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The PAS Domain-Containing Protein HeuR Regulates Heme Uptake in Campylobacter jejuni.
Johnson JG, Gaddy JA, DiRita VJ
(2016) MBio 7:
MeSH Terms: Animals, Bacterial Proteins, Campylobacter jejuni, Catalase, Chickens, Gastrointestinal Tract, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Heme, Humans, Hydrogen Peroxide, Iron, Mutation
Show Abstract · Added April 26, 2017
Campylobacter jejuni is a leading cause of bacterially derived gastroenteritis. A previous mutant screen demonstrated that the heme uptake system (Chu) is required for full colonization of the chicken gastrointestinal tract. Subsequent work identified a PAS domain-containing regulator, termed HeuR, as being required for chicken colonization. Here we confirm that both the heme uptake system and HeuR are required for full chicken gastrointestinal tract colonization, with the heuR mutant being particularly affected during competition with wild-type C. jejuni Transcriptomic analysis identified the chu genes-and those encoding other iron uptake systems-as regulatory targets of HeuR. Purified HeuR bound the chuZA promoter region in electrophoretic mobility shift assays. Consistent with a role for HeuR in chu expression, heuR mutants were unable to efficiently use heme as a source of iron under iron-limiting conditions, and mutants exhibited decreased levels of cell-associated iron by mass spectrometry. Finally, we demonstrate that an heuR mutant of C. jejuni is resistant to hydrogen peroxide and that this resistance correlates to elevated levels of catalase activity. These results indicate that HeuR directly and positively regulates iron acquisition from heme and negatively impacts catalase activity by an as yet unidentified mechanism in C. jejuni IMPORTANCE: Annually, Campylobacter jejuni causes millions of gastrointestinal infections in the United States, due primarily to its ability to reside within the gastrointestinal tracts of poultry, where it can be released during processing and contaminate meat. In the developing world, humans are often infected by consuming contaminated water or by direct contact with livestock. Following consumption of contaminated food or water, humans develop disease that is characterized by mild to severe diarrhea. There is a need to understand both colonization of chickens, to make food safer, and colonization of humans, to better understand disease. Here we demonstrate that to efficiently colonize a host, C. jejuni requires iron from heme, which is regulated by the protein HeuR. Understanding how HeuR functions, we can develop ways to inhibit its function and reduce iron acquisition during colonization, potentially reducing C. jejuni in the avian host, which would make food safer, or limiting human colonization.
Copyright © 2016 Johnson et al.
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13 MeSH Terms
The Role of the Microbiome in Gastrointestinal Cancer.
Wroblewski LE, Peek RM, Coburn LA
(2016) Gastroenterol Clin North Am 45: 543-56
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Cell Proliferation, Colonic Polyps, Colorectal Neoplasms, Diet, Disease Models, Animal, Esophageal Neoplasms, Gastrointestinal Microbiome, Gastrointestinal Neoplasms, Gastrointestinal Tract, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Microbiota, Stem Cells, Stomach Neoplasms
Show Abstract · Added April 6, 2017
Humans are host to complex microbial communities previously termed normal flora and largely overlooked. However, resident microbes contribute to both health and disease. Investigators are beginning to define microbes that contribute to the development of gastrointestinal malignancies and the mechanisms by which this occurs. Resident microbes can induce inflammation, leading to cell proliferation and altered stem cell dynamics, which can lead to alterations in DNA integrity and immune regulation and promote carcinogenesis. Studies in human patients and rodent models of cancer have identified alterations in the microbiota of the stomach, esophagus, and colon that increase the risk for malignancy.
Published by Elsevier Inc.
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19 MeSH Terms
Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.
Li B, Wang A, Liu J, Qi Z, Liu X, Yu K, Wu H, Chen C, Hu C, Wang W, Wu J, Hu Z, Ye L, Zou F, Liu F, Wang B, Wang L, Ren T, Zhang S, Bai M, Zhang S, Liu J, Liu Q
(2016) J Med Chem 59: 8456-72
MeSH Terms: Amides, Animals, Cell Line, Tumor, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Gastrointestinal Tract, Halogenation, Humans, Methylation, Mice, Mice, Nude, Models, Molecular, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Rats, Sprague-Dawley, Structure-Activity Relationship
Show Abstract · Added April 2, 2019
cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.
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Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.
Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD
(2016) J Clin Invest 126: 2221-35
MeSH Terms: Animals, Autism Spectrum Disorder, Enteric Nervous System, Female, Gastrointestinal Motility, Gastrointestinal Tract, Genetic Variation, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Models, Animal, Neurogenesis, Pregnancy, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 31, 2018
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
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Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions.
Zhang LS, Davies SS
(2016) Genome Med 8: 46
MeSH Terms: Animals, Diet, Disease Susceptibility, Energy Metabolism, Fatty Acids, Volatile, Gastrointestinal Microbiome, Gastrointestinal Tract, Homeostasis, Humans, Indoles, Metabolome, Metabolomics, Methylamines, Microbiota, Translational Medical Research, Tryptophan, Tyrosine
Show Abstract · Added May 6, 2016
Mass spectrometry- and nuclear magnetic resonance-based metabolomic studies comparing diseased versus healthy individuals have shown that microbial metabolites are often the compounds most markedly altered in the disease state. Recent studies suggest that several of these metabolites that derive from microbial transformation of dietary components have significant effects on physiological processes such as gut and immune homeostasis, energy metabolism, vascular function, and neurological behavior. Here, we review several of the most intriguing diet-dependent metabolites that may impact host physiology and may therefore be appropriate targets for therapeutic interventions, such as short-chain fatty acids, trimethylamine N-oxide, tryptophan and tyrosine derivatives, and oxidized fatty acids. Such interventions will require modulating either bacterial species or the bacterial biosynthetic enzymes required to produce these metabolites, so we briefly describe the current understanding of the bacterial and enzymatic pathways involved in their biosynthesis and summarize their molecular mechanisms of action. We then discuss in more detail the impact of these metabolites on health and disease, and review current strategies to modulate levels of these metabolites to promote human health. We also suggest future studies that are needed to realize the full therapeutic potential of targeting the gut microbiota.
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17 MeSH Terms
Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment: A Scientific Statement From the American Heart Association.
Ferguson JF, Allayee H, Gerszten RE, Ideraabdullah F, Kris-Etherton PM, Ordovás JM, Rimm EB, Wang TJ, Bennett BJ, American Heart Association Council on Functional Genomics and Translational Biology, Council on Epidemiology and Prevention, and Stroke Council
(2016) Circ Cardiovasc Genet 9: 291-313
MeSH Terms: American Heart Association, Animals, Biomedical Research, Cardiovascular Diseases, Diet, Diffusion of Innovation, Epigenesis, Genetic, Forecasting, Gastrointestinal Microbiome, Gastrointestinal Tract, Gene-Environment Interaction, Genetic Predisposition to Disease, Genetic Variation, Host-Pathogen Interactions, Humans, Metagenomics, Nutrigenomics, Nutrition Assessment, Nutritional Status, Phenotype, Preventive Health Services, Risk Assessment, Risk Factors, United States
Show Abstract · Added June 14, 2016
Cardiometabolic diseases are the leading cause of death worldwide and are strongly linked to both genetic and nutritional factors. The field of nutrigenomics encompasses multiple approaches aimed at understanding the effects of diet on health or disease development, including nutrigenetic studies investigating the relationship between genetic variants and diet in modulating cardiometabolic risk, as well as the effects of dietary components on multiple "omic" measures, including transcriptomics, metabolomics, proteomics, lipidomics, epigenetic modifications, and the microbiome. Here, we describe the current state of the field of nutrigenomics with respect to cardiometabolic disease research and outline a direction for the integration of multiple omics techniques in future nutrigenomic studies aimed at understanding mechanisms and developing new therapeutic options for cardiometabolic disease treatment and prevention.
© 2016 American Heart Association, Inc.
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24 MeSH Terms
IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori.
Dixon BR, Radin JN, Piazuelo MB, Contreras DC, Algood HM
(2016) PLoS One 11: e0148514
MeSH Terms: Animals, Anti-Infective Agents, CD4-Positive T-Lymphocytes, Epithelial Cells, Epithelium, Gastritis, Gastrointestinal Tract, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Interleukin-17, Interleukin-8, Interleukins, Leukocyte L1 Antigen Complex, Lipocalins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Stomach
Show Abstract · Added April 28, 2016
Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.
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MICROBIOME. Rethinking heritability of the microbiome.
van Opstal EJ, Bordenstein SR
(2015) Science 349: 1172-3
MeSH Terms: Gastrointestinal Tract, Humans, Microbiota, Quantitative Trait, Heritable, Symbiosis
Added October 8, 2015
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Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.
Levic DS, Minkel JR, Wang WD, Rybski WM, Melville DB, Knapik EW
(2015) J Mol Med (Berl) 93: 165-76
MeSH Terms: Animals, Animals, Genetically Modified, Body Patterning, Bone and Bones, Brain, Disease Models, Animal, Gastrointestinal Tract, Gene Expression, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Humans, Hypobetalipoproteinemias, Immunohistochemistry, Lipid Metabolism, Malabsorption Syndromes, Monomeric GTP-Binding Proteins, Organogenesis, Phenotype, Zebrafish
Show Abstract · Added February 19, 2015
Anderson disease (ANDD) or chylomicron retention disease (CMRD) is a rare, hereditary lipid malabsorption syndrome associated with mutations in the SAR1B gene that is characterized by failure to thrive and hypocholesterolemia. Although the SAR1B structure has been resolved and its role in formation of coat protein II (COPII)-coated carriers is well established, little is known about the requirement for SAR1B during embryogenesis. To address this question, we have developed a zebrafish model of Sar1b deficiency based on antisense oligonucleotide knockdown. We show that zebrafish sar1b is highly conserved among vertebrates; broadly expressed during development; and enriched in the digestive tract organs, brain, and craniofacial skeleton. Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes. Transgenic expression analysis revealed that Sar1b is required for growth of exocrine pancreas and liver. Furthermore, we found abnormal differentiation and maturation of craniofacial cartilage associated with defects in procollagen II secretion and absence of select, neuroD-positive neurons of the midbrain and hindbrain. The model presented here will help to systematically dissect developmental roles of Sar1b and to discover molecular and cellular mechanisms leading to organ-specific ANDD pathology. Key messages: Sar1b depletion phenotype in zebrafish resembles Anderson disease deficits. Sar1b deficiency results in multi-organ developmental deficits. Sar1b is required for dietary cholesterol uptake into enterocytes.
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19 MeSH Terms
Dominant and context-specific control of endodermal organ allocation by Ptf1a.
Willet SG, Hale MA, Grapin-Botton A, Magnuson MA, MacDonald RJ, Wright CV
(2014) Development 141: 4385-94
MeSH Terms: Animals, Endoderm, Fluorescent Antibody Technique, Gastrointestinal Tract, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Histological Techniques, Mice, Microscopy, Confocal, Organogenesis, Pancreas, SOXB1 Transcription Factors, Transcription Factors
Show Abstract · Added November 19, 2014
The timing and gene regulatory logic of organ-fate commitment from within the posterior foregut of the mammalian endoderm is largely unexplored. Transient misexpression of a presumed pancreatic-commitment transcription factor, Ptf1a, in embryonic mouse endoderm (Ptf1a(EDD)) dramatically expanded the pancreatic gene regulatory network within the foregut. Ptf1a(EDD) temporarily suppressed Sox2 broadly over the anterior endoderm. Pancreas-proximal organ territories underwent full tissue conversion. Early-stage Ptf1a(EDD) rapidly expanded the endogenous endodermal Pdx1-positive domain and recruited other pancreas-fate-instructive genes, thereby spatially enlarging the potential for pancreatic multipotency. Early Ptf1a(EDD) converted essentially the entire glandular stomach, rostral duodenum and extrahepatic biliary system to pancreas, with formation of many endocrine cell clusters of the type found in normal islets of Langerhans. Sliding the Ptf1a(EDD) expression window through embryogenesis revealed differential temporal competencies for stomach-pancreas respecification. The response to later-stage Ptf1a(EDD) changed radically towards unipotent, acinar-restricted conversion. We provide strong evidence, beyond previous Ptf1a inactivation or misexpression experiments in frog embryos, for spatiotemporally context-dependent activity of Ptf1a as a potent gain-of-function trigger of pro-pancreatic commitment.
© 2014. Published by The Company of Biologists Ltd.
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13 MeSH Terms