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infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease.
Mileto SJ, Jardé T, Childress KO, Jensen JL, Rogers AP, Kerr G, Hutton ML, Sheedlo MJ, Bloch SC, Shupe JA, Horvay K, Flores T, Engel R, Wilkins S, McMurrick PJ, Lacy DB, Abud HE, Lyras D
(2020) Proc Natl Acad Sci U S A 117: 8064-8073
MeSH Terms: Animals, Bacterial Proteins, Bacterial Toxins, Cells, Cultured, Clostridium Infections, Clostridium difficile, Colon, Disease Models, Animal, Female, Frizzled Receptors, Humans, Intestinal Mucosa, Mice, Organoids, Primary Cell Culture, Recombinant Proteins, Stem Cells
Show Abstract · Added March 24, 2020
Gastrointestinal infections often induce epithelial damage that must be repaired for optimal gut function. While intestinal stem cells are critical for this regeneration process [R. C. van der Wath, B. S. Gardiner, A. W. Burgess, D. W. Smith, 8, e73204 (2013); S. Kozar , 13, 626-633 (2013)], how they are impacted by enteric infections remains poorly defined. Here, we investigate infection-mediated damage to the colonic stem cell compartment and how this affects epithelial repair and recovery from infection. Using the pathogen we show that infection disrupts murine intestinal cellular organization and integrity deep into the epithelium, to expose the otherwise protected stem cell compartment, in a TcdB-mediated process. Exposure and susceptibility of colonic stem cells to intoxication compromises their function during infection, which diminishes their ability to repair the injured epithelium, shown by altered stem cell signaling and a reduction in the growth of colonic organoids from stem cells isolated from infected mice. We also show, using both mouse and human colonic organoids, that TcdB from epidemic ribotype 027 strains does not require Frizzled 1/2/7 binding to elicit this dysfunctional stem cell state. This stem cell dysfunction induces a significant delay in recovery and repair of the intestinal epithelium of up to 2 wk post the infection peak. Our results uncover a mechanism by which an enteric pathogen subverts repair processes by targeting stem cells during infection and preventing epithelial regeneration, which prolongs epithelial barrier impairment and creates an environment in which disease recurrence is likely.
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1 Members
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17 MeSH Terms
Identification and Characterization of Unique Neutralizing Antibodies to Mouse EGF Receptor.
Jae Huh W, Niitsu H, Carney B, McKinley ET, Houghton JL, Coffey RJ
(2020) Gastroenterology 158: 1500-1502
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Azoxymethane, Carcinogens, Cells, Cultured, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, ErbB Receptors, Gastritis, Hypertrophic, Genes, Reporter, Hepatocytes, Humans, Mice, Mice, Transgenic, Primary Cell Culture
Added January 31, 2020
1 Communities
1 Members
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17 MeSH Terms
Targeted mobilization of Lrig1 gastric epithelial stem cell populations by a carcinogenic type IV secretion system.
Wroblewski LE, Choi E, Petersen C, Delgado AG, Piazuelo MB, Romero-Gallo J, Lantz TL, Zavros Y, Coffey RJ, Goldenring JR, Zemper AE, Peek RM
(2019) Proc Natl Acad Sci U S A 116: 19652-19658
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Disease Models, Animal, Epithelial Cells, Female, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Humans, Male, Membrane Glycoproteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Precancerous Conditions, Primary Cell Culture, Risk Factors, Stem Cells, Stomach, Stomach Neoplasms, Type IV Secretion Systems
Show Abstract · Added September 27, 2019
-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within -infected gastric mucosa. Lineage tracing was induced in (Lrig1/YFP) mice that were uninfected or subsequently infected with or an isogenic mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the mutant. WT -infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic infection stimulates Lrig1-expressing progenitor cells in a -dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
1 Communities
1 Members
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23 MeSH Terms
Direct reprogramming to human nephron progenitor-like cells using inducible piggyBac transposon expression of SNAI2-EYA1-SIX1.
Vanslambrouck JM, Woodard LE, Suhaimi N, Williams FM, Howden SE, Wilson SB, Lonsdale A, Er PX, Li J, Maksimovic J, Oshlack A, Wilson MH, Little MH
(2019) Kidney Int 95: 1153-1166
MeSH Terms: Cells, Cultured, Cellular Reprogramming, DNA Transposable Elements, Gene Transfer Techniques, Genetic Engineering, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Nephrons, Nuclear Proteins, Primary Cell Culture, Protein Tyrosine Phosphatases, Regeneration, Snail Family Transcription Factors
Show Abstract · Added March 28, 2019
All nephrons in the mammalian kidney arise from a transient nephron progenitor population that is lost close to the time of birth. The generation of new nephron progenitors and their maintenance in culture are central to the success of kidney regenerative strategies. Using a lentiviral screening approach, we previously generated a human induced nephron progenitor-like state in vitro using a pool of six transcription factors. Here, we sought to develop a more efficient approach for direct reprogramming of human cells that could be applied in vivo. PiggyBac transposons are a non-viral integrating gene delivery system that is suitable for in vivo use and allows for simultaneous delivery of multiple genes. Using an inducible piggyBac transposon system, we optimized a protocol for the direct reprogramming of HK2 cells to induced nephron progenitor-like cells with expression of only 3 transcription factors (SNAI2, EYA1, and SIX1). Culture in conditions supportive of the nephron progenitor state further increased the expression of nephron progenitor genes. The refined protocol was then applied to primary human renal epithelial cells, which integrated into developing nephron structures in vitro and in vivo. Such inducible reprogramming to nephron progenitor-like cells could facilitate direct cellular reprogramming for kidney regeneration.
Copyright © 2019 International Society of Nephrology. All rights reserved.
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2 Members
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14 MeSH Terms
Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E782-E793
MeSH Terms: Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholic Acids, Deoxycholic Acid, Gene Expression Profiling, Gluconeogenesis, Glucose Clamp Technique, Hep G2 Cells, Hepatocytes, Humans, Insulin Resistance, Liver, Mice, Mice, Knockout, Obesity, Primary Cell Culture, Receptors, G-Protein-Coupled, Taurocholic Acid
Show Abstract · Added April 15, 2019
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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19 MeSH Terms
Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis.
Blackwood EA, Azizi K, Thuerauf DJ, Paxman RJ, Plate L, Kelly JW, Wiseman RL, Glembotski CC
(2019) Nat Commun 10: 187
MeSH Terms: Activating Transcription Factor 6, Animals, Animals, Newborn, Cells, Cultured, Cerebral Infarction, Disease Models, Animal, Endoplasmic Reticulum, Female, Heart Ventricles, Humans, Kidney, Kidney Diseases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Infarction, Myocytes, Cardiac, Primary Cell Culture, Protective Agents, Proteostasis, Rats, Reperfusion Injury, Treatment Outcome, Unfolded Protein Response
Show Abstract · Added March 3, 2020
Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.
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1 Members
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MeSH Terms
Cytokine-mediated changes in K channel activity promotes an adaptive Ca response that sustains β-cell insulin secretion during inflammation.
Dickerson MT, Bogart AM, Altman MK, Milian SC, Jordan KL, Dadi PK, Jacobson DA
(2018) Sci Rep 8: 1158
MeSH Terms: Adult, Animals, Calcium, Female, Gene Expression Regulation, Glucose, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Interferon-gamma, Interleukin-1beta, Ion Transport, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Potassium, Potassium Channels, Tandem Pore Domain, Primary Cell Culture, RNA, Messenger, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tissue Culture Techniques, Tumor Necrosis Factor-alpha
Show Abstract · Added February 7, 2018
Cytokines present during low-grade inflammation contribute to β-cell dysfunction and diabetes. Cytokine signaling disrupts β-cell glucose-stimulated Ca influx (GSCI) and endoplasmic reticulum (ER) Ca ([Ca]) handling, leading to diminished glucose-stimulated insulin secretion (GSIS). However, cytokine-mediated changes in ion channel activity that alter β-cell Ca handling remain unknown. Here we investigated the role of K currents in cytokine-mediated β-cell dysfunction. K currents, which control the termination of intracellular Ca ([Ca]) oscillations, were reduced following cytokine exposure. As a consequence, [Ca] and electrical oscillations were accelerated. Cytokine exposure also increased basal islet [Ca] and decreased GSCI. The effect of cytokines on TALK-1 K currents were also examined as TALK-1 mediates K by facilitating [Ca] release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca] storage while maintaining 2 phase GSCI and GSIS. This adaptive Ca response was absent in TALK-1 KO islets, which exhibited decreased 2 phase GSCI and diminished GSIS. These findings suggest that K and TALK-1 currents play important roles in altered β-cell Ca handling and electrical activity during low-grade inflammation. These results also reveal that a cytokine-mediated reduction in TALK-1 serves an acute protective role in β-cells by facilitating increased Ca content to maintain GSIS.
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1 Members
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25 MeSH Terms
Antibody-Conjugated Single Quantum Dot Tracking of Membrane Neurotransmitter Transporters in Primary Neuronal Cultures.
Bailey DM, Kovtun O, Rosenthal SJ
(2017) Methods Mol Biol 1570: 165-177
MeSH Terms: Algorithms, Animals, Fluorescent Antibody Technique, Immunoconjugates, Models, Theoretical, Molecular Imaging, Neurons, Neurotransmitter Transport Proteins, Primary Cell Culture, Quantum Dots, Rats, Single Molecule Imaging, Statistics as Topic
Show Abstract · Added April 3, 2018
Single particle tracking (SPT) experiments have provided the scientific community with invaluable single-molecule information about the dynamic regulation of individual receptors, transporters, kinases, lipids, and molecular motors. SPT is an alternative to ensemble averaging approaches, where heterogeneous modes of motion might be lost. Quantum dots (QDs) are excellent probes for SPT experiments due to their photostability, high brightness, and size-dependent, narrow emission spectra. In a typical QD-based SPT experiment, QDs are bound to the target of interest and imaged for seconds to minutes via fluorescence video microscopy. Single QD spots in individual frames are then linked to form trajectories that are analyzed to determine their mean square displacement, diffusion coefficient, confinement index, and instantaneous velocity. This chapter describes a generalizable protocol for the single particle tracking of membrane neurotransmitter transporters on cell membranes with either unmodified extracellular antibody probes and secondary antibody-conjugated quantum dots or biotinylated extracellular antibody probes and streptavidin-conjugated quantum dots in primary neuronal cultures. The neuronal cell culture, the biotinylation protocol and the quantum dot labeling procedures, as well as basic data analysis are discussed.
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2 Members
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MeSH Terms
Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis.
Hendrix AS, Spoonmore TJ, Wilde AD, Putnam NE, Hammer ND, Snyder DJ, Guelcher SA, Skaar EP, Cassat JE
(2016) Antimicrob Agents Chemother 60: 5322-30
MeSH Terms: Animals, Anti-Bacterial Agents, Anti-Inflammatory Agents, Non-Steroidal, Bacterial Proteins, Bone Density Conservation Agents, Cell Survival, Delayed-Action Preparations, Diflunisal, Drug Repositioning, Female, Gene Expression, Humans, Mice, Mice, Inbred C57BL, Osteoblasts, Osteomyelitis, Primary Cell Culture, Staphylococcal Infections, Staphylococcus aureus, Trans-Activators, Treatment Outcome
Show Abstract · Added April 8, 2017
Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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3 Members
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21 MeSH Terms
High-Throughput Screening of Myometrial Calcium-Mobilization to Identify Modulators of Uterine Contractility.
Herington JL, Swale DR, Brown N, Shelton EL, Choi H, Williams CH, Hong CC, Paria BC, Denton JS, Reese J
(2015) PLoS One 10: e0143243
MeSH Terms: Animals, Calcium, Calcium Channel Blockers, Cells, Cultured, Dose-Response Relationship, Drug, Drug Discovery, Female, High-Throughput Screening Assays, Humans, Mice, Myometrium, Oxytocin, Pregnancy, Primary Cell Culture, Reproducibility of Results, Uterine Contraction, Uterus
Show Abstract · Added December 20, 2015
The uterine myometrium (UT-myo) is a therapeutic target for preterm labor, labor induction, and postpartum hemorrhage. Stimulation of intracellular Ca2+-release in UT-myo cells by oxytocin is a final pathway controlling myometrial contractions. The goal of this study was to develop a dual-addition assay for high-throughput screening of small molecular compounds, which could regulate Ca2+-mobilization in UT-myo cells, and hence, myometrial contractions. Primary murine UT-myo cells in 384-well plates were loaded with a Ca2+-sensitive fluorescent probe, and then screened for inducers of Ca2+-mobilization and inhibitors of oxytocin-induced Ca2+-mobilization. The assay exhibited robust screening statistics (Z´ = 0.73), DMSO-tolerance, and was validated for high-throughput screening against 2,727 small molecules from the Spectrum, NIH Clinical I and II collections of well-annotated compounds. The screen revealed a hit-rate of 1.80% for agonist and 1.39% for antagonist compounds. Concentration-dependent responses of hit-compounds demonstrated an EC50 less than 10μM for 21 hit-antagonist compounds, compared to only 7 hit-agonist compounds. Subsequent studies focused on hit-antagonist compounds. Based on the percent inhibition and functional annotation analyses, we selected 4 confirmed hit-antagonist compounds (benzbromarone, dipyridamole, fenoterol hydrobromide and nisoldipine) for further analysis. Using an ex vivo isometric contractility assay, each compound significantly inhibited uterine contractility, at different potencies (IC50). Overall, these results demonstrate for the first time that high-throughput small-molecules screening of myometrial Ca2+-mobilization is an ideal primary approach for discovering modulators of uterine contractility.
1 Communities
5 Members
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17 MeSH Terms