1 4955 157 PATHOGENESIS OF COVID-19 DESCRIBED THROUGH THE LENS OF AN UNDERSULFATED AND DEGRADED EPITHELIAL AND ENDOTHELIAL GLYCOCALYX. THE GLYCOCALYX SURROUNDS EVERY EUKARYOTIC CELL AND IS A COMPLEX MESH OF PROTEINS AND CARBOHYDRATES. IT CONSISTS OF PROTEOGLYCANS WITH GLYCOSAMINOGLYCAN SIDE CHAINS, WHICH ARE HIGHLY SULFATED UNDER NORMAL PHYSIOLOGICAL CONDITIONS. THE DEGREE OF SULFATION AND THE POSITION OF THE SULFATE GROUPS MAINLY DETERMINE BIOLOGICAL FUNCTION. THE INTACT HIGHLY SULFATED GLYCOCALYX OF THE EPITHELIUM MAY REPEL SEVERE ACUTE RESPIRATORY SYNDROME-RELATED CORONAVIRUS 2 (SARS-COV-2) THROUGH ELECTROSTATIC FORCES. HOWEVER, IF THE GLYCOCALYX IS UNDERSULFATED AND 3-O-SULFOTRANSFERASE 3B (3OST-3B) IS OVEREXPRESSED, AS IS THE CASE DURING CHRONIC INFLAMMATORY CONDITIONS, SARS-COV-2 ENTRY MAY BE FACILITATED BY THE GLYCOCALYX. THE DEGREE OF SULFATION AND POSITION OF THE SULFATE GROUPS WILL ALSO AFFECT FUNCTIONS SUCH AS IMMUNE MODULATION, THE INFLAMMATORY RESPONSE, VASCULAR PERMEABILITY AND TONE, COAGULATION, MEDIATION OF SHEER STRESS, AND PROTECTION AGAINST OXIDATIVE STRESS. THE RATE-LIMITING FACTOR TO SULFATION IS THE AVAILABILITY OF INORGANIC SULFATE. VARIOUS GENETIC AND EPIGENETIC FACTORS WILL AFFECT SULFUR METABOLISM AND INORGANIC SULFATE AVAILABILITY, SUCH AS VARIOUS DIETARY FACTORS, AND EXPOSURE TO DRUGS, ENVIRONMENTAL TOXINS, AND BIOTOXINS, WHICH WILL DEPLETE INORGANIC SULFATE. THE ROLE THAT UNDERSULFATION PLAYS IN THE VARIOUS COMORBID CONDITIONS THAT PREDISPOSE TO CORONAVIRUS DISEASE 2019 (COVID-19), IS ALSO CONSIDERED. THE UNDERSULFATED GLYCOCALYX MAY NOT ONLY INCREASE SUSCEPTIBILITY TO SARS-COV-2 INFECTION, BUT WOULD ALSO RESULT IN A HYPERINFLAMMATORY RESPONSE, VASCULAR PERMEABILITY, AND SHEDDING OF THE GLYCOCALYX COMPONENTS, GIVING RISE TO A PROCOAGULANT AND ANTIFIBRINOLYTIC STATE AND EVENTUAL MULTIPLE ORGAN FAILURE. THESE SYMPTOMS RELATE TO A DIAGNOSIS OF SYSTEMIC SEPTIC SHOCK SEEN IN ALMOST ALL COVID-19 DEATHS. THE FOCUS OF PREVENTION AND TREATMENT PROTOCOLS PROPOSED IS THE PRESERVATION OF EPITHELIAL AND ENDOTHELIAL GLYCOCALYX INTEGRITY. 2022 2 4096 26 MATRIX METALLOPROTEINASES, NEURAL EXTRACELLULAR MATRIX, AND CENTRAL NERVOUS SYSTEM PATHOLOGY. THE FUNCTIONALITY AND STABILITY OF THE CENTRAL NERVOUS SYSTEM (CNS) PABULUM, CALLED NEURAL EXTRACELLULAR MATRIX (NECM), IS PARAMOUNT FOR THE MAINTENANCE OF A HEALTHY NETWORK. THE LOOSENING OR THE DAMAGE OF THE SCAFFOLD DISRUPTS SYNAPTIC TRANSMISSION WITH THE CONSEQUENT IMBALANCE OF THE NEUROTRANSMITTERS, REACTIVE CELLS INVASION, ASTROCYTOSIS, NEW MATRIX DEPOSITION, DIGESTION OF THE PREVIOUS STRUCTURE AND ULTIMATELY, MALADAPTIVE PLASTICITY WITH THE LOSS OF NEURONAL VIABILITY. NECM IS CONSTANTLY AFFECTED BY CNS DISORDERS, PARTICULARLY IN CHRONIC MODIFYING SUCH AS NEURODEGENERATIVE DISEASE, OR IN ACUTE/SUBACUTE WITH CHRONIC SEQUELAE, LIKE CEREBROVASCULAR AND INFLAMMATORY PATHOLOGY. MATRIX METALLOPROTEINASES (MMPS) ARE THE MAIN INTERFERING AGENT OF NECM, GUIDING THE BALANCE OF DEGRADATION AND NEW DEPOSITION OF PROTEINS SUCH AS PROTEOGLYCANS AND GLYCOPROTEINS, OR GLYCOSAMINOGLYCANS, SUCH AS HYALURONIC ACID. ACTIVATION OF THESE ENZYMES IS MODULATED BY THEIR PHYSIOLOGIC INHIBITORS, THE TISSUE INHIBITORS OF MMPS OR VIA OTHER PROTEASES INHIBITORS, AS WELL AS GENETIC OR EPIGENETIC UP- OR DOWNREGULATION THROUGH MOLECULAR INTERACTION OR RECEPTOR ACTIVATION. THE APPROPRIATE UNDERSTANDING OF THE PATHWAYS UNDERLYING NECM MODIFICATIONS IN CNS PATHOLOGY IS PROBABLY ONE OF THE PIVOTAL FUTURE DIRECTIONS TO IDENTIFY THE HEALTHY BRAIN NETWORK AND SUBSEQUENTLY DESIGN NEW THERAPIES TO INTERFERE WITH THE PROGRESSION OF THE CNS DISEASE AND EVENTUALLY FIND APPROPRIATE THERAPIES. 2017 3 6843 28 [MEDICAL APPLICATIONS OF GENOME DISCOVERY]. THE DISCOVERY OF THE COMPLETE BASE SEQUENCE OF HUMAN GENOME UNVEILS SEVERAL PERSPECTIVES TO UNDERSTAND HUMAN DISEASES AND DEVELOP NEW THERAPIES. HUMAN GENOME CONTAINS APPROXIMATELY 39,000 GENES OF WHICH 26,000 CODE SPECIFIC PROTEINS THAT HAVE BEEN IDENTIFIED. THERE ARE APPROXIMATELY 1,500 DISEASES WITH IDENTIFIED MOLECULAR DISTURBANCES. GENES CAN MODIFY SIGNS AND SYMPTOMS OF COMMON DISEASES. THUS, THERE ARE NO PURE MONOGENIC DISEASES. CHRONIC DISEASES OF ADULTS ARE COMPLEX AND DEPENDENT ON MULTIPLE FACTORS. SEVERAL GENES THAT PREDISPOSE TO CHRONIC DEGENERATIVE DISEASES HAVE BEEN IDENTIFIED. THIS IS REVEALING THE COMPLEX NATURE AND THE INTERACTION OF THESE AILMENTS WITH THE ENVIRONMENT. THE DISCOVERY OF BACTERIAL AND VIRAL GENOMIC SEQUENCES WILL ALLOW THE MANUFACTURING OF NEW VACCINES AND SPECIFIC MOLECULAR ANTIMICROBIALS. THE NEW PHARMACOGENOMICS WILL DEVISE TREATMENTS FOR EACH SUBJECT ACCORDING TO HER SPECIFIC GENOMIC PROFILE. THE NEW APPLICATIONS OF GENOMIC TECHNOLOGY IS CREATING NEW PARADIGMS IN BIOMEDICAL RESEARCH SUCH AS FUNCTIONAL GENOMICS, PROTEONOMICS, EPIGENETIC REGULATION. GENE DIAGNOSIS AND THERAPY WILL CONSIDERABLY IMPROVE THE FUTURE OF MEDICINE. 2001 4 3931 21 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 5 5791 26 STABLE HISTONE METHYLATION CHANGES AT PROTEOGLYCAN NETWORK GENES FOLLOWING ETHANOL EXPOSURE. ALCOHOL USE DISORDER (AUD) IS A CHRONIC MENTAL ILLNESS IN WHICH PATIENTS OFTEN ACHIEVE PROTRACTED PERIODS OF ABSTINENCE PRIOR TO RELAPSE. EPIGENETIC MECHANISMS MAY PROVIDE AN EXPLANATION FOR THE PERSISTING GENE EXPRESSION CHANGES THAT CAN BE OBSERVED EVEN AFTER LONG PERIODS OF ABSTINENCE AND MAY CONTRIBUTE TO RELAPSE. IN THIS STUDY, WE EXAMINED TWO HISTONE MODIFICATIONS, HISTONE 3 LYSINE 4 TRI-METHYLATION (H3K4ME3) AND HISTONE 3 LYSINE 27 TRI-METHYLATION (H3K27ME3), IN THE PREFRONTAL CORTEX OF WITHDRAWAL SEIZURE RESISTANT (WSR) MICE 21 DAYS AFTER 72 H OF ETHANOL VAPOR EXPOSURE. THESE HISTONE MODIFICATIONS WERE SELECTED BECAUSE THEY ARE ASSOCIATED WITH ACTIVE PROMOTERS (H3K4ME3) AND REPRESSED GENE EXPRESSION IN A EUCHROMATIC ENVIRONMENT (H3K27ME3). WE PERFORMED A GENOME-WIDE ANALYSIS TO IDENTIFY DIFFERENCES IN H3K4ME3 AND H3K27ME3 LEVELS IN POST-ETHANOL EXPOSURE VS. CONTROL MICE BY CHIP-SEQ. WE DETECTED A GLOBAL REDUCTION IN H3K4ME3 PEAKS AND INCREASE IN H3K27ME3 PEAKS IN POST-ETHANOL EXPOSURE MICE COMPARED TO CONTROLS, THESE CHANGES ARE CONSISTENT WITH PERSISTENT REDUCTIONS IN GENE EXPRESSION. PATHWAY ANALYSIS OF GENES DISPLAYING CHANGES IN H3K4ME3 AND H3K27ME3 REVEALED ENRICHMENT FOR GENES INVOLVED IN PROTEOGLYCAN AND CALCIUM SIGNALING PATHWAYS, RESPECTIVELY. MICROARRAY ANALYSIS OF 7,683 GENES AND QPCR ANALYSIS IDENTIFIED EIGHT GENES DISPLAYING CONCORDANT REGULATION OF GENE EXPRESSION AND H3K4ME3/H3K27ME3. WE ALSO COMPARED CHANGES IN H3K4ME3 AND/OR H3K27ME3 FROM OUR STUDY WITH CHANGES IN GENE EXPRESSION IN RESPONSE TO ETHANOL FROM PUBLISHED LITERATURE AND WE FOUND THAT THE EXPRESSION OF 52% OF THE GENES WITH ALTERED H3K4ME3 BINDING AND 40% OF GENES WITH H3K27ME3 DIFFERENCES ARE ALTERED BY ETHANOL EXPOSURE. THE CHROMATIN CHANGES ASSOCIATED WITH THE 21-DAY POST-EXPOSURE PERIOD SUGGEST THAT THIS PERIOD IS A UNIQUE STATE IN THE ADDICTION CYCLE THAT DIFFERS FROM ETHANOL INTOXICATION AND ACUTE WITHDRAWAL. THESE RESULTS PROVIDE INSIGHTS INTO THE ENDURING EFFECTS OF ETHANOL ON PROTEOGLYCAN AND CALCIUM SIGNALING GENES IN THE BRAIN. 2018 6 1410 32 DIETARY INTERVENTIONS FOR AUTISM SPECTRUM DISORDER: AN UPDATED SYSTEMATIC REVIEW OF HUMAN STUDIES. AUTISM IS A COMPLEX SPECTRUM OF DISORDERS WITH GENETIC, EPIGENETIC, AUTOIMMUNE, OXIDATIVE STRESS, AND ENVIRONMENTAL ETIOLOGIES. TREATMENT OF ASD USING DIETARY APPROACH IS A PROMISING STRATEGY, ESPECIALLY OWING TO ITS SAFETY AND AVAILABILITY. OUR STUDY CRITICALLY ANALYSED THE ROLES AND EFFICACY OF ANTIOXIDANTS, PROBIOTICS, PREBIOTICS, CAMEL MILK AND VITAMIN D. THIS SYSTEMATIC REVIEW PROVIDES AN UPDATED SYNOPSIS OF HUMAN STUDIES THAT INVESTIGATED THERAPEUTIC BENEFITS OF THESE DIETARY INTERVENTIONS IN AUTISM. A TOTAL OF 943 PAPERS WERE IDENTIFIED OUT OF WHICH 21 ARTICLES WERE INCLUDED IN THE SYSTEMATIC REVIEW. THE SELECTED STUDIES INVESTIGATED THE IMPACT OF 5 DIFFERENT DIETARY SUPPLEMENTATIONS IN ASD SYMPTOM AND BEHAVIOURS. THESE AGENTS INCLUDE; ANTIOXIDANTS/POLYPHENOLIC COMPOUNDS, PROBIOTICS, PREBIOTICS, CAMEL MILK AND VITAMIN D. FROM THE RESULTS OF THE PRESENT REVIEW, ANTIOXIDANTS/POLYPHENOLIC COMPOUNDS DECREASED THE LEVELS OF INFLAMMATORY CYTOKINES AND IMPROVED BEHAVIOURAL SYMPTOMS. PROBIOTICS IMPROVED BEHAVIOURAL AND GI SYMPTOMS AS WELL AS RESTORED GUT MICROBIOTA EQUILIBRIUM. PREBIOTICS DECREASED LEVELS OF INFLAMMATORY CYTOKINES, IMPROVED BEHAVIOURAL AND GI SYMPTOMS AND IMPROVED GUT MICROBIOTA. VITAMIN D IMPROVED BEHAVIOURAL SYMPTOMS AND OFFERED PROTECTIVE EFFECTS AGAINST NEUROTOXICITY. CAMEL MILK REDUCED INFLAMMATORY RESPONSES AND OXIDATIVE STRESS. GIVEN THE CHRONIC NATURE AS WELL AS EARLY ONSET OF ASD, DIETARY SUPPLEMENTS BECOME USEFUL TO COMPLEMENT NUTRITIONAL DEFICIENCIES IN CHILDREN WITH ASD. KEY BENEFITS OF THESE AGENTS STEM FROM THEIR ABILITY TO TARGET MULTIPLE PHYSIOLOGICAL AREAS VIA THE GUT BRAIN-AXIS AND ARE DEVOID OF POTENTIAL HARMFUL OR AGGRAVATING EFFECTS ON ASD PATIENTS. THE EVIDENCE COLLATED IN THIS REVIEW PROPOSE THAT DIETARY INTERVENTION MAY PROVIDE A NEW PLATFORM FOR THE MANAGEMENT OF AUTISM. 2022 7 3888 31 KLOTHO PATHWAYS, MYELINATION DISORDERS, NEURODEGENERATIVE DISEASES, AND EPIGENETIC DRUGS. IN THIS REVIEW WE OUTLINE A RATIONALE FOR IDENTIFYING NEUROPROTECTANTS AIMED AT INDUCING ENDOGENOUS KLOTHO ACTIVITY AND EXPRESSION, WHICH IS EPIGENETIC ACTION, BY DEFINITION. SUCH AN APPROACH SHOULD PROMOTE REMYELINATION AND/OR STIMULATE MYELIN REPAIR BY ACTING ON MITOCHONDRIAL FUNCTION, THEREBY HERALDING A LIFE-SAVING PATH FORWARD FOR PATIENTS SUFFERING FROM NEUROINFLAMMATORY DISEASES. DISORDERS OF MYELIN IN THE NERVOUS SYSTEM DAMAGE THE TRANSMISSION OF SIGNALS, RESULTING IN LOSS OF VISION, MOTION, SENSATION, AND OTHER FUNCTIONS DEPENDING ON THE AFFECTED NERVES, CURRENTLY WITH NO EFFECTIVE TREATMENT. KLOTHO GENES AND THEIR SINGLE-PASS TRANSMEMBRANE KLOTHO PROTEINS ARE POWERFUL GOVERNORS OF THE THREADS OF LIFE AND DEATH, TRUE TO THE ORIGIN OF THEIR NAME, FATES, IN GREEK MYTHOLOGY. AMONG ITS MANY IMPORTANT FUNCTIONS, KLOTHO IS AN OBLIGATORY CO-RECEPTOR THAT BINDS, ACTIVATES, AND/OR POTENTIATES CRITICAL FIBROBLAST GROWTH FACTOR ACTIVITY. SINCE THE DISCOVERY OF KLOTHO A LITTLE OVER TWO DECADES AGO, IT HAS BECOME EVER MORE APPARENT THAT WHEN KLOTHO PATHWAYS GO AWRY, OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION TAKE OVER, AND AGE-RELATED CHRONIC DISORDERS ARE LIKELY TO FOLLOW. THE PHYSIOLOGICAL CONSEQUENCES CAN BE WIDE RANGING, POTENTIALLY WREAKING HAVOC ON THE BRAIN, EYE, KIDNEY, MUSCLE, AND MORE. CENTRAL NERVOUS SYSTEM DISORDERS, NEURODEGENERATIVE IN NATURE, AND ESPECIALLY THOSE AFFECTING THE MYELIN SHEATH, REPRESENT WORTHY TARGETS FOR ADVANCING THERAPIES THAT ACT UPON KLOTHO PATHWAYS. CURRENT DRUGS FOR THESE DISEASES, EVEN THERAPEUTICS THAT ARE DISEASE MODIFYING RATHER THAN TREATING ONLY THE SYMPTOMS, LEAVE MUCH ROOM FOR IMPROVEMENT. IT IS THUS NO WONDER THAT THIS TOPIC HAS CAUGHT THE ATTENTION OF BIOMEDICAL RESEARCHERS AROUND THE WORLD. 2020 8 4424 33 MOLECULAR AND NEUROLOGIC RESPONSES TO CHRONIC ALCOHOL USE. THIS CHAPTER PROVIDES AN OVERVIEW OF CURRENT KNOWLEDGE ON THE MOLECULAR AND CLINICAL ASPECTS OF CHRONIC ALCOHOL EFFECTS ON THE CENTRAL NERVOUS SYSTEM. THIS DRUG IS ALMOST UBIQUITOUS, WIDELY ENJOYED SOCIALLY, BUT PRODUCES A DIVERSE SPECTRUM OF NEUROLOGIC DISEASE WHEN ABUSED. ACUTELY, ALCOHOL INTERACTS PREDOMINANTLY WITH GAMMA-AMINOBUTYRIC ACID-A (GABA-A) AND N-METHYL-D-ASPARTATE (NMDA) RECEPTORS, BUT TRIGGERS DIVERSE SIGNALING EVENTS WITHIN WELL-DEFINED NEURAL PATHWAYS. THESE EVENTS RESULT IN ADAPTIVE CHANGES IN GENE EXPRESSION THAT ULTIMATELY PRODUCE TWO MAJOR STATES: ADDICTION AND TOXICITY. EPIGENETIC MODIFICATIONS OF CHROMATIN COULD LEAD TO LONG-LIVED OR EVEN TRANSGENERATIONAL CHANGES IN GENE EXPRESSION, THUS PRODUCING ASPECTS OF THE HERITABILITY OF ALCOHOL USE DISORDERS (AUD) AND LONG-TERM BEHAVIORS SUCH AS RECIDIVISM. THE DIVERSE CLINICAL SYNDROMES PRODUCED BY CHRONIC ALCOHOL ACTIONS IN THE CENTRAL NERVOUS SYSTEM REFLECT THE MOLECULAR PATHOLOGY AND PREDOMINANTLY INVOLVE ASPECTS OF TOLERANCE/WITHDRAWAL, SELECTIVE VULNERABILITY (MANIFEST AS CENTRAL PONTINE MYELINOLYSIS, MARCHIAFAVA-BIGNAMI DISEASE), AND ADDITIONAL ENVIRONMENTAL FACTORS (E.G., THIAMINE DEFICIENCY IN WERNICKE-KORSAKOFF'S SYNDROME). ADDITIONALLY, DELETERIOUS ASPECTS OF CHRONIC ALCOHOL ON SIGNALING, SYNAPTIC TRANSMISSION, AND CELL TOXICITY LEAD TO PRIMARY ALCOHOLIC DEMENTIA. GENETICALLY DETERMINED ASPECTS OF MYELIN STRUCTURE AND ALCOHOL ACTIONS ON MYELIN GENE EXPRESSION MAY BE A PROMINENT MOLECULAR MECHANISM RESULTING IN A PREDISPOSITION TO, OR CAUSATION OF, AUD AND MULTIPLE OTHER NEUROLOGIC COMPLICATIONS OF CHRONIC ALCOHOL. THE DRAMATIC PROGRESS MADE IN UNDERSTANDING MOLECULAR ACTIONS OF ALCOHOL HOLDS GREAT PROMISE FOR OUR EVENTUAL TREATMENT OR PREVENTION OF AUD AND NEUROLOGIC COMPLICATIONS RESULTING FROM CHRONIC ALCOHOL ABUSE. 2014 9 4909 31 PAIN AND STRESS IN A SYSTEMS PERSPECTIVE: RECIPROCAL NEURAL, ENDOCRINE, AND IMMUNE INTERACTIONS. THIS PAPER ADVANCES A PSYCHOPHYSIOLOGICAL SYSTEMS VIEW OF PAIN IN WHICH PHYSICAL INJURY, OR WOUNDING, GENERATES A COMPLEX STRESS RESPONSE THAT EXTENDS BEYOND THE NERVOUS SYSTEM AND CONTRIBUTES TO THE EXPERIENCE OF PAIN. THROUGH A COMMON CHEMICAL LANGUAGE COMPRISING NEUROTRANSMITTERS, PEPTIDES, ENDOCANNABINOIDS, CYTOKINES, AND HORMONES, AN ENSEMBLE OF INTERDEPENDENT NERVOUS, ENDOCRINE, AND IMMUNE PROCESSES OPERATES IN CONCERT TO COPE WITH THE INJURY. THESE PROCESSES ACT AS A SINGLE AGENT AND COMPRISE A SUPERSYSTEM. ACUTE PAIN IN ITS MULTIPLE DIMENSIONS, AND THE RELATED SYMPTOMS THAT COMMONLY OCCUR WITH IT, ARE PRODUCTS OF THE SUPERSYSTEM. CHRONIC PAIN CAN DEVELOP AS A RESULT OF UNUSUAL STRESS. SOCIAL STRESSORS CAN COMPOUND THE STRESS RESULTING FROM A WOUND OR ACT ALONE TO DYSREGULATE THE SUPERSYSTEM. WHEN THE SUPERSYSTEM SUFFERS DYSREGULATION, HEALTH, FUNCTION, AND SENSE OF WELL-BEING SUFFER. SOME CHRONIC PAIN CONDITIONS ARE THE PRODUCT OF SUPERSYSTEM DYSREGULATION. INDIVIDUALS VARY AND ARE VULNERABLE TO DYSREGULATION AND DYSFUNCTION IN PARTICULAR ORGAN SYSTEMS DUE TO THE UNIQUE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, AS WELL AS THE PAST EXPERIENCES THAT CHARACTERIZE EACH PERSON. PERSPECTIVE: ACUTE TISSUE INJURY ACTIVATES AN ENSEMBLE OF INTERDEPENDENT NERVOUS, ENDOCRINE, AND IMMUNE PROCESSES THAT OPERATE IN CONCERT AND COMPRISE A SUPERSYSTEM. SOME CHRONIC PAIN CONDITIONS RESULT FROM SUPERSYSTEM DYSREGULATION. INDIVIDUALS VARY AND ARE VULNERABLE TO DYSREGULATION DUE TO THE UNIQUE INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AND PAST EXPERIENCES THAT CHARACTERIZE EACH PERSON. THIS PERSPECTIVE CAN POTENTIALLY ASSIST CLINICIANS IN ASSESSING AND MANAGING CHRONIC PAIN PATIENTS. 2008 10 6254 28 THE MICROBIOME AND IRRITABLE BOWEL SYNDROME - A REVIEW ON THE PATHOPHYSIOLOGY, CURRENT RESEARCH AND FUTURE THERAPY. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER WHICH AFFECTS A LARGE PROPORTION OF THE POPULATION GLOBALLY. THE PRECISE ETIOLOGY OF IBS IS STILL UNKNOWN, ALTHOUGH CONSENSUS UNDERSTANDING PROPOSES IBS TO BE OF MULTIFACTORIAL ORIGIN WITH YET UNDEFINED SUBTYPES. GENETIC AND EPIGENETIC FACTORS, STRESS-RELATED NERVOUS AND ENDOCRINE SYSTEMS, IMMUNE DYSREGULATION AND THE BRAIN-GUT AXIS SEEM TO BE CONTRIBUTING FACTORS THAT PREDISPOSE INDIVIDUALS TO IBS. IN ADDITION TO FOOD HYPERSENSITIVITY, TOXINS AND ADVERSE LIFE EVENTS, CHRONIC INFECTIONS AND DYSBIOTIC GUT MICROBIOTA HAVE BEEN SUGGESTED TO TRIGGER IBS SYMPTOMS IN TANDEM WITH THE PREDISPOSING FACTORS. THIS REVIEW WILL SUMMARIZE THE PATHOPHYSIOLOGY OF IBS AND THE ROLE OF GUT MICROBIOTA IN RELATION TO IBS. CURRENT METHODOLOGIES FOR MICROBIOME STUDIES IN IBS SUCH AS GENOME SEQUENCING, METAGENOMICS, CULTUROMICS AND ANIMAL MODELS WILL BE DISCUSSED. THE MYRIAD OF THERAPY OPTIONS SUCH AS IMMUNOGLOBULINS (IMMUNE-BASED THERAPY), PROBIOTICS AND PREBIOTICS, DIETARY MODIFICATIONS INCLUDING FODMAP RESTRICTION DIET AND GLUTEN-FREE DIET, AS WELL AS FECAL TRANSPLANTATION WILL BE REVIEWED. FINALLY THIS REVIEW WILL HIGHLIGHT FUTURE DIRECTIONS IN IBS THERAPY RESEARCH, INCLUDING IDENTIFICATION OF NEW MOLECULAR TARGETS, APPLICATION OF 3-D GUT MODEL, GUT-ON-A-CHIP AND PERSONALIZED THERAPY. 2019 11 5280 33 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 12 6874 26 [PROGRESS IN THE REGULATION OF ENERGY METABOLIC HOMEOSTASIS BY THE SWI/SNF COMPLEX SUBUNIT BAF60A]. METABOLIC SYNDROME IS A GLOBAL CHRONIC EPIDEMIC. ITS PATHOGENESIS IS DETERMINED BY GENETIC AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATION IS REPORTED TO REGULATE GENE EXPRESSION WITHOUT ALTERING ITS NUCLEOTIDE SEQUENCES. IN RECENT YEARS, EPIGENETIC MODIFICATION IS SENSITIVELY RESPONDED TO ENVIRONMENTAL SIGNALS, FURTHER AFFECTING THE GENE EXPRESSION AND SIGNALING TRANSDUCTION. AMONG THESE REGULATORS, CHROMATIN REMODELING SWI/SNF (SWITCH/SUCROSE NON FERMENTABLE, SWI/SNF) COMPLEX SUBUNIT BAF60A PLAYS AN IMPORTANT ROLE IN MAINTAINING ENERGY HOMEOSTASIS IN MAMMALS. IN THIS PAPER, WE DESCRIBED THE PATHOPHYSIOLOGICAL ROLES OF BAF60A IN MAINTAINING THE BALANCE OF ENERGY METABOLISM, INCLUDING LIPID METABOLISM, CHOLESTEROL METABOLISM, UREA METABOLISM, AS WELL AS THEIR RHYTHMICITY. THEREFORE, IN-DEPTH UNDERSTANDING OF BAF60A-ORCHESTRATED TRANSCRIPTIONAL NETWORK OF ENERGY METABOLISM WILL PROVIDE POTENTIAL THERAPEUTIC TARGETS AND RELIABLE THEORETICAL SUPPORTS FOR THE TREATMENT OF METABOLIC SYNDROME. 2021 13 5541 27 ROLE OF DIETARY PHENOLS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. CHRONIC NEUROINFLAMMATION IS A PATHOLOGICAL FEATURE OF A NUMBER OF CENTRAL NERVOUS SYSTEM (CNS) DISEASES AND IS MEDIATED BY SUSTAINED ACTIVATION OF MICROGLIAL CELLS, THE INNATE IMMUNE CELLS OF THE CNS. STUDIES HAVE MAINLY FOCUSED ON IDENTIFYING THE MOLECULAR AND EPIGENETIC MECHANISMS OF MICROGLIAL ACTIVATION. THIS IS CRUCIAL IN DESIGNING THERAPEUTIC STRATEGIES FOR NEUROPATHOLOGIES IN WHICH PROLONGED MICROGLIAL ACTIVATION IS KNOWN TO EXACERBATE DISEASE CONDITION. IN RECENT YEARS, INCREASING EVIDENCE SHOW THAT NATURALLY OCCURRING COMPOUNDS PRESENT IN REGULAR DIET COULD FUNCTION AS "NUTRACEUTICALS," ARRESTING MICROGLIAL ACTIVATION, AND THUS CONFERRING NEUROPROTECTION. THIS REVIEW SUMMARIZES OUR UNDERSTANDING OF THE ROLE OF DIETARY PHENOLIC NUTRACEUTICALS IN MITIGATING MICROGLIA-MEDIATED NEUROINFLAMMATION. STUDIES SHOW THAT THESE NATURAL PHENOLS INHIBIT KEY SIGNALING PATHWAYS IN ACTIVATED MICROGLIA SUCH AS THE NFKAPPAB, MAPK AND JAK-STAT THAT TRIGGER MICROGLIA-MEDIATED INFLAMMATION IN VARIOUS NEUROPATHOLOGICAL CONDITIONS SUCH AS INJURY, INFECTION, STROKE, AUTISM AND NEURODEGENERATIVE DISEASES, I.E., ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE. THE ANTI-INFLAMMATORY AND ANTIOXIDANT EFFECT EXERTED BY THESE NATURAL PHENOLS HAVE SHOWN CONSIDERABLE SUCCESS IN IMPROVING DISEASE CONDITION IN ANIMAL MODELS OF NEUROPATHOLOGIES, AND THUS SEEM TO BE SUITABLE CANDIDATES FOR DEVELOPING THERAPEUTIC STRATEGIES. 2016 14 5585 37 ROLE OF OXIDATIVE STRESS AND GENETIC POLYMORPHISM OF MATRIX METALLOPROTEINASE-2 AND TISSUE INHIBITOR OF METALLOPROTEINASE-2 IN COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), A COMPLAINT DESCRIBED BY PROGRESSIVE AND INADEQUATELY REVERSIBLE LIMITATION IN LUNGS WITH SYSTEMIC INFLAMMATION, IS LARGELY CURRENT IN INDIA. THERE'S NO REMEDY AVAILABLE SO FAR IT IS, THUS, IMPERATIVE TO UNDERSTAND THE UNDERPINNING PATHOGENESIS OF THE COMPLAINANT. A SET OF PROTEASES KNOWN AS MATRIX METALLOPROTEINASE (MMPS) ARE ESPECIALLY INVOLVED IN THE PROCESS OF ALVEOLAR DESTRUCTION AND MUCUS HYPERSECRETION. THERE ARE RESPONSIBLE FACTORS IN AN INHERITABLE POSITION TO CONTROL COPD LIKE MMPS AND TIMPS (TISSUE INHIBITOR OF METALLOPROTEINASES). MMPS DEGRADE EXTRACELLULAR MATRIX AND LEAD TO THE PATHOGENESIS OF COPD [1]. TIMPS PROTEINS THAT HELP TO INHIBIT THE MATRIX METALLOPROTEINASES. [2]. THIS REVIEW SUMMARIZES THE IMPLICIT PART OF CRUCIAL MMP-2 AND TIMP-2 IN COPD DISEASE. THOUGH THE CONCEPT SEEMS PROMISING, LIMITED KNOWLEDGE ABOUT THE EXACT FUNCTIONS OF A PARTICULAR MMP IN COPD AND THE COMPLICATIONS OF MMP IN SUBSTRATE AFFINITY MAKES THIS A GRUELING TASK. MMP2 AND TIMP2 BOTH ARE DIRECTLY OR INDIRECTLY REGULATED BY OXIDATIVE STRESS AND EPIGENETIC MECHANISM WHICH REGULATES THEIR EXPRESSIONS. COPD IS A SEDITIOUS RESPONSE TO FACTORS LIKE DUST, SMOKE, ETC., AND TRIGGERS EXTRA-PULMONARY GOODS WHICH CAUSE INFLAMMATION. [3]. THIS REVIEW EXPLAINS THE RELATIONSHIP BETWEEN MMP2 AND TIMP2 IN COPD PATIENTS WITH OXIDATIVE STRESS, ITS IMPACT ON COPD PATHOGENESIS, AND GENE EXPRESSION OF TIMP2 AND MMP2 WITH THEIR DOWNSTREAM EFFECTS. THIS ALSO GIVES SOME INSIGHTS INTO THERAPEUTIC INTERVENTIONS FOR TARGETING THESE ENZYMES. MMP2 AND TIMP2 BOTH PLAY A ROLE IN THE DEVELOPMENT OF COPD AND THEY NEED TO BE STUDIED WITH THE UTMOST FOCUS. 2023 15 6728 35 VOLTAGE-GATED CALCIUM CHANNELS AND PARKINSON'S DISEASE. A COMPLEX INTERACTION OF ENVIRONMENTAL, GENETIC AND EPIGENETIC FACTORS COMBINE WITH AGEING TO CAUSE THE MOST PREVALENT OF MOVEMENT DISORDERS PARKINSON'S DISEASE. CURRENT PHARMACOLOGICAL TREATMENTS ONLY TACKLE THE SYMPTOMS AND DO NOT STOP PROGRESSION OF THE DISEASE OR REVERSE THE NEURODEGENERATIVE PROCESS. WHILE SOME INCIDENCES OF PARKINSON'S DISEASE ARISE THROUGH HERITABLE GENETIC DEFECTS, THE CAUSE OF THE MAJORITY OF CASES REMAINS UNKNOWN. LIKEWISE, WHY SOME NEURONAL POPULATIONS ARE MORE SUSCEPTIBLE TO NEURODEGENERATION THAN OTHERS IS NOT CLEAR, BUT AS THE MOLECULAR PATHWAYS RESPONSIBLE FOR THE PROCESS OF CELL DEATH ARE UNRAVELLED, IT IS INCREASINGLY APPARENT THAT DISRUPTED CELLULAR ENERGY METABOLISM PLAYS A CENTRAL ROLE. PRECISE CONTROL OF CELLULAR CALCIUM CONCENTRATIONS IS CRUCIAL FOR MAINTENANCE OF ENERGY HOMEOSTASIS. RECENTLY, DIFFERENTIAL CELLULAR EXPRESSION OF NEURONAL VOLTAGE-GATED CALCIUM CHANNEL (CA(V)) ISOFORMS HAS BEEN IMPLICATED IN THE SUSCEPTIBILITY OF VULNERABLE NEURONS TO NEURODEGENERATION IN PARKINSON'S DISEASE. CA(V) CHANNELS ARE ALSO INVOLVED IN THE SYNAPTIC PLASTICITY RESPONSE TO THE DENERVATION THAT OCCURS IN PARKINSON'S DISEASE AND FOLLOWING CHRONIC TREATMENT WITH ANTI-PARKINSONIAN DRUGS. THIS REVIEW WILL EXAMINE THE PUTATIVE ROLE NEURONAL CA(V) CHANNELS HAVE IN THE PATHOGENESIS AND TREATMENT OF PARKINSON'S DISEASE. 2012 16 4006 25 LOST AMONG THE TREES? THE AUTONOMIC NERVOUS SYSTEM AND PAEDIATRICS. THE AUTONOMIC NERVOUS SYSTEM (ANS) HAS BEEN STRIKINGLY NEGLECTED IN WESTERN MEDICINE. DESPITE ITS PROFOUND IMPORTANCE FOR REGULATION, ADJUSTMENT AND COORDINATION OF BODY SYSTEMS, IT LACKS PRIORITY IN TRAINING AND PRACTICE AND RECEIVES SCANT ATTENTION IN NUMEROUS MAJOR TEXTBOOKS. THE ANS IS INTEGRAL TO MANIFESTATIONS OF ILLNESS, UNDERLYING FAMILIAR PHYSICAL AND PSYCHOLOGICAL SYMPTOMS. WHEN ANS ACTIVITY IS ITSELF DYSFUNCTIONAL, USUAL INDICATORS OF ACUTE ILLNESS MAY PROVE DECEPTIVE. RECOGNISING THE RELEVANCE OF THE ANS CAN INVOLVE SEEING THE FAMILIAR THROUGH FRESH EYES, CHALLENGING ASSUMPTIONS IN CLINICAL ASSESSMENT AND IN APPROACHES TO PRACTICE. ITS IMPORTANCE EXTENDS FROM PHYSICAL AND PSYCHOLOGICAL WELL-BEING TO PARENTING AND SAFEGUARDING, PUBLIC SERVICES AND THE FUNCTIONING OF SOCIETY. EXPLORATION OF ITS ROLE IN CONDITIONS RANGING FROM NEUROLOGICAL, GASTROINTESTINAL AND CONNECTIVE TISSUE DISORDERS, DIABETES AND CHRONIC FATIGUE SYNDROME, TO AUTISM, BEHAVIOURAL AND MENTAL HEALTH DIFFICULTIES MAY OPEN THERAPEUTIC AVENUES. THE ANS OFFERS A MECHANISM FOR SO-CALLED FUNCTIONAL ILLNESSES AND ILLUSTRATES THE IMPORTANCE OF RECOGNISING THAT 'STRESS' TAKES MANY FORMS, PHYSICAL, PSYCHOLOGICAL AND ENVIRONMENTAL, DESIRABLE AND OTHERWISE. EVIDENCE OF INTRAUTERINE AND POST-NATAL PROGRAMMING OF ANS REACTIVITY SUGGESTS THAT NEONATAL CARE AND SAFEGUARDING PRACTICE MAY OFFER PREVENTIVE OPPORTUNITY, AS MAY GREATER UNDERSTANDING OF EPIGENETIC CHANGE OF ANS ACTIVITY THROUGH, FOR EXAMPLE, ACCIDENTAL OR PSYCHOLOGICAL TRAUMA OR INFECTION. THE AIM OF THIS ARTICLE IS TO ACCELERATE RECOGNITION OF THE IMPORTANCE OF THE ANS THROUGHOUT PAEDIATRICS, AND OF THE POTENTIAL PHYSICAL AND PSYCHOLOGICAL COST OF NEGLECTING IT. 2014 17 4777 25 NUTRACEUTICALS AND NETWORK PHARMACOLOGY APPROACH FOR ACUTE KIDNEY INJURY: A REVIEW FROM THE DRUG DISCOVERY ASPECT. ACUTE KIDNEY INJURY (AKI) HAS BECOME A GLOBAL HEALTH ISSUE, WITH APPROXIMATELY 12 MILLION REPORTS YEARLY, RESULTING IN A PERSISTENT INCREASE IN MORBIDITY AND MORTALITY RATES. AKI PATHOPHYSIOLOGY IS MULTIFACTORIAL INVOLVING OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC MODIFICATIONS, INFLAMMATION, AND EVENTUALLY, CELL DEATH. HENCE, THERAPIES ABLE TO TARGET MULTIPLE PATHOMECHANISMS CAN AID IN AKI MANAGEMENT. TO CHANGE THE DRUG DISCOVERY FRAMEWORK FROM "ONE DRUG, ONE TARGET" TO "MULTICOMPONENT, MULTITARGET," NETWORK PHARMACOLOGY IS EVOLVING AS A NEXT-GENERATION RESEARCH APPROACH. RESEARCHERS HAVE USED THE NETWORK PHARMACOLOGY APPROACH TO PREDICT THE ROLE OF NUTRACEUTICALS AGAINST DIFFERENT AILMENTS INCLUDING AKI. NUTRACEUTICALS (HERBAL PRODUCTS, ISOLATED NUTRIENTS, AND DIETARY SUPPLEMENTS) BELONG TO THE PIONEERING CATEGORY OF NATURAL PRODUCTS AND HAVE SHOWN PROTECTIVE ACTION AGAINST AKI. NUTRACEUTICALS HAVE RECENTLY DRAWN ATTENTION BECAUSE OF THEIR ABILITY TO PROVIDE PHYSIOLOGICAL BENEFITS WITH LESS TOXIC EFFECTS. THIS REVIEW EMPHASIZES THE NUTRACEUTICALS THAT EXHIBITED RENOPROTECTION AGAINST AKI AND CAN BE USED EITHER AS MONOTHERAPY OR ADJUVANT WITH CONVENTIONAL THERAPIES TO BOOST THEIR EFFECTIVENESS AND LESSEN THE ADVERSE EFFECTS. ADDITIONALLY, THE STUDY SHEDS LIGHT ON THE APPLICATION OF NETWORK PHARMACOLOGY AS A COST-EFFECTIVE AND TIME-SAVING APPROACH FOR THE THERAPEUTIC TARGET PREDICTION OF NUTRACEUTICALS AGAINST AKI. 2023 18 105 33 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS. 2018 19 3245 22 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 20 5351 29 RATIONALE FOR DIETARY ANTIOXIDANT TREATMENT OF ADHD. INCREASING UNDERSTANDING ARISES REGARDING DISADVANTAGES OF STIMULANT MEDICATION IN CHILDREN WITH ADHD (ATTENTION-DEFICIT HYPERACTIVITY DISORDER). THIS REVIEW PRESENTS SCIENTIFIC FINDINGS SUPPORTING DIETARY ANTIOXIDANT TREATMENT OF ADHD AND DESCRIBES SUBSTANTIAL ALTERATIONS IN THE IMMUNE SYSTEM, EPIGENETIC REGULATION OF GENE EXPRESSION, AND OXIDATIVE STRESS REGULATION IN ADHD. AS A RESULT, CHRONIC INFLAMMATION AND OXIDATIVE STRESS COULD DEVELOP, WHICH CAN LEAD TO ADHD SYMPTOMS, FOR EXAMPLE BY CHRONIC T-CELL-MEDIATED NEUROINFLAMMATION, AS WELL AS BY NEURONAL OXIDATIVE DAMAGE AND LOSS OF NORMAL CEREBRAL FUNCTIONS. THEREFORE, MODULATION OF IMMUNE SYSTEM ACTIVITY AND OXIDANT-ANTIOXIDANT BALANCE USING NUTRITIONAL APPROACHES MIGHT HAVE POTENTIAL IN ADHD TREATMENT. THE USE OF NATURAL ANTIOXIDANTS AGAINST OXIDATIVE CONDITIONS IS AN EMERGING FIELD IN THE MANAGEMENT OF NEURODEGENERATIVE DISEASES. DIETARY POLYPHENOLS, FOR EXAMPLE, HAVE ANTIOXIDANT CAPACITIES AS WELL AS IMMUNOREGULATORY EFFECTS AND, THEREFORE, APPEAR APPROPRIATE IN ADHD THERAPY. THIS REVIEW CAN STIMULATE THE DEVELOPMENT AND INVESTIGATION OF DIETARY ANTIOXIDANT TREATMENT IN ADHD, WHICH IS HIGHLY DESIRED. 2018