1   906 126 CHRONIC EXPOSURE TO ENVIRONMENTAL LEVEL PHENANTHRENE INDUCES NON-OBESITY-DEPENDENT INSULIN RESISTANCE IN MALE MICE. EPIDEMIOLOGICAL EVIDENCE SHOWS THAT THE BODY BURDEN OF POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) IS RELATED TO THE DISRUPTION OF GLUCOSE HOMEOSTASIS. HOWEVER, THE CONTRIBUTION OF PAHS TO THE DEVELOPMENT OF DIABETES REMAINS POORLY DOCUMENTED. IN THE CURRENT WORK, MALE KUNMING MICE RECEIVED PHENANTHRENE (PHE) (5, 50, AND 500 NG/KG) BY GAVAGE ADMINISTRATION ONCE EVERY 2 DAYS FOR 28 WEEKS. THE SIGNIFICANT ELEVATION OF HOMEOSTASIS MODEL ASSESSMENT-INSULIN RESISTANCE (HOMA-IR) AND HOMA-BETA CELL, ACCOMPANIED BY HYPERINSULINEMIA, INDICATED THE OCCURRENCE OF INSULIN RESISTANCE. THE SUPPRESSION OF THE INSULIN RECEPTOR SIGNALING PATHWAY IN SKELETAL MUSCLE MIGHT BE RESPONSIBLE FOR GLUCOSE INTOLERANCE. UNDER THE NONOBESE STATE, THE SERUM LEVELS OF RESISTIN, TUMOR NECROSIS FACTOR-ALPHA, AND INTERLEUKIN-6 WERE ELEVATED, WHEREAS THE LEVELS OF ADIPONECTIN WERE REDUCED. THESE CHANGES IN ADIPOCYTOKINE LEVELS WERE CONSISTENT WITH THEIR TRANSCRIPTION IN WHITE ADIPOSE TISSUE. THE PROMOTER METHYLATION LEVELS OF RETN (ENCODING RESISTIN) AND ADIPOQ (ENCODING ADIPONECTIN) WERE INVERSELY CORRELATED WITH THEIR MRNA LEVELS, INDICATING THAT PHE EXPOSURE COULD CAUSE THE DISRUPTION OF ADIPOCYTOKINE SECRETION VIA EPIGENETIC MODIFICATION. THE RESULTS WOULD BE HELPFUL FOR UNDERSTANDING THE PATHOGENESIS IN THE DEVELOPMENT OF T2DM CAUSED BY NONOBESOGENIC POLLUTANTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  4769  24 NUCLEAR MORPHOMETRY, NUCLEOMICS AND PROSTATE CANCER PROGRESSION. PROSTATE CANCER (PCA) RESULTS FROM A MULTISTEP PROCESS. THIS PROCESS INCLUDES INITIATION, WHICH OCCURS THROUGH VARIOUS AGING EVENTS AND MULTIPLE INSULTS (SUCH AS CHRONIC INFECTION, INFLAMMATION AND GENETIC INSTABILITY THROUGH REACTIVE OXYGEN SPECIES CAUSING DNA DOUBLE-STRAND BREAKS), FOLLOWED BY A MULTISTEP PROCESS OF PROGRESSION. THESE STEPS INCLUDE SEVERAL GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS ALTERATIONS TO THE CHROMATIN STRUCTURE, WHICH OCCUR IN RESPONSE TO THE CARCINOGENIC STRESS-RELATED EVENTS THAT SUSTAIN PROLIFERATIVE SIGNALING. EVENTS SUCH AS EVADING GROWTH SUPPRESSORS, RESISTING CELL DEATH, ENABLING REPLICATIVE IMMORTALITY, INDUCING ANGIOGENESIS, AND ACTIVATING INVASION AND METASTASIS ARE READILY OBSERVED. IN ADDITION, IN CONJUNCTION WITH THESE CRITICAL DRIVERS OF CARCINOGENESIS, OTHER FACTORS RELATED TO THE ETIOPATHOGENESIS OF PCA, INVOLVING ENERGY METABOLISM AND EVASION OF THE IMMUNE SURVEILLANCE SYSTEM, APPEAR TO BE INVOLVED. IN ADDITION, WHEN CANCER SPREAD AND METASTASIS OCCUR, THE 'TUMOR MICROENVIRONMENT' IN THE BONE OF PCA PATIENTS MAY PROVIDE A WAY TO SUSTAIN DORMANCY OR SENESCENCE AND EVENTUALLY ESTABLISH A 'SEED AND SOIL' SITE WHERE PCA PROLIFERATION AND GROWTH MAY OCCUR OVER TIME. WHEN PCA IS INITIATED AND PROGRESSION ENSUES, SIGNIFICANT ALTERATIONS IN NUCLEAR SIZE, SHAPE AND HETEROCHROMATIN (DNA TRANSCRIPTION) ORGANIZATION ARE FOUND, AND KEY NUCLEAR TRANSCRIPTIONAL AND STRUCTURAL PROTEINS, AS WELL AS MULTIPLE NUCLEAR BODIES CAN LEAD TO PRECANCEROUS AND MALIGNANT CHANGES. THESE SERIES OF CELLULAR AND TISSUE-RELATED MALIGNANCY-ASSOCIATED EVENTS CAN BE QUANTIFIED TO ASSESS DISEASE PROGRESSION AND MANAGEMENT.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3   128  19 A UNIFYING MECHANISM OF KETOGENIC DIET ACTION: THE MULTIPLE ROLES OF NICOTINAMIDE ADENINE DINUCLEOTIDE. THE ABILITY OF A KETOGENIC DIET TO TREAT SEIZURES AND RENDER A NEURONAL NETWORK MORE RESISTANT TO STRONG ELECTRICAL ACTIVITY HAS BEEN OBSERVED FOR A CENTURY IN CLINICS AND FOR DECADES IN RESEARCH LABORATORIES. ALONGSIDE ONGOING EFFORTS TO UNDERSTAND HOW THIS THERAPY WORKS TO STOP SEIZURES, METABOLIC HEALTH IS INCREASINGLY APPRECIATED AS CRITICAL BUFFER TO RESISTING AND RECOVERING FROM ACUTE AND CHRONIC DISEASE. ACCORDINGLY, LINKS BETWEEN METABOLISM AND HEALTH, AND THE BROADER EMERGING IMPACT OF THE KETOGENIC DIET IN IMPROVING DIVERSE METABOLIC, IMMUNOLOGICAL AND NEUROLOGICAL CONDITIONS, HAVE SERVED TO INTENSIFY THE SEARCH FOR ITS KEY AND/OR COMMON MECHANISMS. HERE WE REVIEW DIVERSE EVIDENCE FOR INCREASED LEVELS OF NAD(+), AND THUS AN ALTERED RATIO OF NAD(+)/NADH, DURING METABOLIC THERAPY WITH A KETOGENIC DIET. WE PROPOSE THIS AS A POTENTIAL UNIFYING MECHANISM, AND HIGHLIGHT SOME OF THE EVIDENCE LINKING ALTERED NAD(+)/NADH WITH REDUCED SEIZURES AND WITH A RANGE OF SHORT AND LONG-TERM CHANGES ASSOCIATED WITH THE BENEFICIAL EFFECTS OF A KETOGENIC DIET. AN INCREASE IN NAD(+)/NADH IS CONSISTENT WITH MULTIPLE LINES OF EVIDENCE AND HYPOTHESES, AND THEREFORE WE SUGGEST THAT INCREASED NAD(+) MAY BE A COMMON MECHANISM UNDERLYING BENEFICIAL EFFECTS OF KETOGENIC DIET THERAPY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4    75  27 A MURINE CELL LINE BASED MODEL OF CHRONIC CDK9 INHIBITION TO STUDY WIDESPREAD NON-GENETIC TRANSCRIPTIONAL ELONGATION DEFECTS (TEDEFF) IN CANCERS. WE HAVE PREVIOUSLY REPORTED THAT A SUBSET OF CANCERS IS DEFINED BY GLOBAL TRANSCRIPTIONAL DEREGULATIONS WITH WIDESPREAD DEFICIENCIES IN MRNA TRANSCRIPTION ELONGATION (TE)-WE CALL SUCH CANCERS AS TE(DEFF). NOTABLY, TE(DEFF) CANCERS ARE CHARACTERIZED BY SPURIOUS TRANSCRIPTION AND FAULTY MRNA PROCESSING IN A LARGE SET OF GENES, SUCH AS INTERFERON/JAK/STAT AND TNF/NF-KAPPAB PATHWAYS, LEADING TO THEIR SUPPRESSION. THE TE(DEFF) SUBTYPE OF TUMORS IN RENAL CELL CARCINOMA AND METASTATIC MELANOMA PATIENTS SIGNIFICANTLY CORRELATE WITH POOR RESPONSE AND OUTCOME IN IMMUNOTHERAPY. GIVEN THE IMPORTANCE OF INVESTIGATING TE(DEFF) CANCERS-AS IT PORTENDS A SIGNIFICANT ROADBLOCK AGAINST IMMUNOTHERAPY-THE GOAL OF THIS PROTOCOL IS TO ESTABLISH AN IN VITRO TE(DEFF) MOUSE MODEL TO STUDY THESE WIDESPREAD, NON-GENETIC TRANSCRIPTIONAL ABNORMALITIES IN CANCERS AND GAIN NEW INSIGHTS, NOVEL USES FOR EXISTING DRUGS, OR FIND NEW STRATEGIES AGAINST SUCH CANCERS. WE DETAIL THE USE OF CHRONIC FLAVOPIRIDOL MEDIATED CDK9 INHIBITION TO ABROGATE PHOSPHORYLATION OF SERINE 2 RESIDUE ON THE C-TERMINAL REPEAT DOMAIN (CTD) OF RNA POLYMERASE II (RNA POL II), SUPPRESSING THE RELEASE OF RNA POL II INTO PRODUCTIVE TRANSCRIPTION ELONGATION. GIVEN THAT TE(DEFF) CANCERS ARE NOT CLASSIFIED UNDER ANY SPECIFIC SOMATIC MUTATION, A PHARMACOLOGICAL MODEL IS ADVANTAGEOUS, AND BEST MIMICS THE WIDESPREAD TRANSCRIPTIONAL AND EPIGENETIC DEFECTS OBSERVED IN THEM. THE USE OF AN OPTIMIZED SUBLETHAL DOSE OF FLAVOPIRIDOL IS THE ONLY EFFICACIOUS STRATEGY IN CREATING A GENERALIZABLE MODEL OF NON-GENETIC WIDESPREAD DISRUPTION IN TRANSCRIPTION ELONGATION AND MRNA PROCESSING DEFECTS, CLOSELY MIMICKING THE CLINICALLY OBSERVED TE(DEFF) CHARACTERISTICS. THEREFORE, THIS MODEL OF TE(DEFF) CAN BE LEVERAGED TO DISSECT, CELL-AUTONOMOUS FACTORS ENABLING THEM IN RESISTING IMMUNE-MEDIATED CELL ATTACK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  3431  24 HYDROGEN SULFIDE ALLEVIATES HYPERTENSIVE KIDNEY DYSFUNCTION THROUGH AN EPIGENETIC MECHANISM. HYPERTENSION IS A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD), AND RENAL INFLAMMATION IS AN INTEGRAL PART IN THIS PATHOLOGY. HYDROGEN SULFIDE (H(2)S) HAS BEEN SHOWN TO MITIGATE RENAL DAMAGE THROUGH REDUCTION IN BLOOD PRESSURE AND ROS; HOWEVER, THE EXACT MECHANISMS ARE NOT CLEAR. WHILE SEVERAL STUDIES HAVE UNDERLINED THE ROLE OF EPIGENETICS IN RENAL INFLAMMATION AND DYSFUNCTION, THE MECHANISMS THROUGH WHICH EPIGENETIC REGULATORS PLAY A ROLE IN HYPERTENSION ARE NOT WELL DEFINED. IN THIS STUDY, WE SOUGHT TO IDENTIFY WHETHER MICRORNAS ARE DYSREGULATED IN RESPONSE TO ANGIOTENSIN II (ANG II)-INDUCED HYPERTENSION IN THE KIDNEY AND WHETHER A H(2)S DONOR, GYY4137, COULD REVERSE THE MICRORNA ALTERATION AND KIDNEY FUNCTION. WILD-TYPE (C57BL/6J) MICE WERE TREATED WITHOUT OR WITH ANG II AND GYY4137 FOR 4 WK. BLOOD PRESSURE, RENAL BLOOD FLOW, AND RESISTIVE INDEX (RI) WERE MEASURED. MICRORNA MICROARRAYS WERE CONDUCTED AND SUBSEQUENT TARGET PREDICTION REVEALED GENES ASSOCIATED WITH A PROINFLAMMATORY RESPONSE. ANG II TREATMENT SIGNIFICANTLY INCREASED BLOOD PRESSURE, DECREASED BLOOD FLOW IN THE RENAL CORTEX, INCREASED RI, AND REDUCED RENAL FUNCTION. THESE EFFECTS WERE AMELIORATED IN MICE TREATED WITH GYY4137. MICROARRAY ANALYSIS REVEALED DOWNREGULATION OF MIR-129 IN ANG II-TREATED MICE AND UPREGULATION AFTER GYY4137 TREATMENT. QUANTITATION OF PROTEINS INVOLVED IN THE INFLAMMATORY RESPONSE AND DNA METHYLATION REVEALED UPREGULATION OF IL-17A AND DNA METHYLTRANSFERASE 3A, WHEREAS H(2)S PRODUCTION ENZYMES AND ANTI-INFLAMMATORY IL-10 WERE REDUCED. TAKEN TOGETHER, OUR DATA SUGGEST THAT DOWNREGULATION OF MIR-129 PLAYS A SIGNIFICANT ROLE IN ANG II-INDUCED RENAL INFLAMMATION AND FUNCTIONAL OUTCOMES AND THAT GYY4137 IMPROVES RENAL FUNCTION BY REVERSING MIR-129 EXPRESSION.NEW & NOTEWORTHY WE INVESTIGATED EPIGENETIC CHANGES THAT OCCUR IN THE HYPERTENSIVE KIDNEY AND HOW H(2)S SUPPLEMENTATION REVERSES ADVERSE EFFECTS. INFLAMMATION, ABERRANT METHYLATION, AND DYSFUNCTION WERE OBSERVED IN THE HYPERTENSIVE KIDNEY, AND THESE EFFECTS WERE ALLEVIATED WITH H(2)S SUPPLEMENTATION. WE IDENTIFY MIR-129 AS A POTENTIAL REGULATOR OF BLOOD PRESSURE AND H(2)S REGULATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  3553  29 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  6126  31 THE EPIGENETIC MODIFIER PBRM1 RESTRICTS THE BASAL ACTIVITY OF THE INNATE IMMUNE SYSTEM BY REPRESSING RETINOIC ACID-INDUCIBLE GENE-I-LIKE RECEPTOR SIGNALLING AND IS A POTENTIAL PROGNOSTIC BIOMARKER FOR COLON CANCER. IT HAS LONG BEEN KNOWN THAT PATIENTS SUFFERING FROM INFLAMMATORY BOWEL DISEASE (IBD) HAVE AN INCREASED RISK OF DEVELOPING COLORECTAL CANCER (CRC). THE INNATE IMMUNE SYSTEM OF HOST CELLS PROVIDES A FIRST-LINE DEFENCE AGAINST PATHOGENIC INFECTION, WHEREAS AN UNCONTROLLED INFLAMMATORY RESPONSE UNDER HOMEOSTATIC CONDITIONS USUALLY LEADS TO PATHOLOGICAL CONSEQUENCES, AS EXEMPLIFIED BY THE CHRONIC INFLAMMATION OF IBD. THE KEY MOLECULES AND PATHWAYS KEEPING INNATE IMMUNITY IN CHECK ARE STILL POORLY DEFINED. HERE, WE REPORT THAT THE CHROMATIN REMODELLER POLYBROMO-1 (PBRM1) IS A REPRESSOR OF INNATE IMMUNE SIGNALLING MEDIATED BY RETINOIC ACID-INDUCIBLE GENE-I (RIG-I)-LIKE RECEPTORS (RLRS). KNOCKDOWN OF PBRM1 IN COLON CANCER CELLS INCREASED THE EXPRESSION OF TWO RECEPTOR GENES (RIG-I AND MDA5) AND UPREGULATED INTERFERON (IFN)-RELATED AND INFLAMMATION-RELATED GENE SIGNATURES. THE INNATE IMMUNE SIGNAL STIMULATED BY A DOUBLE-STRANDED RNA VIRAL MIMIC WAS EXAGGERATED BY PBRM1 SUPPRESSION. PBRM1 COOPERATED WITH POLYCOMB PROTEIN EZH2 TO DIRECTLY BIND THE CIS-REGULATORY ELEMENTS OF RIG-I AND MDA5, THEREBY SUPPRESSING THEIR TRANSCRIPTION. MOREOVER, UPREGULATION OF RIG-I AND MDA5 IS REQUIRED FOR IFN RESPONSE ACTIVATION INDUCED BY PBRM1 SILENCING. TRIM25, A PROTEIN STIMULATED BY THE RLR PATHWAY AND IFN PRODUCTION, PHYSICALLY INTERACTED WITH PBRM1 AND INDUCED PBRM1 PROTEIN DESTABILIZATION BY PROMOTING ITS UBIQUITINATION. THESE FINDINGS REVEAL A PBRM1-RLR REGULATORY CIRCUIT THAT CAN KEEP INNATE IMMUNE ACTIVITY AT A MINIMAL LEVEL IN RESTING CELLS, AND ALSO ENSURE A ROBUST INFLAMMATORY RESPONSE IN THE CASE OF PATHOGEN INVASION. PBRM1 WAS FOUND TO BE DOWNREGULATED IN PRIMARY TISSUES FROM PATIENTS WITH CRC OR IBD, AND ITS EXPRESSION CORRELATED NEGATIVELY WITH THAT OF RLR GENES AND INTERFERON-STIMULATED GENES IN CRC SAMPLES. LOWER PBRM1 EXPRESSION WAS ASSOCIATED WITH ADVANCED PATHOLOGICAL GRADE AND POORER SURVIVAL OF CRC PATIENTS, INDICATING THAT PBRM1 COULD SERVE AS A POTENTIAL PROGNOSTIC BIOMARKER FOR CRC. COPYRIGHT (C) 2017 PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. PUBLISHED BY JOHN WILEY & SONS, LTD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  5416  17 REGULATION OF CELLULAR METABOLISM: PROGRAMMING AND MAINTAINING METABOLIC HOMEOSTASIS. MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION IS PROGRAMMED TO SET AND MAINTAIN METABOLIC HOMEOSTASIS. THIS IS ACCOMPLISHED THROUGH AN INTRINSIC PROGRAM THAT DETERMINES THE METABOLIC [ATP]/[ADP]/[PI], WHERE [PI] IS THE CONCENTRATION OF INORGANIC PHOSPHATE (ENERGY STATE) AND MAINTAINS IT THROUGH A BIDIRECTIONAL SENSORY/SIGNALING CONTROL NETWORK THAT REACHES EVERY ASPECT OF CELLULAR METABOLISM. THE PROGRAM SETS THE ENERGY STATE WITH HIGH PRECISION (TO BETTER THAN ONE PART IN 10(9)) AND CAN RESPOND TO TRANSIENT CHANGES IN ENERGY DEMAND (ATP USE) TO MORE THAN 100 TIMES THE RESTING RATE. EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ABLE TO "FINE TUNE" THE PROGRAMMED SET POINT OVER A NARROW RANGE TO MEET THE SPECIAL NEEDS ASSOCIATED WITH CELL DIFFERENTIATION AND CHRONIC CHANGES IN METABOLIC REQUIREMENTS. THE RESULT IS ROBUST, ACROSS PLATFORM CONTROL OF METABOLISM, ESSENTIAL TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF COMPLEX ORGANISMS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  4428  19 MOLECULAR BASIS OF THE IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER CHARACTERIZED BY ABDOMINAL PAIN, DISCOMFORT AND BLOATING. THE PATHOPHYSIOLOGY OF IBS IS POORLY UNDERSTOOD, BUT THE PRESENCE OF PSYCHOSOCIAL BASIS IS NOW KNOWN. THERE IS AN INCREASING NUMBER OF PUBLICATIONS SUPPORTING THE ROLE OF GENETICS IN IBS. MOST OF THE VARIATIONS ARE FOUND IN GENES ASSOCIATED WITH THE BRAIN-GUT AXIS, REVEALING THE STRONG CORRELATION OF BRAIN-GUT AXIS AND IBS. MIRNAS, WHICH PLAY CRITICAL ROLES IN PHYSIOLOGICAL PROCESSES, ARE NOT WELL STUDIED IN IBS. HOWEVER, SO FAR THERE IS FOUND AN INVOLVEMENT OF ALTERATIONS IN MIRNA EXPRESSION OR SEQUENCE, IN IBS SYMPTOMS. IBS PHENOTYPE IS AFFECTED BY EPIGENETIC ALTERATION AND ENVIRONMENT. CHANGES IN DNA AND HISTONE METHYLATION ARE OBSERVED IN PATIENTS WHO SUFFERED CHILDHOOD TRAUMA OR ABUSE, RESULTING IN ALTERED GENE EXPRESSION, SUCH AS THE GLUCOCORTICOID RECEPTOR GENE. FINALLY, DIET IS ANOTHER FACTOR ASSOCIATED WITH IBS, WHICH MAY CONTRIBUTE TO SYMPTOM ONSET. CERTAIN FOODS MAY AFFECT ON BACTERIAL METABOLISM AND EPIGENETIC MODIFICATIONS, PREDISPOSING TO IBS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10  6267  21 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11  5251  24 PROGRAMMED INCREASES IN LXRALPHA INDUCED BY PATERNAL ALCOHOL USE ENHANCE OFFSPRING METABOLIC ADAPTATION TO HIGH-FAT DIET INDUCED OBESITY. OBJECTIVES: PATERNALLY INHERITED ALTERATIONS IN EPIGENETIC PROGRAMMING ARE EMERGING AS RELEVANT FACTORS IN NUMEROUS DISEASE STATES, INCLUDING THE GROWTH AND METABOLIC DEFECTS OBSERVED IN FETAL ALCOHOL SPECTRUM DISORDERS. IN RODENTS, CHRONIC PATERNAL ALCOHOL USE INDUCES FETAL GROWTH RESTRICTION, AS WELL AS SEX-SPECIFIC ALTERATIONS IN INSULIN SIGNALING AND LIPID HOMEOSTASIS IN THE OFFSPRING. BASED ON PREVIOUS STUDIES, WE HYPOTHESIZED THAT THE OBSERVED METABOLIC IRREGULARITIES ARE THE CONSEQUENCE OF PATERNALLY INHERITED ALTERATIONS LIVER X RECEPTOR (LXR) ACTIVITY. METHODS: MALE OFFSPRING OF ALCOHOL-EXPOSED SIRES WERE CHALLENGED WITH A HIGH-FAT DIET AND THE MOLECULAR PATHWAYS CONTROLLING GLUCOSE AND LIPID HOMEOSTASIS ASSAYED FOR LXR-INDUCED ALTERATIONS. RESULTS: SIMILAR TO FINDINGS IN STUDIES EMPLOYING LXR AGONISTS WE FOUND THAT THE MALE OFFSPRING OF ALCOHOL-EXPOSED SIRES DISPLAY RESISTANCE TO DIET-INDUCED OBESITY AND IMPROVED GLUCOSE HOMEOSTASIS WHEN CHALLENGED WITH A HIGH-FAT DIET. THIS IMPROVED METABOLIC ADAPTATION IS MEDIATED BY LXRALPHA TRANS-REPRESSION OF INFLAMMATORY CYTOKINES, RELEASING IKKBETA INHIBITION OF THE INSULIN SIGNALING PATHWAY. INTERESTINGLY, PATERNALLY PROGRAMMED INCREASES IN LXRALPHA EXPRESSION ARE LIVER-SPECIFIC AND DO NOT MANIFEST IN THE PANCREAS OR VISCERAL FAT. CONCLUSIONS: THESE STUDIES IDENTIFY LXRALPHA AS A KEY MEDIATOR OF THE LONG-TERM METABOLIC ALTERATIONS INDUCED BY PRECONCEPTION PATERNAL ALCOHOL USE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12  5815  21 STRESS AND GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL PROGRAMMING IN TIME AND SPACE: IMPLICATIONS FOR THE BRAIN-GUT AXIS. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ENHANCED ABDOMINAL PAIN AND ALTERED INTESTINAL BARRIER FUNCTION THAT MAY RESULT FROM A PERTURBATION IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE GLUCOCORTICOID RECEPTOR (GR) EXPLOITS DIVERSE MECHANISMS TO ACTIVATE OR SUPPRESS CONGENERIC GENE EXPRESSION, WITH REGULATORY VARIATION ASSOCIATED WITH STRESS-RELATED DISORDERS IN PSYCHIATRY AND GASTROENTEROLOGY. PURPOSE: DURING ACUTE AND CHRONIC STRESS, CORTICOTROPIN-RELEASING HORMONE DRIVES SECRETION OF ADRENOCORTICOTROPIC HORMONE FROM THE PITUITARY, ULTIMATELY LEADING TO THE RELEASE OF CORTISOL (HUMAN) AND CORTICOSTERONE (RODENT) FROM THE ADRENAL GLANDS. CORTISOL BINDS WITH THE GR IN THE CYTOSOL, TRANSLOCATES TO THE NUCLEUS, AND ACTIVATES THE NR3C1 (NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 [GR]) GENE. THIS REVIEW FOCUSES ON THE RAPIDLY DEVELOPING OBSERVATIONS THAT CORTISOL IS RESPONSIBLE FOR DRIVING CIRCADIAN AND ULTRADIAN BURSTS OF TRANSCRIPTIONAL ACTIVITY IN THE CLOCK (CLOCK CIRCADIAN REGULATOR) AND PER (PERIOD CIRCADIAN CLOCK 1) GENE FAMILIES, AND THIS RHYTHM IS DISRUPTED IN MAJOR DEPRESSIVE DISORDER, BIPOLAR DISORDER, AND STRESS-RELATED GASTROINTESTINAL AND IMMUNE DISORDERS. GLUCOCORTICOID RECEPTOR REGULATES DIFFERENT SETS OF TRANSCRIPTS IN A TISSUE-SPECIFIC MANNER, THROUGH PULSATILE WAVES OF GENE EXPRESSION THAT INCLUDES OCCUPANCY OF GLUCOCORTICOID RESPONSE ELEMENTS LOCATED WITHIN CONSTITUTIVELY OPEN SPATIAL DOMAINS IN CHROMATIN. EMERGING EVIDENCE SUPPORTS A POTENTIALLY PIVOTAL ROLE FOR EPIGENETIC REGULATION OF HOW GR INTERACTS WITH OTHER CHROMATIN REGULATORS TO CONTROL THE EXPRESSION OF ITS TARGET GENES. DYSREGULATION OF THE CENTRAL AND PERIPHERAL GR REGULOME HAS POTENTIALLY SIGNIFICANT CONSEQUENCES FOR STRESS-RELATED DISORDERS AFFECTING THE BRAIN-GUT AXIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13   788  20 CELLULAR ALLOSTATIC LOAD IS LINKED TO INCREASED ENERGY EXPENDITURE AND ACCELERATED BIOLOGICAL AGING. STRESS TRIGGERS ANTICIPATORY PHYSIOLOGICAL RESPONSES THAT PROMOTE SURVIVAL, A PHENOMENON TERMED ALLOSTASIS. HOWEVER, THE CHRONIC ACTIVATION OF ENERGY-DEPENDENT ALLOSTATIC RESPONSES RESULTS IN ALLOSTATIC LOAD, A DYSREGULATED STATE THAT PREDICTS FUNCTIONAL DECLINE, ACCELERATES AGING, AND INCREASES MORTALITY IN HUMANS. THE ENERGETIC COST AND CELLULAR BASIS FOR THE DAMAGING EFFECTS OF ALLOSTATIC LOAD HAVE NOT BEEN DEFINED. HERE, BY LONGITUDINALLY PROFILING THREE UNRELATED PRIMARY HUMAN FIBROBLAST LINES ACROSS THEIR LIFESPAN, WE FIND THAT CHRONIC GLUCOCORTICOID EXPOSURE INCREASES CELLULAR ENERGY EXPENDITURE BY APPROXIMATELY 60%, ALONG WITH A METABOLIC SHIFT FROM GLYCOLYSIS TO MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION (OXPHOS). THIS STATE OF STRESS-INDUCED HYPERMETABOLISM IS LINKED TO MTDNA INSTABILITY, NON-LINEARLY AFFECTS AGE-RELATED CYTOKINES SECRETION, AND ACCELERATES CELLULAR AGING BASED ON DNA METHYLATION CLOCKS, TELOMERE SHORTENING RATE, AND REDUCED LIFESPAN. PHARMACOLOGICALLY NORMALIZING OXPHOS ACTIVITY WHILE FURTHER INCREASING ENERGY EXPENDITURE EXACERBATES THE ACCELERATED AGING PHENOTYPE, POINTING TO TOTAL ENERGY EXPENDITURE AS A POTENTIAL DRIVER OF AGING DYNAMICS. TOGETHER, OUR FINDINGS DEFINE BIOENERGETIC AND MULTI-OMIC RECALIBRATIONS OF STRESS ADAPTATION, UNDERSCORING INCREASED ENERGY EXPENDITURE AND ACCELERATED CELLULAR AGING AS INTERRELATED FEATURES OF CELLULAR ALLOSTATIC LOAD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  2836  28 FOOD INTAKE IN EARLY LIFE AND EPIGENETIC MODIFICATIONS OF PRO-OPIOMELANOCORTIN EXPRESSION IN ARCUATE NUCLEUS. THE PREVALENCE OF OBESITY IS INCREASING IN NOWADAYS SOCIETIES AND, DESPITE BEING A MULTIFACTORIAL DISEASE, IT HAS A SIGNIFICANT CORRELATION WITH FOOD INTAKE. THE CONTROL OF FOOD INTAKE IS PERFORMED BY NEURONS OF THE ARCUATE NUCLEUS OF THE HYPOTHALAMUS (ARC), WHICH SECRET OREXIGENIC AND ANOREXIGENIC NEUROPEPTIDES, SUCH AS PROOPIOMELANOCORTIN (POMC), UNDER STIMULATION OF, E.G., GHRELIN, INSULIN, AND LEPTIN. INSULIN, USES INOSITOL 1,4,5-TRISPHOSPHATE/SERINE-THREONINE KINASE (IP3/AKT) PATHWAYS AND STIMULATES THE EXCLUSION OF (FORKHEAD BOX PROTEIN O1) FOXO1 FROM THE NUCLEUS AND THEREBY DOES THE INACTIVATION OF THE INHIBITION OF POMC EXPRESSION, WHILE LEPTIN STIMULATES SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) PHOSPHORYLATION AND POMC EXPRESSION. EPIGENETIC MODIFICATIONS OF THE SYNTHESIS OF THESE NEUROPEPTIDES CAN LEAD TO AN INCREASED CALORIC INTAKE, WHICH, IN TURN, IS AN IMPORTANT RISK FACTOR FOR OBESITY AND ITS COMORBIDITIES. EPIGENETIC MODIFICATIONS ARE REVERSIBLE, SO THE SEARCH FOR EPIGENETIC TARGETS HAS SIGNIFICANT SCIENTIFIC AND THERAPEUTIC APPEAL. IN THIS REVIEW, WE SYNTHESIZE THE EFFECT OF FOOD INTAKE ON THE EPIGENETIC MODIFICATIONS OF NEUROPEPTIDE Y AND PRO-OPIOMELANOCORTIN OF ARC AND ITS RELATIONSHIPS WITH OBESITY DEVELOPMENT AND COMORBIDITIES. WE FOUND THAT THERE IS NO CONSENSUS ON THE METHYLATION OF NEUROPEPTIDES WHEN THE EVALUATIONS ARE CARRIED OUT IN DIFFERENT PROMOTERS. BASED ON REPORTS CARRIED ON IN THE EARLY LIFE IN LABORATORY ANIMALS, WHICH IS THE TIMELINE THAT THE VAST MAJORITY OF AUTHOR USED TO STUDY THIS TOPIC, CHRONIC INFLAMMATION, DEFECTS IN INSULIN AND LEPTIN SIGNALING MAY BE LINKED TO CHANGES OCCURRING IN THE PHOSPHOINOSITIDE 3-KINASE/AKT (PI3K/AKT) AND/OR STAT3/SOCS3 (CYTOKINE SIGNALING 3) PATHWAYS. IN ITS TURN, THE EPIGENETIC MODIFICATIONS RELATED TO INCREASED FOOD INTAKE AND REDUCED ENERGY EXPENDITURE MAY BE ASSOCIATED WITH PI3K/AKT AND STAT3/SOCS3 SIGNALING DISRUPTION AND PRO-OPIOMELANOCORTIN EXPRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  4672  21 NEW INSIGHTS INTO THE MECHANISMS OF THE KETOGENIC DIET. PURPOSE OF REVIEW: HIGH-FAT, LOW-CARBOHYDRATE KETOGENIC DIETS HAVE BEEN USED FOR ALMOST A CENTURY FOR THE TREATMENT OF EPILEPSY. USED TRADITIONALLY FOR THE TREATMENT OF REFRACTORY PEDIATRIC EPILEPSIES, IN RECENT YEARS THE USE OF KETOGENIC DIETS HAS EXPERIENCED A REVIVAL TO INCLUDE THE TREATMENT OF ADULTHOOD EPILEPSIES AS WELL AS CONDITIONS RANGING FROM AUTISM TO CHRONIC PAIN AND CANCER. DESPITE THE ABILITY OF KETOGENIC DIET THERAPY TO SUPPRESS SEIZURES REFRACTORY TO ANTIEPILEPTIC DRUGS AND REPORTS OF LASTING SEIZURE FREEDOM, THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. THIS REVIEW EXPLORES NEW INSIGHTS INTO MECHANISMS MOBILIZED BY KETOGENIC DIET THERAPIES. RECENT FINDINGS: KETOGENIC DIETS ACT THROUGH A COMBINATION OF MECHANISMS, WHICH ARE LINKED TO THE EFFECTS OF KETONES AND GLUCOSE RESTRICTION, AND TO INTERACTIONS WITH RECEPTORS, CHANNELS, AND METABOLIC ENZYMES. DECANOIC ACID, A COMPONENT OF MEDIUM-CHAIN TRICLYCERIDES, CONTRIBUTES TO SEIZURE CONTROL THROUGH DIRECT ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID (AMPA) RECEPTOR INHIBITION, WHEREAS DRUGS TARGETING LACTATE DEHYDROGENASE REDUCE SEIZURES THROUGH INHIBITION OF A METABOLIC PATHWAY. KETOGENIC DIET THERAPY ALSO AFFECTS DNA METHYLATION, A NOVEL EPIGENETIC MECHANISM OF THE DIET. SUMMARY: KETOGENIC DIET THERAPY COMBINES SEVERAL BENEFICIAL MECHANISMS THAT PROVIDE BROAD BENEFITS FOR THE TREATMENT OF EPILEPSY WITH THE POTENTIAL TO NOT ONLY SUPPRESS SEIZURES BUT ALSO TO MODIFY THE COURSE OF THE EPILEPSY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  5252  23 PROGRAMMING AND REGULATION OF METABOLIC HOMEOSTASIS. EVIDENCE IS PRESENTED THAT THE RATE AND EQUILIBRIUM CONSTANTS IN MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION SET AND MAINTAIN METABOLIC HOMEOSTASIS IN EUKARYOTIC CELLS. THESE INTERNAL CONSTANTS DETERMINE THE ENERGY STATE ([ATP]/[ADP][PI]), AND THE ENERGY STATE MAINTAINS HOMEOSTASIS THROUGH A BIDIRECTIONAL SENSORY/SIGNALING CONTROL NETWORK THAT REACHES EVERY ASPECT OF CELLULAR METABOLISM. THE ENERGY STATE IS MAINTAINED WITH HIGH PRECISION (TO APPROXIMATELY 1 PART IN 10(10)), AND THE CONTROL SYSTEM CAN RESPOND TO TRANSIENT CHANGES IN ENERGY DEMAND (ATP UTILIZATION) OF MORE THAN 100 TIMES THE RESTING RATE. EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ABLE TO "FINE-TUNE" THE PROGRAMMED SET POINT OVER A NARROW RANGE TO MEET THE SPECIAL NEEDS ASSOCIATED WITH CELL DIFFERENTIATION AND CHRONIC CHANGES IN METABOLIC REQUIREMENTS. THE RESULT IS ROBUST ACROSS-PLATFORM CONTROL OF METABOLISM, WHICH IS ESSENTIAL TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF COMPLEX ORGANISMS. A MODEL OF OXIDATIVE PHOSPHORYLATION IS PRESENTED, FOR WHICH THE STEADY-STATE RATE EXPRESSION HAS BEEN DERIVED AND COMPUTER PROGRAMMED. THE BEHAVIOR OF OXIDATIVE PHOSPHORYLATION PREDICTED BY THE MODEL IS SHOWN TO FIT THE EXPERIMENTAL DATA AVAILABLE FOR ISOLATED MITOCHONDRIA AS WELL AS FOR CELLS AND TISSUES. THIS INCLUDES MEASUREMENTS FROM SEVERAL DIFFERENT MAMMALIAN TISSUES AS WELL AS FROM INSECT FLIGHT MUSCLE AND PLANTS. THE RESPIRATORY CHAIN AND OXIDATIVE PHOSPHORYLATION IS REMARKABLY SIMILAR FOR ALL HIGHER PLANTS AND ANIMALS. THIS IS CONSISTENT WITH THE EFFICIENT SYNTHESIS OF ATP AND PRECISE CONTROL OF METABOLIC HOMEOSTASIS PROVIDED BY OXIDATIVE PHOSPHORYLATION BEING A KEY TO CELLULAR DIFFERENTIATION AND THE EVOLUTION OF STRUCTURES WITH SPECIALIZED FUNCTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  6887  29 [ROLE OF METAFLAMMATION AS A SYSTEMIC MANIFESTATION OF METABOLIC DISEASES]. VISCERAL OBESITY AS A COMPONENT OF THE METABOLIC SYNDROME IS CHARACTERIZED BY SYSTEMIC AND LOCAL INFLAMMATION, WHICH CAN BE QUANTIFIED IN ORGANS (METAFLAMMATION). THIS PROCESS CAN BE REGARDED AS A CHRONIC, STERILE, AND LOW-GRADE STATE OF INFLAMMATION WITHOUT INFECTION, TRAUMA, TUMOR OR AUTOIMMUNITY. IT IS CAUSED BY AN INFLAMMATION OF THE VISCERAL ADIPOSE TISSUE (ADIPOSE INFLAMMATION OR ADIPOFLAMMATION) DUE TO ADIPOCYTE HYPERTROPHY AND HYPERPLASIA WITH INCREASED INFILTRATION BY MONOCYTES AND MACROPHAGES. IMPORTANT IS THE PRESENCE OF PROINFLAMMATORY, SO-CALLED POLARIZED M1 MACROPHAGES THAT ARE INDUCED BY INTERFERON GAMMA (IFN-GAMMA) AND LIPOPOLYSACCHARIDES (LPS) WITH SECRETION OF INTERLEUKIN (IL)-6, TUMOR NECROSIS FACTOR (TNF) AND IL?1. IN CONTRAST, THE ANTI-INFLAMMATORY, SO-CALLED POLARIZED M2 MACROPHAGES INDUCED BY IL?4 AND IL-13 WITH SECRETION OF IL?8 AND IL-10 DECREASE. IN ADDITION, THE SECRETED ADIPOKINE PATTERN CHANGES FROM ANTI-INFLAMMATORY TO PROINFLAMMATORY. ADIPOCYTE NECROSIS, LOCAL HYPOXIA, DYSREGULATED AUTOPHAGY, ACTIVATION OF INFLAMMASOMES, MODULATION OF TOLL-LIKE RECEPTORS, AND EPIGENETIC FACTORS PLAY A COMPLEX ROLE. THIS MECHANISM RESULTS IN LOCAL INSULIN RESISTANCE AND SUBSEQUENTLY A SYSTEMIC INSULIN RESISTANCE OF PERIPHERAL ORGANS AS WELL AS A SPILLOVER OF LOCAL MEDIATORS OF INFLAMMATION INTO THE SYSTEMIC CIRCULATION (MEASURED AS OBESITY C?REACTIVE PROTEIN, CRP). THE ACTIVATION OF INFLAMMATORY SIGNAL TRANSDUCTION CASCADES LEADS TO INHIBITORY PHOSPHORYLATION OF THE INSULIN SIGNALING PATHWAY AND A WEAKENING OF THE EFFECT OF INSULIN. IN PARALLEL, ECTOPIC LIPID ACCUMULATION OCCURS IN THE LIVER, MUSCULATURE, PANCREAS, PERICARDIUM AND LUNGS. DIACYLGLYCEROL (DAG) ACTIVATES SPECIFIC ISOFORMS OF PROTEIN KINASE C (EPSILON IN THE LIVER AND TAU IN THE MUSCULATURE), WHICH IN TURN LEAD TO INHIBITION OF THE INSULIN SIGNALING PATHWAY. INSULIN RESISTANCE IN OBESITY AND TYPE 2 DIABETES MELLITUS IS AN INFLAMMATORY DISEASE. THE AIM OF FUTURE TRANSLATIONAL APPROACHES IS AN ANTI-INFLAMMATORY, MOLECULARLY INDIVIDUALIZED (PRECISION MEDICINE) TREATMENT IN ADIPOSE TISSUE (TARGETED THERAPY) AND IN ORGANS OF INSULIN RESISTANCE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  4075  34 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES.	2019	

19  2617  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                      
20  5313  26 PSYCHOLOGICAL STRESS AS A MODULATOR OF FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY. THERE IS STRONG EVIDENCE INDICATING THAT THE SOCIAL ENVIRONMENT TRIGGERS CHANGES TO THE PSYCHOLOGICAL STRESS RESPONSE AND GLUCOCORTICOID RECEPTOR FUNCTION. CONSIDERABLE LITERATURE LINKS THE SUBSEQUENT CHANGES IN STRESS RESILIENCY TO PHYSICAL HEALTH. HERE, CONVERGING EVIDENCE FOR THE MODULATORY ROLE OF CHRONIC PSYCHOLOGICAL STRESS IN THE RECOVERY PROCESS FOLLOWING SPINAL CORD INJURY (SCI) IS PRESENTED. DESPITE THE CONSIDERABLE ADVANCES IN SCI RESEARCH, WE ARE STILL UNABLE TO IDENTIFY THE CAUSES OF VARIABILITY IN PATIENTS' RECOVERY FOLLOWING INJURY. WE PROPOSE THAT INDIVIDUALS' PAST AND PRESENT LIFE EXPERIENCES (IN THE FORM OF STRESS EXPOSURE) MAY SIGNIFICANTLY MODULATE PATIENTS' OUTCOME POST-SCI. WE PROPOSE A THEORETICAL MODEL TO EXPLAIN THE NEGATIVE IMPACT OF CHRONIC PSYCHOLOGICAL STRESS ON PHYSICAL AND PSYCHOLOGICAL RECOVERY. THE STRESS EXPERIENCED IN LIFE PRIOR TO SCI AND ALSO AS A RESULT OF THE TRAUMATIC INJURY, COULD COMPROMISE GLUCOCORTICOID RECEPTOR SENSITIVITY AND FUNCTION, AND CONTRIBUTE TO HIGH LEVELS OF INFLAMMATION AND APOPTOSIS POST-SCI, DECREASING THE TISSUE REMAINING AT THE INJURY SITE AND UNDERMINING RECOVERY OF FUNCTION. BOTH STRESS-INDUCED GLUCOCORTICOID RESISTANCE AND STRESS-INDUCED EPIGENETIC CHANGES TO THE GLUCOCORTICOID RECEPTOR CAN MODULATE THE NUCLEAR FACTOR-KAPPA B REGULATED INFLAMMATORY PATHWAYS AND THE BCL-2 REGULATED APOPTOSIS PATHWAYS. THIS MODEL NOT ONLY CONTRIBUTES TO THE THEORETICAL UNDERSTANDING OF THE RECOVERY PROCESS FOLLOWING INJURY, BUT ALSO PROVIDES CONCRETE TESTABLE HYPOTHESES FOR FUTURE STUDIES.	2014