1 4152 137 MECHANISTIC INSIGHTS INTO THE PLEIOTROPIC EFFECTS OF BUTYRATE AS A POTENTIAL THERAPEUTIC AGENT ON NAFLD MANAGEMENT: A SYSTEMATIC REVIEW. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC DISEASES WORLDWIDE. AS A MULTIFACETED DISEASE, NAFLD'S PATHOGENESIS IS NOT ENTIRELY UNDERSTOOD, BUT RECENT EVIDENCE REVEALS THAT GUT MICROBIOTA PLAYS A SIGNIFICANT ROLE IN ITS PROGRESSION. BUTYRATE, A GUT MICROBIOTA METABOLITE, HAS BEEN REPORTED TO HAVE HEPATO-PROTECTIVE EFFECTS IN NAFLD ANIMAL MODELS. THE PURPOSE OF THIS SYSTEMATIC REVIEW IS TO DETERMINE HOW BUTYRATE AFFECTS THE RISK FACTORS FOR NAFLD. SEARCHES WERE CONDUCTED USING RELEVANT KEYWORDS IN ELECTRONIC DATABASES UP TO MARCH 2022. ACCORDING TO THE EVIDENCE PRESENTED IN THIS STUDY, BUTYRATE CONTRIBUTES TO A WIDE VARIETY OF BIOLOGICAL PROCESSES IN THE GUT-LIVER AXIS. ITS BENEFICIAL PROPERTIES INCLUDE IMPROVING INTESTINAL HOMEOSTASIS AND LIVER HEALTH AS WELL AS ANTI-INFLAMMATORY, METABOLISM REGULATORY AND ANTI-OXIDATIVE EFFECTS. THESE EFFECTS MAY BE ATTRIBUTED TO BUTYRATE'S ABILITY TO REGULATE GENE EXPRESSION AS AN EPIGENETIC MODULATOR AND TRIGGER CELLULAR RESPONSES AS A SIGNALLING MOLECULE. HOWEVER, THE EXACT UNDERLYING MECHANISMS REMAIN UNCLEAR. HUMAN TRIALS HAVE NOT BEEN PERFORMED ON THE EFFECT OF BUTYRATE ON NAFLD, SO THERE ARE CONCERNS ABOUT WHETHER THE RESULTS OF ANIMAL STUDIES CAN BE TRANSLATED TO HUMANS. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ABOUT THE PROPERTIES OF BUTYRATE, PARTICULARLY ITS POTENTIAL EFFECTS AND MECHANISMS ON LIVER HEALTH AND NAFLD MANAGEMENT. 2022 2 5558 38 ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY: PROPOSED MECHANISMS AND REVIEW OF THE LITERATURE. THE AETIOLOGY OF OBESITY HAS BEEN ATTRIBUTED TO SEVERAL FACTORS (ENVIRONMENTAL, DIETARY, LIFESTYLE, HOST, AND GENETIC FACTORS); HOWEVER NONE OF THESE FULLY EXPLAIN THE INCREASE IN THE PREVALENCE OF OBESITY WORLDWIDE. GUT MICROBIOTA LOCATED AT THE INTERFACE OF HOST AND ENVIRONMENT IN THE GUT ARE A NEW AREA OF RESEARCH BEING EXPLORED TO EXPLAIN THE EXCESS ACCUMULATION OF ENERGY IN OBESE INDIVIDUALS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANIPULATION TO REDUCE HOST ENERGY STORAGE. SEVERAL MECHANISMS HAVE BEEN SUGGESTED TO EXPLAIN THE ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY SUCH AS SHORT CHAIN FATTY ACID PRODUCTION, STIMULATION OF HORMONES, CHRONIC LOW-GRADE INFLAMMATION, LIPOPROTEIN AND BILE ACID METABOLISM, AND INCREASED ENDOCANNABINOID RECEPTOR SYSTEM TONE. HOWEVER, EVIDENCE FROM ANIMAL AND HUMAN STUDIES CLEARLY INDICATES CONTROVERSIES IN DETERMINING THE CAUSE OR EFFECT RELATIONSHIP BETWEEN THE GUT MICROBIOTA AND OBESITY. METAGENOMICS BASED STUDIES INDICATE THAT FUNCTIONALITY RATHER THAN THE COMPOSITION OF GUT MICROBIOTA MAY BE IMPORTANT. FURTHER MECHANISTIC STUDIES CONTROLLING FOR ENVIRONMENTAL AND EPIGENETIC FACTORS ARE THEREFORE REQUIRED TO HELP UNRAVEL OBESITY PATHOGENESIS. 2016 3 4273 39 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 4 4710 36 NON-ALCOHOLIC FATTY LIVER DISEASE AND THE IMPACT OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS IN THE OFFSPRING. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE AND IS STRONGLY ASSOCIATED WITH METABOLIC DEREGULATION. MORE RECENTLY, A SIGNIFICANT IMPACT OF PARENTAL NAFLD IN THE OFFSPRING WAS DEMONSTRATED AND HAS BEEN WIDELY DISCUSSED. HOWEVER, PATHOGENETIC PATHWAYS IMPLICATED IN THE INHERITANCE BY THE OFFSPRING AND RELATIVES ARE STILL UNDER DEBATE. PROBABLY, MULTIPLE MECHANISMS ARE INVOLVED AS WELL AS IN NAFLD PATHOGENESIS ITSELF. AMONG THE MULTIFACTORIAL INVOLVED MECHANISMS, GENETIC, EPIGENETIC AND ENVIRONMENTAL BACKGROUNDS ARE STRONGLY RELATED TO NAFLD DEVELOPMENT IN THE OFFSPRING. THUS, BASED ON RECENT EVIDENCE FROM THE AVAILABLE LITERATURE CONCERNING GENETIC, EPIGENETIC AND ENVIRONMENTAL DISEASE MODIFIERS, THIS REVIEW AIMED TO DISCUSS THE RELATIONSHIP BETWEEN PARENTAL NAFLD AND ITS IMPACT ON THE OFFSPRING. 2022 5 2617 50 EPIGENOME TARGETING BY PROBIOTIC METABOLITES. BACKGROUND: THE INTESTINAL MICROBIOTA PLAYS AN IMPORTANT ROLE IN IMMUNE DEVELOPMENT AND HOMEOSTASIS. A DISTURBED MICROBIOTA DURING EARLY INFANCY IS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING INFLAMMATORY AND ALLERGIC DISEASES LATER IN LIFE. THE MECHANISMS UNDERLYING THESE EFFECTS ARE POORLY UNDERSTOOD BUT ARE LIKELY TO INVOLVE ALTERATIONS IN MICROBIAL PRODUCTION OF FERMENTATION-DERIVED METABOLITES, WHICH HAVE POTENT IMMUNE MODULATING PROPERTIES AND ARE REQUIRED FOR MAINTENANCE OF HEALTHY MUCOSAL IMMUNE RESPONSES. PROBIOTICS ARE BENEFICIAL BACTERIA THAT HAVE THE CAPACITY TO ALTER THE COMPOSITION OF BACTERIAL SPECIES IN THE INTESTINE THAT CAN IN TURN INFLUENCE THE PRODUCTION OF FERMENTATION-DERIVED METABOLITES. PRINCIPAL AMONG THESE METABOLITES ARE THE SHORT-CHAIN FATTY ACIDS BUTYRATE AND ACETATE THAT HAVE POTENT ANTI-INFLAMMATORY ACTIVITIES IMPORTANT IN REGULATING IMMUNE FUNCTION AT THE INTESTINAL MUCOSAL SURFACE. THEREFORE STRATEGIES AIMED AT RESTORING THE MICROBIOTA PROFILE MAY BE EFFECTIVE IN THE PREVENTION OR TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES. PRESENTATION OF THE HYPOTHESIS: PROBIOTIC BACTERIA HAVE DIVERSE EFFECTS INCLUDING ALTERING MICROBIOTA COMPOSITION, REGULATING EPITHELIAL CELL BARRIER FUNCTION AND MODULATING OF IMMUNE RESPONSES. THE PRECISE MOLECULAR MECHANISMS MEDIATING THESE PROBIOTIC EFFECTS ARE NOT WELL UNDERSTOOD. SHORT-CHAIN FATTY ACIDS SUCH AS BUTYRATE ARE A CLASS OF HISTONE DEACETYLASE INHIBITORS IMPORTANT IN THE EPIGENETIC CONTROL OF HOST CELL RESPONSES. IT IS HYPOTHESIZED THAT THE BIOLOGICAL FUNCTION OF PROBIOTICS MAY BE A RESULT OF EPIGENETIC MODIFICATIONS THAT MAY EXPLAIN THE WIDE RANGE OF EFFECTS OBSERVED. STUDIES DELINEATING THE EFFECTS OF PROBIOTICS ON SHORT-CHAIN FATTY ACID PRODUCTION AND THE EPIGENETIC ACTIONS OF SHORT-CHAIN FATTY ACIDS WILL ASSIST IN UNDERSTANDING THE ASSOCIATION BETWEEN MICROBIOTA AND ALLERGIC OR AUTOIMMUNE DISORDERS. TESTING THE HYPOTHESIS: WE PROPOSE THAT TREATMENT WITH SPECIFIC PROBIOTIC BACTERIA UNDER IN VIVO CONDITIONS WOULD OFFER THE IDEAL CONDITIONS TO EXAMINE THE MICROBIOLOGICAL, IMMUNOLOGICAL AND EPIGENETIC MECHANISMS OF ACTION. ADVANCES IN EPIGENETIC TECHNOLOGY NOW ALLOW INVESTIGATORS TO BETTER UNDERSTAND THE COMPLEX BIOLOGICAL PROPERTIES OF PROBIOTICS AND THEIR METABOLITES. IMPLICATIONS OF THE HYPOTHESIS: DETERMINING THE PRECISE MECHANISMS OF PROBIOTIC ACTION WILL LEAD TO MORE SPECIFIC AND EFFICACIOUS THERAPEUTIC STRATEGIES IN THE PREVENTION OR TREATMENT OF CHRONIC INFLAMMATORY CONDITIONS. 2010 6 1400 35 DIET-REGULATING MICROBIOTA AND HOST IMMUNE SYSTEM IN LIVER DISEASE. THE GUT MICROBIOTA HAS BEEN KNOWN TO MODULATE THE IMMUNE RESPONSES IN CHRONIC LIVER DISEASES. RECENT EVIDENCE SUGGESTS THAT EFFECTS OF DIETARY FOODS ON HEALTH CARE AND HUMAN DISEASES ARE RELATED TO BOTH THE IMMUNE REACTION AND THE MICROBIOME. THE GUT-MICROBIOME AND INTESTINAL IMMUNE SYSTEM PLAY A CENTRAL ROLE IN THE CONTROL OF BACTERIAL TRANSLOCATION-INDUCED LIVER DISEASE. DYSBIOSIS, SMALL INTESTINAL BACTERIAL OVERGROWTH, TRANSLOCATION, ENDOTOXEMIA, AND THE DIRECT EFFECTS OF METABOLITES ARE THE MAIN EVENTS IN THE GUT-LIVER AXIS, AND IMMUNE RESPONSES ACT ON EVERY PATHWAYS OF CHRONIC LIVER DISEASE. MICROBIOME-DERIVED METABOLITES OR BACTERIA THEMSELVES REGULATE IMMUNE CELL FUNCTIONS SUCH AS RECOGNITION OR ACTIVATION OF RECEPTORS, THE CONTROL OF GENE EXPRESSION BY EPIGENETIC CHANGE, ACTIVATION OF IMMUNE CELLS, AND THE INTEGRATION OF CELLULAR METABOLISM. HERE, WE REVIEWED RECENT REPORTS ABOUT THE IMMUNOLOGIC ROLE OF GUT MICROBIOTAS IN LIVER DISEASE, HIGHLIGHTING THE ROLE OF DIET IN CHRONIC LIVER DISEASE. 2021 7 6913 28 [VARIOUS PATHWAYS LEADING TO THE PROGRESSION OF CHRONIC LIVER DISEASES]. AS THE RESULT OF VARIOUS EFFECTS (VIRUSES, METABOLIC DISEASES, NUTRITIONAL FACTORS, TOXIC AGENTS, AUTOIMMUNE PROCESSES) ABNORMAL LIVER FUNCTION, LIVER STEATOSIS AND CONNECTIVE TISSUE REMODELING MAY DEVELOP. PROGRESSION OF THIS PROCESS IS COMPLEX INCLUDING VARIOUS PATHWAYS AND A NUMBER OF FACTORS. THE AUTHORS SUMMARIZE THE FACTORS INVOLVED IN THE PROGRESSION OF CHRONIC LIVER DISEASE. THEY DESCRIBE THE ROLE OF CELLS AND THE PRODUCED INFLAMMATORY MEDIATORS AND CYTOKINES, AS WELL AS THE RELATIONSHIP BETWEEN THE DISEASE AND THE INTESTINAL FLORA. THEY EMPHASIZE THE ROLE OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL DEATH IN DISEASE PROGRESSION. INSULIN RESISTANCE AND MICRO-ELEMENTS (IRON, COPPER) IN RELATION TO LIVER DAMAGE ARE ALSO DISCUSSED, AND GENETIC AND EPIGENETIC ASPECTS UNDERLYING DISEASE PROGRESSION ARE SUMMARIZED. DISCOVERY OF NOVEL TREATMENT OPTIONS, ASSESSMENT OF THE EFFECTIVENESS OF TREATMENT, AS WELL AS THE SUCCESS AND PROPER TIMING OF LIVER TRANSPLANTATION MAY DEPEND ON A BETTER UNDERSTANDING OF THE PROCESS OF DISEASE PROGRESSION. 2016 8 2954 37 GENETIC AND EPIGENETIC FACTORS DETERMINING NAFLD RISK. BACKGROUND: HEPATIC STEATOSIS IS A COMMON CHRONIC LIVER DISEASE THAT CAN PROGRESS INTO MORE SEVERE STAGES OF NAFLD OR PROMOTE THE DEVELOPMENT OF LIFE-THREATENING SECONDARY DISEASES FOR SOME OF THOSE AFFECTED. THESE INCLUDE THE LIVER ITSELF (NONALCOHOLIC STEATOHEPATITIS OR NASH; FIBROSIS AND CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA) OR OTHER ORGANS SUCH AS THE VESSELS AND THE HEART (CARDIOVASCULAR DISEASE) OR THE ISLETS OF LANGERHANS (TYPE 2 DIABETES). IN ADDITION TO ELEVATED CALORIC INTAKE AND A SEDENTARY LIFESTYLE, GENETIC AND EPIGENETIC PREDISPOSITION CONTRIBUTE TO THE DEVELOPMENT OF NAFLD AND THE SECONDARY DISEASES. SCOPE OF REVIEW: WE PRESENT DATA FROM GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND FUNCTIONAL STUDIES IN RODENTS WHICH DESCRIBE POLYMORPHISMS IDENTIFIED IN GENES RELEVANT FOR THE DISEASE AS WELL AS CHANGES CAUSED BY ALTERED DNA METHYLATION AND GENE REGULATION VIA SPECIFIC MIRNAS. THE REVIEW ALSO PROVIDES INFORMATION ON THE CURRENT STATUS OF THE USE OF GENETIC AND EPIGENETIC FACTORS AS RISK MARKERS. MAJOR CONCLUSION: WITH OUR OVERVIEW WE PROVIDE AN INSIGHT INTO THE GENETIC AND EPIGENETIC LANDSCAPE OF NAFLD AND ARGUE ABOUT THE APPLICABILITY OF CURRENTLY DEFINED RISK SCORES FOR RISK STRATIFICATION AND CONCLUDE THAT FURTHER EFFORTS ARE NEEDED TO MAKE THE SCORES MORE USABLE AND MEANINGFUL. 2021 9 5390 42 REDOX-FIBROSIS: IMPACT OF TGFBETA1 ON ROS GENERATORS, MEDIATORS AND FUNCTIONAL CONSEQUENCES. FIBROSIS IS ONE OF THE MOST PREVALENT FEATURES OF AGE-RELATED DISEASES LIKE OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE, OR CARDIOMYOPATHY AND AFFECTS MILLIONS OF PEOPLE IN ALL COUNTRIES. ALTHOUGH THE UNDERSTANDING ABOUT THE PATHOPHYSIOLOGY OF FIBROSIS HAS IMPROVED A LOT DURING THE RECENT YEARS, A NUMBER OF MECHANISMS STILL REMAIN UNKNOWN. ALTHOUGH TGF-BETA1 SIGNALING, LOSS OF METABOLIC HOMEOSTASIS AND CHRONIC LOW-GRADE INFLAMMATION APPEAR TO PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS, RECENT EVIDENCE INDICATES THAT OXIDATIVE STRESS AND THE ANTIOXIDANT SYSTEM MAY ALSO BE CRUCIAL FOR FIBROSIS DEVELOPMENT AND PERSISTENCE. THESE FINDINGS POINT TO A CONCEPT OF A REDOX-FIBROSIS WHERE THE CELLULAR OXIDANT AND ANTIOXIDANT SYSTEM COULD BE POTENTIAL THERAPEUTIC TARGETS. THE CURRENT REVIEW AIMS TO SUMMARIZE THE EXISTING LINKS BETWEEN TGF-BETA1 SIGNALING, GENERATION AND ACTION OF REACTIVE OXYGEN SPECIES, EXPRESSION OF ANTIOXIDATIVE ENZYMES, AND FUNCTIONAL CONSEQUENCES INCLUDING EPIGENETIC REDOX-MEDIATED RESPONSES DURING FIBROSIS. 2015 10 3022 36 GENETICS AND EPIGENETICS PURPOSE IN NONALCOHOLIC FATTY LIVER DISEASE. INTRODUCTION: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) COMPRISES A BROAD SPECTRUM OF DISEASES, WHICH CAN PROGRESS FROM BENIGN STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE IN DEVELOPED COUNTRIES, AFFECTING APPROXIMATELY 25% OF THE GENERAL POPULATION. INSULIN RESISTANCE, ADIPOSE TISSUE DYSFUNCTION, MITOCHONDRIAL AND ENDOPLASMIC RETICULUM STRESS, CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS ARE NAFLD TRIGGERS THAT CONTROL THE DISEASE SUSCEPTIBILITY AND PROGRESSION. AREAS COVERED: IN RECENT YEARS A LARGE NUMBER OF INVESTIGATIONS HAVE BEEN CARRIED OUT TO ELUCIDATE GENETIC AND EPIGENETIC FACTORS IN THE DISEASE PATHOGENESIS, AS WELL AS THE SEARCH FOR DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS. THIS PAPER OBJECTIVE IS TO REPORT THE MOST STUDIED GENETIC AND EPIGENETIC VARIANTS AROUND NAFLD. EXPERT OPINION: NAFLD LEAD TO VARIOUS COMORBIDITIES, WHICH HAVE A CONSIDERABLE IMPACT ON THE PATIENT WELLNESS AND LIFE QUALITY, AS WELL AS ON THE COSTS THEY GENERATE FOR THE COUNTRY'S HEALTH SERVICES. IT IS ESSENTIAL TO CONTINUE WITH MOLECULAR RESEARCH, SINCE IT COULD BE USED AS A CLINICAL TOOL FOR PROGNOSIS AND DISEASE SEVERITY. SPECIFICALLY, IN THE FIELD OF HEPATOLOGY, PLASMA MIRNAS COULD PROVIDE A NOVEL TOOL IN LIVER DISEASES DIAGNOSIS AND MONITORING, REPRESENTING AN ALTERNATIVE TO INVASIVE DIAGNOSTIC PROCEDURES. 2020 11 3293 43 HIGH FAT DIET-TRIGGERED NON-ALCOHOLIC FATTY LIVER DISEASE: A REVIEW OF PROPOSED MECHANISMS. OBESITY IS CHARACTERIZED BY THE DEPOSITION OF EXCESSIVE BODY FAT, AND IS CAUSED BY ENERGY IMBALANCE, ESPECIALLY WHEN CONSUMING FAT-RICH DIETS. HIGH FAT DIET (HFD)-ASSOCIATED OBESITY IS GREATLY COMMON IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) THAT IS EMERGING AS ONE OF THE MOST UNIVERSAL CAUSES OF LIVER DISEASE WORLDWIDE, ESPECIALLY IN WESTERN COUNTRIES. IN SPITE OF ITS HIGH PREVALENCE, ONLY A SMALL PROPORTION OF AFFECTED INDIVIDUALS WILL BECOME INFLAMED, FOLLOWED BY FIBROSIS AND CHRONIC LIVER DISEASES, AND MOST PATIENTS ONLY SHOW SIMPLE STEATOSIS. IN THIS CASE, THE FULL COMPREHENSION OF THE MECHANISMS UNDERLYING THE PROGRESSION OF NAFLD IS OF EXTREME SIGNIFICANCE; IN SPITE OF PROGRESS IN THIS FIELD, AWARENESS ON THE DEVELOPMENT OF NAFLD IS STILL INCOMPLETE. TRADITIONALLY, LIVER STEATOSIS IS COMMONLY CONNECTED WITH HFD, OBESITY, AND INSULIN RESISTANCE (IR). RECENTLY, VARIOUS POSSIBLE MECHANISMS HAVE BEEN PUT FORWARD FOR LIVER DAMAGE, INCLUDING ENDOPLASMIC RETICULUM STRESS, PERTURBATION OF AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, HEPATOCELLULAR APOPTOSIS, GUT MICROBIOTA IMBALANCE, DYSREGULATION OF MICRORNAS, AND GENETIC/EPIGENETIC RISK FACTORS, AS WELL AS AN INCREASE IN INFLAMMATORY RESPONSES, AMONG MANY OTHERS. COLLECTIVELY, THESE PROPOSED MECHANISMS ALLOW FOR A VARIETY OF HITS ACTING TOGETHER ON SUBJECTS TO MEDIATED NAFLD AND WILL OFFER A MORE ACCURATE EXPLANATION FOR PROGRESSION OF NAFLD. THEREFORE, THIS REVIEW SUMMARIZES THE PRESENT INFORMATION CONCERNING NAFLD AFTER HFD EXPOSURE, AS WELL AS DISCUSSES POSSIBLE MECHANISMS THROUGH WHICH IT MAY ARISE. 2020 12 1491 42 DNA HYDROXYMETHYLATION AT THE INTERFACE OF THE ENVIRONMENT AND NONALCOHOLIC FATTY LIVER DISEASE. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST PREVALENT FORMS OF CHRONIC LIVER DISORDERS AMONG ADULTS, CHILDREN, AND ADOLESCENTS, AND A GROWING EPIDEMIC, WORLDWIDE. NOTWITHSTANDING THE KNOWN SUSCEPTIBILITY FACTORS FOR NAFLD, I.E., OBESITY AND METABOLIC SYNDROME, THE EXACT CAUSE(S) OF THIS DISEASE AND THE UNDERLYING MECHANISMS OF ITS INITIATION AND PROGRESSION ARE NOT FULLY ELUCIDATED. NAFLD IS A MULTI-FACETED DISEASE WITH METABOLIC, GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. ACCUMULATING EVIDENCE SHOWS THAT EXPOSURE TO ENVIRONMENTAL TOXICANTS CONTRIBUTES TO THE DEVELOPMENT OF NAFLD BY PROMOTING MITOCHONDRIAL DYSFUNCTION AND GENERATING REACTIVE OXYGEN SPECIES IN THE LIVER. IMBALANCES IN THE REDOX STATE OF THE CELLS ARE KNOWN TO CAUSE ALTERATIONS IN THE PATTERNS OF 5-HYDROXYMETHYLCYTOSINE (5HMC), THE OXIDATIVE PRODUCT OF 5-METHYLCYTOSINE (5MC), THEREBY INFLUENCING GENE REGULATION. THE 5HMC-MEDIATED DEREGULATION OF GENES INVOLVED IN HEPATIC METABOLISM IS AN EMERGING AREA OF RESEARCH IN NAFLD. THIS REVIEW SUMMARIZES OUR CURRENT KNOWLEDGE ON THE INTERACTIVE ROLE OF XENOBIOTIC EXPOSURE AND DNA HYDROXYMETHYLATION IN THE PATHOGENESIS OF FATTY LIVER DISEASE. INCREASING THE MECHANISTIC KNOWLEDGE OF NAFLD INITIATION AND PROGRESSION IS CRUCIAL FOR THE DEVELOPMENT OF NEW AND EFFECTIVE STRATEGIES FOR PREVENTION AND TREATMENT OF THIS DISEASE. 2019 13 3404 46 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 14 5079 38 PHYSIOPATHOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE: FROM DIET TO NUTRIGENOMICS. PURPOSE OF REVIEW: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND IS STRONGLY ASSOCIATED WITH METABOLIC DISORDERS, SUCH AS OBESITY, TYPE 2 DIABETES MELLITUS, AND METABOLIC SYNDROME, TO THE EXTENT THAT A NEW DEFINITION OF METABOLIC ASSOCIATED FATTY LIVER DISEASE HAS BEEN PROPOSED. RECENT FINDINGS: INSULIN RESISTANCE, WORSENED BY A HIGH-FAT AND HIGH-CARBOHYDRATE DIET, IS THE KEY TO THE PHYSIOPATHOLOGY OF HEPATIC STEATOSIS. THIS IS DRIVEN BY SEVERAL MECHANISMS THAT ARE MOSTLY ACTIVATED AT A GENETIC LEVEL, SUCH AS DE-NOVO LIPOGENESIS AND TRIGLYCERIDE SYNTHESIS. THEREFORE, MANY DIET REGIMENS HAVE BEEN STUDIED, ALTHOUGH SIGNIFICANT CONTROVERSIES REMAIN REGARDING THEIR METABOLIC EFFECTS AND LONG-TERM SUSTAINABILITY. SUMMARY: IN THIS REVIEW, WE SUMMARIZED THE ROLE AND EFFECTS OF THE MAIN MACRONUTRIENTS ON THE DEVELOPMENT OF NAFLD AND DISCUSSED THE MOLECULAR MECHANISMS INVOLVED. WE ALSO DISCUSSED THE IMPORTANCE OF GENETIC POLYMORPHISMS, EPIGENETIC ALTERATIONS, AND DYSBIOSIS TO DETERMINE IF LIFESTYLE MODIFICATION AND A SPECIFIC DIETARY REGIMEN COULD BE AN ESSENTIAL PART OF NAFLD TREATMENT. 2022 15 6253 35 THE MICROBIOME AND HEPATOCELLULAR CARCINOMA. THE HUMAN MICROBIOME IS A VAST AND COMPLEX SYSTEM ENCOMPASSING ALL OF THE MICROBES AND THEIR GENES THAT OCCUPY THE ENVIRONMENTALLY EXPOSED SURFACES OF THE HUMAN BODY. THE GUT MICROBIOTA AND ITS ASSOCIATED MICROBIOME PLAY AN INTEGRAL ROLE IN MAMMALIAN METABOLISM AND IMMUNE TOLERANCE AS WELL AS IN IMMUNOCOMPETENCE. DISRUPTIONS IN THE HUMAN GUT MICROBIOME ARE ASSOCIATED WITH A CYCLE OF HEPATOCYTE INJURY AND REGENERATION CHARACTERISTIC OF CHRONIC LIVER DISEASE. THE PERSISTENCE OF THIS INFLAMMATION HAS BEEN SHOWN TO INDUCE THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES LEADING TO HEPATOCELLULAR CARCINOMA (HCC). THEREFORE, THE IMPORTANCE AND PROGNOSTIC INFLUENCE OF THE GUT MICROBIOME ON HEPATOCARCINOGENESIS HAS BEEN INCREASINGLY STUDIED IN RECENT YEARS. THIS REVIEW DISCUSSES THE MECHANISMS BY WHICH IMBALANCES IN THE GUT MICROBIOME DISTURB THE GUT-LIVER AXIS TO IMPACT HEPATOCARCINOGENESIS, INCLUDING DISRUPTION OF THE INTESTINAL BARRIER, CHANGES IN BILE ACID METABOLISM, AND REDUCTION IN TUMOR-SUPPRESSING MICRORNA. FURTHERMORE, THIS REVIEW SUMMARIZES RECENT ADVANCES IN POTENTIAL MICROBIOME-BASED THERAPEUTIC OPPORTUNITIES IN HCC. 2020 16 2704 29 EXERCISE AND COLORECTAL CANCER: PREVENTION AND MOLECULAR MECHANISMS. EXERCISE AND PHYSICAL ACTIVITY HAVE BEEN SHOWN TO BE STRONGLY ASSOCIATED WITH A DECREASED INCIDENCE RATE OF VARIOUS CHRONIC DISEASES ESPECIALLY NUMEROUS HUMAN MALIGNANCIES. A HUGE NUMBER OF CLINICAL TRIALS AND META-ANALYSIS HAVE DEMONSTRATED THAT EXERCISE IS SIGNIFICANTLY EFFECTIVE IN LOWERING THE RISK OF COLORECTAL CANCER. IN ADDITION, IT IS SUGGESTED AS AN EFFECTIVE THERAPEUTIC MODALITY AGAINST THIS CANCER TYPE. THEREFORE, IN THIS REVIEW, WE WILL REVIEW COMPREHENSIBLY THE EFFECTS OF EXERCISE IN PREVENTING, TREATING, AND ALLEVIATING THE ADVERSE EFFECTS OF CONVENTIONAL THERAPEUTIC OPTIONS IN COLORECTAL CANCER. MOREOVER, THE POSSIBLE MECHANISMS UNDERLYING THE POSITIVE EFFECTS OF EXERCISE AND PHYSICAL ACTIVITY IN COLORECTAL CANCER, INCLUDING REGULATION OF INFLAMMATION, APOPTOSIS, GROWTH FACTOR AXIS, IMMUNITY, EPIGENETIC, ETC. WILL BE ALSO DISCUSSED. 2022 17 3547 41 IMMUNOMODULATORY ROLE OF NUTRIENTS: HOW CAN PULMONARY DYSFUNCTIONS IMPROVE? NUTRITION IS AN IMPORTANT TOOL THAT CAN BE USED TO MODULATE THE IMMUNE RESPONSE DURING INFECTIOUS DISEASES. IN ADDITION, THROUGH DIET, IMPORTANT SUBSTRATES ARE ACQUIRED FOR THE BIOSYNTHESIS OF REGULATORY MOLECULES IN THE IMMUNE RESPONSE, INFLUENCING THE PROGRESSION AND TREATMENT OF CHRONIC LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN THIS WAY, NUTRITION CAN PROMOTE LUNG HEALTH STATUS. A RANGE OF NUTRIENTS, SUCH AS VITAMINS (A, C, D, AND E), MINERALS (ZINC, SELENIUM, IRON, AND MAGNESIUM), FLAVONOIDS AND FATTY ACIDS, PLAY IMPORTANT ROLES IN REDUCING THE RISK OF PULMONARY CHRONIC DISEASES AND VIRAL INFECTIONS. THROUGH THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS, NUTRIENTS ARE ASSOCIATED WITH BETTER LUNG FUNCTION AND A LOWER RISK OF COMPLICATIONS SINCE THEY CAN DECREASE THE HARMFUL EFFECTS FROM THE IMMUNE SYSTEM DURING THE INFLAMMATORY RESPONSE. IN ADDITION, BIOACTIVE COMPOUNDS CAN EVEN CONTRIBUTE TO EPIGENETIC CHANGES, INCLUDING HISTONE DEACETYLASE (HDAC) MODIFICATIONS THAT INHIBIT THE TRANSCRIPTION OF PROINFLAMMATORY CYTOKINES, WHICH CAN CONTRIBUTE TO THE MAINTENANCE OF HOMEOSTASIS IN THE CONTEXT OF INFECTIONS AND CHRONIC INFLAMMATORY DISEASES. THESE NUTRIENTS ALSO PLAY AN IMPORTANT ROLE IN ACTIVATING IMMUNE RESPONSES AGAINST PATHOGENS, WHICH CAN HELP THE IMMUNE SYSTEM DURING INFECTIONS. HERE, WE PROVIDE AN UPDATED OVERVIEW OF THE ROLES PLAYED BY DIETARY FACTORS AND HOW THEY CAN AFFECT RESPIRATORY HEALTH. THEREFORE, WE WILL SHOW THE ANTI-INFLAMMATORY ROLE OF FLAVONOIDS, FATTY ACIDS, VITAMINS AND MICROBIOTA, IMPORTANT FOR THE CONTROL OF CHRONIC INFLAMMATORY DISEASES AND ALLERGIES, IN ADDITION TO THE ANTIVIRAL ROLE OF VITAMINS, FLAVONOIDS, AND MINERALS DURING PULMONARY VIRAL INFECTIONS, ADDRESSING THE MECHANISMS INVOLVED IN EACH FUNCTION. THESE MECHANISMS ARE INTERESTING IN THE DISCUSSION OF PERSPECTIVES ASSOCIATED WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION AND ITS PULMONARY COMPLICATIONS SINCE PATIENTS WITH SEVERE DISEASE HAVE VITAMINS DEFICIENCY, ESPECIALLY VITAMIN D. IN ADDITION, RESEARCHES WITH THE USE OF FLAVONOIDS HAVE BEEN SHOWN TO DECREASE VIRAL REPLICATION IN VITRO. THIS WAY, A FULL UNDERSTANDING OF DIETARY INFLUENCES CAN IMPROVE THE LUNG HEALTH OF PATIENTS. 2021 18 2333 37 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 19 5110 41 POLYPHENOLS AND THE MODULATION OF GENE EXPRESSION PATHWAYS: CAN WE EAT OUR WAY OUT OF THE DANGER OF CHRONIC DISEASE? PLANT-DERIVED DIETARY POLYPHENOLS MAY IMPROVE SOME DISEASE STATES AND PROMOTE HEALTH. EXPERIMENTAL EVIDENCE SUGGESTS THAT THIS IS PARTIALLY ATTRIBUTABLE TO CHANGES IN GENE EXPRESSION. THE RATIONAL USE OF BIOACTIVE FOOD COMPONENTS MAY THEREFORE PRESENT AN OPPORTUNITY TO ACTIVATE OR REPRESS SELECTED GENE EXPRESSION PATHWAYS AND, CONSEQUENTLY, TO MANAGE OR PREVENT DISEASE. IT REMAINS TO BE DETERMINED WHETHER THIS USE OF BIOACTIVE FOOD COMPONENTS CAN BE DONE SAFELY. THIS ARTICLE REVIEWS THE ASSOCIATED CONTROVERSIES AND LIMITATIONS OF POLYPHENOL THERAPY. THERE IS A PAUCITY OF CLINICAL DATA ON THE RATIONAL USE OF POLYPHENOLS, INCLUDING A LACK OF KNOWLEDGE ON EFFECTIVE DOSAGE, ACTUAL CHEMICAL FORMULATIONS, BIOAVAILABILITY, DISTRIBUTION IN TISSUES, THE EFFECT OF GENETIC VARIATIONS, DIFFERENCES IN GUT MICROFLORA, THE SYNERGISTIC (OR ANTAGONISTIC) EFFECTS OBSERVED IN EXTRACTS, AND THE POSSIBLE INTERACTION BETWEEN POLYPHENOLS AND LIPID DOMAINS OF CELL MEMBRANES THAT MAY ALTER THE FUNCTION OF RELEVANT RECEPTORS. THE SEMINAL QUESTION OF WHY PLANTS MAKE SUBSTANCES THAT BENEFIT HUMANS REMAINS UNANSWERED, AND THERE IS STILL MUCH TO LEARN IN TERMS OF CORRELATIVE VERSUS CAUSAL EFFECTS OF HUMAN EXPOSURE TO VARIOUS NUTRIENTS. THE AVAILABLE DATA STRONGLY SUGGEST SIGNIFICANT EFFECTS AT THE MOLECULAR LEVEL THAT REPRESENT INTERACTIONS WITH THE EPIGENOME. THE ADVENT OF RELATIVELY SIMPLE TECHNOLOGIES IS HELPING THE FIELD OF EPIGENETICS PROGRESS AND FACILITATING THE ACQUISITION OF MULTIPLE TYPES OF DATA THAT WERE PREVIOUSLY DIFFICULT TO OBTAIN. IN THIS REVIEW, WE SUMMARIZE THE MOLECULAR BASIS OF THE EPIGENETIC REGULATION OF GENE EXPRESSION AND THE EPIGENETIC CHANGES ASSOCIATED WITH THE CONSUMPTION OF POLYPHENOLS THAT ILLUSTRATE HOW MODIFICATIONS IN HUMAN NUTRITION MAY BECOME RELEVANT TO HEALTH AND DISEASE. 2014 20 5069 31 PHYSICAL ACTIVITY IN THE PREVENTION OF HUMAN DISEASES: ROLE OF EPIGENETIC MODIFICATIONS. EPIGENETIC MODIFICATION REFERS TO HERITABLE CHANGES IN GENE FUNCTION THAT CANNOT BE EXPLAINED BY ALTERATIONS IN THE DNA SEQUENCE. THE CURRENT LITERATURE CLEARLY DEMONSTRATES THAT THE EPIGENETIC RESPONSE IS HIGHLY DYNAMIC AND INFLUENCED BY DIFFERENT BIOLOGICAL AND ENVIRONMENTAL FACTORS SUCH AS AGING, NUTRIENT AVAILABILITY AND PHYSICAL EXERCISE. AS SUCH, IT IS WELL ACCEPTED THAT PHYSICAL ACTIVITY AND EXERCISE CAN MODULATE GENE EXPRESSION THROUGH EPIGENETIC ALTERNATIONS ALTHOUGH THE TYPE AND DURATION OF EXERCISE ELICITING SPECIFIC EPIGENETIC EFFECTS THAT CAN RESULT IN HEALTH BENEFITS AND PREVENT CHRONIC DISEASES REMAINS TO BE DETERMINED. THIS REVIEW HIGHLIGHTS THE MOST SIGNIFICANT FINDINGS FROM EPIGENETIC STUDIES INVOLVING PHYSICAL ACTIVITY/EXERCISE INTERVENTIONS KNOWN TO BENEFIT CHRONIC DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, CANCER, CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. 2017