMPLICATIONS SUCH AS NEPHROPATHY, PERIPHERAL NEUROPATHY, CARDIOMYOPATHY, RETINOPATHY, HYPERTENSION, AND LIVER DISEASE. UNDER DIABETIC CONDITIONS, ACCOMPANYING GENOME/EPIGENOME AND METABOLITE MARKERS ALTERATIONS MAY ALSO AFFECT GLUCOSE HOMEOSTASIS, PANCREATIC BETA-CELLS, MUSCLE, LIVER, AND ADIPOSE TISSUE. BY PROVIDING DEEPER GENETIC/EPIGENETIC INSIGHT OF DIRECT OR INDIRECT DIETARY EFFECTS, NUTRIGENOMICS OFFERS A PROMISING OPPORTUNITY TO IMPROVE THE QUALITY OF LIFE OF DIABETIC PATIENTS. NATURAL PLANT EXTRACTS, OR THEIR NATURALLY OCCURRING COMPOUNDS, WERE SHOWN TO BE VERY PROFICIENT IN THE PREVENTION AND TREATMENT OF DIFFERENT PATHOLOGIES ASSOCIATED WITH OXIDATIVE STRESS INCLUDING DIABETES AND ITS COMPLICATIONS. CONSIDERING THAT FOOD INTAKE IS ONE OF THE CRUCIAL COMPONENTS IN DIABETES' PREVALENCE, PROGRESSION AND COMPLICATIONS, THIS REVIEW SUMMARIZES THE EFFECT OF THE MAJOR PLANT SECONDARY METABOLITE AND PHYTOCONSTITUENTS ON THE ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION UNDER DIABETIC CONDITIONS. 2021 14 2546 36 EPIGENETICS IN MULTIPLE SCLEROSIS: MOLECULAR MECHANISMS AND DIETARY INTERVENTION. INTRODUCTION: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, INFLAMMATORY, NEURODEGENERATIVE DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS). UNFORTUNATELY, MS CAUSES IMPORTANT DISABILITY IN YOUNG ADULTS AND ITS PREVALENCE IS INCREASING. WHILE THE ETIOLOGY OF MS ETIOLOGY IS NOT COMPLETELY UNDERSTOOD, IT SEEMS TO BE A MULTIFACTORIAL ENTITY THAT IS INFLUENCED BY BOTH GENETIC AND EPIGENETIC MODIFICATIONS. EPIGENETIC MECHANISMS ADD OR REMOVE DIFFERENT CHEMICAL GROUPS FOR THE ACTIVATION OR INHIBITION OF GENE EXPRESSION TO BLOCK THE PRODUCTION OF PROINFLAMMATORY PROTEINS. IT IS TRULY IMPORTANT TO IDENTIFY THE FACTORS THAT CAN TRIGGER EPIGENETIC CHANGES IN MS TO COMPLEMENT THE THERAPEUTIC APPROACH, PREVENT DISABILITY AND IMPROVE PATIENTS QUALITY OF LIFE. HERE, WE HAVE CONDUCTED A REVIEW OF EXTERNAL FACTORS THAT INFLUENCE IN MS AND THEIR EPIGENETIC MECHANISMS. FOR EXAMPLE, HYPOMETHYLATION CAN PROMOTE CHANGES IN THE MYELIN AND SUBSEQUENT AUTOIMMUNE REACTIONS. THERAPEUTIC TOOLS CAN BE USED, INCLUDING THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A, WHICH AMELIORATES DEMYELINATING DISEASES IN RODENTS. HOWEVER, DRUGS ARE NOT ONLY THE THERAPEUTIC OPTION: RECENT STUDIES HAVE ALSO EVALUATED THE THERAPEUTIC POTENTIAL OF SEVERAL BIOACTIVE DIETARY COMPONENTS IN NEURODEGENERATION AND AXONAL DYSFUNCTION. NUMEROUS FOOD-DERIVED MOLECULES EXERT IMPORTANT METABOLIC ACTIONS. THESE MOLECULES INCLUDE PLANT POLYPHENOLS SUCH AS CATECHINS AND ISOFLAVONES, OMEGA-3 AND OMEGA-6 POLYUNSATURATED FATTY ACIDS, SHORT-CHAIN FATTY ACIDS, SULFUR-CONTAINING COMPOUNDS SUCH AS DALLY SULFIDE AND OTHER COMPOUNDS. ANTIOXIDANT AND ANTI-INFLAMMATORY COMPONENTS IN THE DIET INVOLVE TRANSCRIPTION FACTORS AS WELL. HOWEVER, MANY EXTERNAL FACTORS HAVE SHOWN TO INFLUENCE MS, ALTHOUGH NO SPECIFIC EPIGENETIC MECHANISMS ARE KNOWN. CONCLUSION: IN THIS REVIEW, WE GATHER BOTH ESTABLISHED AND NEW EVIDENCES ABOUT THE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS INFLUENCING MS AND THE DIETARY COMPONENTS THAT COULD MODULATE MS RELAPSE AND PROGRESSION. 2018 15 5112 15 POLYUNSATURATED FATTY ACIDS: BIOCHEMICAL, NUTRITIONAL AND EPIGENETIC PROPERTIES. DIETARY POLYUNSATURATED FATTY ACIDS (PUFA) HAVE EFFECTS ON DIVERSE PHYSIOLOGICAL PROCESSES IMPACTING NORMAL HEALTH AND CHRONIC DISEASES, SUCH AS THE REGULATION OF PLASMA LIPID LEVELS, CARDIOVASCULAR AND IMMUNE FUNCTION, INSULIN ACTION AND NEURONAL DEVELOPMENT AND VISUAL FUNCTION. INGESTION OF PUFA WILL LEAD TO THEIR DISTRIBUTION TO VIRTUALLY EVERY CELL IN THE BODY WITH EFFECTS ON MEMBRANE COMPOSITION AND FUNCTION, EICOSANOID SYNTHESIS, CELLULAR SIGNALING AND REGULATION OF GENE EXPRESSION. CELL SPECIFIC LIPID METABOLISM, AS WELL AS THE EXPRESSION OF FATTY ACID-REGULATED TRANSCRIPTION FACTORS, LIKELY PLAY AN IMPORTANT ROLE IN DETERMINING HOW CELLS RESPOND TO CHANGES IN PUFA COMPOSITION. THIS REVIEW WILL FOCUS ON RECENT ADVANCES ON THE ESSENTIALITY OF THESE MOLECULES AND ON THEIR INTERPLAY IN CELL PHYSIOLOGY, LEADING TO NEW PERSPECTIVE IN DIFFERENT THERAPEUTIC FIELDS. 2004 16 5010 31 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 17 6259 18 THE MOLECULAR MECHANISMS BY WHICH VITAMIN D PREVENTS INSULIN RESISTANCE AND ASSOCIATED DISORDERS. NUMEROUS STUDIES HAVE SHOWN THAT VITAMIN D DEFICIENCY IS VERY COMMON IN MODERN SOCIETIES AND IS PERCEIVED AS AN IMPORTANT RISK FACTOR IN THE DEVELOPMENT OF INSULIN RESISTANCE AND RELATED DISEASES SUCH AS OBESITY AND TYPE 2 DIABETES (T2DM). WHILE IT IS GENERALLY ACCEPTED THAT VITAMIN D IS A REGULATOR OF BONE HOMEOSTASIS, ITS ABILITY TO COUNTERACT INSULIN RESISTANCE IS SUBJECT TO DEBATE. THE GOAL OF THIS COMMUNICATION IS TO REVIEW THE MOLECULAR MECHANISM BY WHICH VITAMIN D REDUCES INSULIN RESISTANCE AND RELATED COMPLICATIONS. THE UNIVERSITY LIBRARY, PUBMED, AND GOOGLE SCHOLAR WERE SEARCHED TO FIND RELEVANT STUDIES TO BE SUMMARIZED IN THIS REVIEW ARTICLE. INSULIN RESISTANCE IS ACCOMPANIED BY CHRONIC HYPERGLYCAEMIA AND INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT VITAMIN D EXHIBITS INDIRECT ANTIOXIDATIVE PROPERTIES AND PARTICIPATES IN THE MAINTENANCE OF NORMAL RESTING ROS LEVEL. APPEALINGLY, VITAMIN D REDUCES INFLAMMATION AND REGULATES CA(2+) LEVEL IN MANY CELL TYPES. THEREFORE, THE BENEFICIAL ACTIONS OF VITAMIN D INCLUDE DIMINISHED INSULIN RESISTANCE WHICH IS OBSERVED AS AN IMPROVEMENT OF GLUCOSE AND LIPID METABOLISM IN INSULIN-SENSITIVE TISSUES. 2020 18 1395 37 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 19 1637 32 DOES DYSREGULATION OF KEY EPIGENETIC AND BIOCHEMICAL PATHWAYS OCCUR IN POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE DISORDERS? AUTOIMMUNE DYSFUNCTION OF CERTAIN VASOACTIVE NEUROPEPTIDES (VNS) HAS BEEN POSTULATED AS A CONTRIBUTING CAUSE OF SUDDEN INFANT DEATH SYNDROME (SIDS), CHRONIC FATIGUE SYNDROME (CFS), GULF WAR SYNDROME (GWS) AND OTHER FATIGUE-RELATED DISORDERS. THIS FAMILY OF VNS INCLUDES PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP), VASOACTIVE INTESTINAL PEPTIDE (VIP) AND CALCITONIN GENE RELATED PEPTIDE (CGRP). THE POSTULATED MECHANISM IS COMPROMISE OF ADENYLATE CYCLASE ACTIVATION, A VITAL AND UNIQUE STEP IN CYCLIC AMP PRODUCTION FROM ATP, THROUGH AUTOIMMUNE DYSFUNCTION OF VNS, THEIR RECEPTORS OR THEIR GENES POSSIBLY INVOLVING CYTOSINE-PHOSPHATE-GUANINE (CPG) FRAGMENTS. CPG FRAGMENTS ARE IMMUNOMODULATORY DINUCLEOTIDES SERVING AS 'FRIEND OR FOE' RECOGNITION SYSTEMS TO DIFFERENTIATE BACTERIAL AND VIRAL (HYPOMETHYLATED CPG) FROM MAMMALIAN (METHYLATED CPG) DNA. HOWEVER HYPOMETHYLATION DISORDERS AFFECTING THESE FRAGMENTS IN MAMMALS MAY CONVERT THEM TO DYSFUNCTIONAL STATES BY PROMOTING AUTOIMMUNE INFLAMMATORY REACTIONS. EPIGENETIC MECHANISMS ACTING ON GENE PROMOTER REGIONS MAY CONTRIBUTE TO THE DEVELOPMENT OF VN AUTOIMMUNE FATIGUE-RELATED DISORDERS THROUGH CPG FRAGMENTS LOCATED IN VITAL SEGMENTS OF VN/RECEPTOR GENES BY CAUSING SIGNALLING DEFECTS WITH PROFOUND IMPLICATIONS FOR VN FUNCTION. NEUROTRANSMITTER DYSFUNCTION PARTICULARLY GLUTAMATERGIC TRANSMISSION COULD ALSO RESULT WITH DISRUPTION OF NEURONAL CELLULAR BIOCHEMICAL FUNCTIONS SUCH AS AMMONIA REGULATION. ENDOSOMAL ACIDITY AND MITOCHONDRIAL MEMBRANE POTENTIAL MODIFIERS SUCH AS CHLOROQUINE, TOGETHER WITH IMMUNOREGULATORY THERAPIES, MAY HAVE THERAPEUTIC IMPLICATIONS IN PROTECTING AGAINST THESE APPARENT AUTOIMMUNE DISORDERS. THIS PAPER EXAMINES SPECIFIC EPIGENETIC AND BIOCHEMICAL MECHANISMS POSSIBLY MEDIATED BY VN OR RECEPTOR GENES RESULTING IN POSTULATED VN AUTOIMMUNE FATIGUE-RELATED DISORDERS. THESE MECHANISMS MAY HAVE IMPLICATIONS FOR TREATMENT AND PREVENTION OPTIONS FOR VN AUTOIMMUNE DISORDERS. VN AUTOIMMUNE PROCESSES HAVE IMPLICATIONS FOR MILITARY MEDICINE WHERE RADIOLOGICAL, CHEMICAL AND BIOLOGICAL AGENTS MAY PLAY AN IMPORTANT ROLE IN PATHOGENESIS. 2005 20 6166 31 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