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Results: 1 to 10 of 27

Publication Record


Pancreatic Inflammation Redirects Acinar to β Cell Reprogramming.
Clayton HW, Osipovich AB, Stancill JS, Schneider JD, Vianna PG, Shanks CM, Yuan W, Gu G, Manduchi E, Stoeckert CJ, Magnuson MA
(2016) Cell Rep 17: 2028-2041
MeSH Terms: Acinar Cells, Adenoviridae, Alleles, Animals, Cellular Reprogramming, Diabetes Mellitus, Experimental, Doxycycline, Gene Expression Profiling, Homeodomain Proteins, Immunity, Inflammation, Insulin-Secreting Cells, Macrophages, Metaplasia, Mice, Transgenic, Organ Size, Pancreas, Pancreatic Ducts, Reproducibility of Results, Transcription Factors, Transgenes
Show Abstract · Added November 18, 2016
Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
3 Communities
2 Members
2 Resources
21 MeSH Terms
Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance.
Dadi PK, Vierra NC, Ustione A, Piston DW, Colbran RJ, Jacobson DA
(2014) J Biol Chem 289: 12435-45
MeSH Terms: Action Potentials, Animals, Biological Transport, Blotting, Western, Calcium, Calcium Channels, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cells, Cultured, Cytoplasm, Doxycycline, Endoplasmic Reticulum, Glucose, Glucose Intolerance, Green Fluorescent Proteins, Homeostasis, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Patch-Clamp Techniques, Peptides, Potassium Channels
Show Abstract · Added March 20, 2014
Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is caused by Ca(2+) entry via voltage-dependent Ca(2+) channels. CaMKII is a key mediator and feedback regulator of Ca(2+) signaling in many tissues, but its role in β-cells is poorly understood, especially in vivo. Here, we report that mice with conditional inhibition of CaMKII in β-cells show significantly impaired glucose tolerance due to decreased GSIS. Moreover, β-cell CaMKII inhibition dramatically exacerbates glucose intolerance following exposure to a high fat diet. The impairment of islet GSIS by β-cell CaMKII inhibition is not accompanied by changes in either glucose metabolism or the activities of KATP and voltage-gated potassium channels. However, glucose-stimulated Ca(2+) entry via voltage-dependent Ca(2+) channels is reduced in islet β-cells with CaMKII inhibition, as well as in primary wild-type β-cells treated with a peptide inhibitor of CaMKII. The levels of basal β-cell cytoplasmic Ca(2+) and of endoplasmic reticulum Ca(2+) stores are also decreased by CaMKII inhibition. In addition, CaMKII inhibition suppresses glucose-stimulated action potential firing frequency. These results reveal that CaMKII is a Ca(2+) sensor with a key role as a feed-forward stimulator of β-cell Ca(2+) signals that enhance GSIS under physiological and pathological conditions.
1 Communities
5 Members
0 Resources
25 MeSH Terms
Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo.
Wang DD, Englot DJ, Garcia PA, Lawton MT, Young WL
(2012) Epilepsy Behav 24: 314-8
MeSH Terms: Animals, Anti-Bacterial Agents, Anticonvulsants, Dose-Response Relationship, Drug, Doxycycline, Epilepsies, Partial, Male, Mice, Minocycline, Neurons, Rats, Rats, Sprague-Dawley, Seizures, Tetracycline
Show Abstract · Added August 12, 2016
INTRODUCTION - Increasing evidence suggests the role of inflammation in enhancing neuronal excitability and contributing to epileptogenesis. Tetracycline-class antibiotics minocycline, doxycycline and tetracycline have been shown to have anti-apoptotic and anti-inflammatory effects.
METHODS - We investigated the anti-seizure effects of tetracycline-class antibiotics minocycline, doxycycline and tetracycline in vivo by using the maximal electric shock (MES), 6-Hz (minimal clonic seizure) test and subcutaneous Metrazol (scMET) models of epilepsy.
RESULTS - Minocycline, doxycycline and tetracycline showed anticonvulsant effects in abolishing partial seizures in the mouse 6-Hz seizure test. A dose-dependent effect was found, with ED(50) of 170 mg/kg for minocycline, 157 mg/kg for doxycycline, and 255 mg/kg for tetracycline with peak onset at 0.5h. At high doses, minocycline (250 mg/kg) and doxycycline (150 mg/kg) also had toxic effects, from motor impairments to respiratory failure and death. These drugs had no effects on the MES and scMET tests.
CONCLUSIONS - In the three tests of anti-seizure activity, minocycline, doxycycline, and tetracycline were found to be protective in one: the 6-Hz seizure model. Our data suggest that minocycline and other tetracycline-class drugs may offer some degree of anticonvulsant effect in the setting of CNS disease trials.
Published by Elsevier Inc.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Induction of podocyte-derived VEGF ameliorates podocyte injury and subsequent abnormal glomerular development caused by puromycin aminonucleoside.
Ma J, Matsusaka T, Yang HC, Zhong J, Takagi N, Fogo AB, Kon V, Ichikawa I
(2011) Pediatr Res 70: 83-9
MeSH Terms: Actinin, Animals, Animals, Newborn, Apoptosis, Autocrine Communication, Caspase 3, Cells, Cultured, Desmin, Disease Models, Animal, Doxycycline, Glomerulonephritis, Humans, Intracellular Signaling Peptides and Proteins, Kidney Glomerulus, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Podocytes, Puromycin Aminonucleoside, Response Elements, Vascular Endothelial Growth Factor A, bcl-2-Associated X Protein, bcl-X Protein
Show Abstract · Added January 25, 2012
Our previous studies using puromycin aminonucleoside (PAN) established that podocyte damage leads to glomerular growth arrest during development and glomerulosclerosis later in life. This study examined the potential benefit of maintaining podocyte-derived VEGF in podocyte defense and survival after PAN injury using conditional transgenic podocytes and mice, in which human VEGF-A (hVEGF) transgene expression is controlled by tetracycline responsive element (TRE) promoter and reverse tetracycline transactivator (rtTA) in podocytes. In vitro experiments used primary cultured podocytes harvested from mice carrying podocin-rtTA and TRE-hVEGF transgenes, in which hVEGF can be induced selectively. Induction of VEGF in PAN-exposed podocytes resulted in preservation of intrinsic VEGF, α-actinin-4 and synaptopodin, antiapoptotic marker Bcl-xL/Bax, as well as attenuation in apoptotic marker cleaved/total caspase-3. In vivo, compared with genotype controls, PAN-sensitive neonatal mice with physiologically relevant levels of podocyte-derived VEGF showed significantly larger glomeruli. Furthermore, PAN-induced up-regulation of desmin, down-regulation of synaptopodin and nephrin, and disruption of glomerular morphology were significantly attenuated in VEGF-induced transgenic mice. Our data indicate that podocyte-derived VEGF provides self-preservation functions, which can rescue the cell after injury and preempt subsequent deterioration of the glomerulus in developing mice.
2 Communities
3 Members
0 Resources
25 MeSH Terms
Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden.
Connelly L, Barham W, Onishko HM, Sherrill T, Chodosh LA, Blackwell TS, Yull FE
(2011) Oncogene 30: 1402-12
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Disease Models, Animal, Doxycycline, Epithelium, Female, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mice, Mice, Transgenic, NF-kappa B, Tumor Burden
Show Abstract · Added February 26, 2013
The transcription factor nuclear factor kappa B (NF-κB) is activated in human breast cancer tissues and cell lines. However, it is unclear whether NF-κB activation is a consequence of tumor formation or a contributor to tumor development. We developed a doxycycline (dox)-inducible mouse model, termed DNMP, to inhibit NF-κB activity specifically within the mammary epithelium during tumor development in the polyoma middle T oncogene (PyVT) mouse mammary tumor model. DNMP females and PyVT littermate controls were treated with dox from 4 to 12 weeks of age. We observed an increase in tumor latency and a decrease in final tumor burden in DNMP mice compared with PyVT controls. A similar effect with treatment from 8 to 12 weeks indicates that outcome is independent of effects on postnatal virgin ductal development. In both cases, DNMP mice were less likely to develop lung metastases than controls. Treatment from 8 to 9 weeks was sufficient to impact primary tumor formation. Inhibition of NF-κB increases apoptosis in hyperplastic stages of tumor development and decreases proliferation at least in part by reducing Cyclin D1 expression. To test the therapeutic potential of NF-κB inhibition, we generated palpable tumors by orthotopic injection of PyVT cells and then treated systemically with the NF-κB inhibitor thymoquinone (TQ). TQ treatment resulted in a reduction in tumor volume and weight as compared with vehicle-treated control. These data indicate that epithelial NF-κB is an active contributor to tumor progression and demonstrate that inhibition of NF-κB could have a significant therapeutic impact even at later stages of mammary tumor progression.
3 Communities
3 Members
0 Resources
13 MeSH Terms
DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration.
Osada M, Jardine L, Misir R, Andl T, Millar SE, Pezzano M
(2010) PLoS One 5: e9062
MeSH Terms: Animals, Apoptosis, Cell Count, Cell Proliferation, Doxycycline, Epithelial Cells, Female, Gene Expression Regulation, In Situ Hybridization, Intercellular Signaling Peptides and Proteins, Keratins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Stem Cells, Tetracycline, Thymus Gland, Trans-Activators, Wnt Proteins
Show Abstract · Added January 30, 2013
BACKGROUND - Thymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus.
METHODOLOGY/PRINCIPAL FINDINGS - Here we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+) Foxn1(+) and Aire(+) TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments.
CONCLUSIONS/SIGNIFICANCE - Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated with cancer therapy and bone marrow transplants.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Conditional control of the differentiation competence of pancreatic endocrine and ductal cells by Fgf10.
Kobberup S, Schmerr M, Dang ML, Nyeng P, Jensen JN, MacDonald RJ, Jensen J
(2010) Mech Dev 127: 220-34
MeSH Terms: Animals, Cell Differentiation, Cell Lineage, Doxycycline, Fibroblast Growth Factor 10, Mice, Mice, Transgenic, Pancreas
Show Abstract · Added November 6, 2013
Fgf10 is a critical component of mesenchymal-to-epithelial signaling during endodermal development. In the Fgf10 null pancreas, the embryonic progenitor population fails to expand, while ectopic Fgf10 expression forces progenitor arrest and organ hyperplasia. Using a conditional Fgf10 gain-of-function model, we observed that the timing of Fgf10 expression affected the cellular competence of the arrested pancreatic progenitors. We present evidence that the Fgf10-arrested progenitor state is reversible and that terminal differentiation resumes upon cessation of Fgf10 production. However, competence towards the individual pancreatic cell lineages depended upon the gestational time of when Fgf10 expression was attenuated. This revealed a competence window of endocrine and ductal cell formation that coincided with the pancreatic secondary transition between E13.5 and E15.5. We demonstrate that maintaining the Fgf10-arrested state during this period leads to permanent loss of competence for the endocrine and ductal cell fates. However, competence of the arrested progenitors towards the exocrine cell fate was retained throughout the secondary transition. Sustained Fgf10 expression caused irreversible loss of Ngn3 expression, which may underlie the loss of endocrine competence. Maintenance of exocrine competence may be attributable to continuous Ptf1a expression in the Fgf10-arrested progenitors. This may explain the rapid induction of Bhlhb8, a normally distalized cell intrinsic marker, following loss of ectopic Fgf10 expression. We conclude that the window for endocrine and ductal cell competence ceases during the secondary transition in pancreatic development.
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary development and infection.
Connelly L, Barham W, Pigg R, Saint-Jean L, Sherrill T, Cheng DS, Chodosh LA, Blackwell TS, Yull FE
(2010) J Cell Physiol 222: 73-81
MeSH Terms: Animals, Apoptosis, Disease Models, Animal, Doxycycline, Epithelial Cells, Epithelium, Female, Lactation, Lipopolysaccharides, Mammary Glands, Animal, Mastitis, Mice, Mice, Transgenic, Milk, Milk Proteins, NF-kappa B, Signal Transduction, Up-Regulation
Show Abstract · Added February 26, 2013
We investigated whether nuclear factor kappa B (NF-kappaB), which exhibits a regulated pattern of activity during murine mammary gland development, plays an important role during lactation and involution, when milk production ceases and the gland undergoes apoptosis and re-modeling. We generated a doxycycline inducible transgenic mouse model to activate NF-kappaB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappaB signaling cascade. We found that activation of NF-kappaB during involution resulted in a more rapid reduction in milk levels and increased cleavage of caspase-3, an indicator of apoptosis. We also found that activation of NF-kappaB during lactation with no additional involution signals had a similar effect. The observation that NF-kappaB is a key regulator of milk production led us to investigate the role of NF-kappaB during mastitis, an infection of the mammary gland in which milk loss is observed. Mammary gland injection of E. coli LPS resulted in activation of NF-kappaB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappaB in mammary epithelium. Together, our data reveal that activation of NF-kappaB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappaB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.
2 Communities
3 Members
0 Resources
18 MeSH Terms
PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression.
Gauthier BR, Wiederkehr A, Baquié M, Dai C, Powers AC, Kerr-Conte J, Pattou F, MacDonald RJ, Ferrer J, Wollheim CB
(2009) Cell Metab 10: 110-8
MeSH Terms: Animals, Base Sequence, DNA-Binding Proteins, Doxycycline, Glucose, High Mobility Group Proteins, Homeodomain Proteins, Humans, Insulin, Insulin Secretion, Islets of Langerhans, Male, Mice, Mice, Transgenic, Mitochondria, Mitochondrial Proteins, Promoter Regions, Genetic, Rats, Rats, Wistar, Sodium-Calcium Exchanger, Trans-Activators, Transcription Factors
Show Abstract · Added November 6, 2013
Mutations in the transcription factor Pdx1 cause maturity-onset diabetes of the young 4 (MODY4). Islet transduction with dominant-negative Pdx1 (RIPDN79PDX1) impairs mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). Transcript profiling revealed suppression of nuclear-encoded mitochondrial factor A (TFAM). Herein, we show that Pdx1 suppression in adult mice reduces islet TFAM expression coinciding with hyperglycemia. We define TFAM as a direct target of Pdx1 both in rat INS1 cells and human islets. Adenoviral overexpression of TFAM along with RIPDN79PDX1 in isolated rat islets rescued mitochondrial DNA (mtDNA) copy number and restored respiratory chain activity as well as glucose-induced ATP synthesis and insulin secretion. CGP37157, which blocks the mitochondrial Na(+)/Ca(2+) exchanger, restored ATP generation and GSIS in RIPDN79PDX1 islets, thereby bypassing the transcriptional defect. Thus, the genetic control by the beta cell-specific factor Pdx1 of the ubiquitous gene TFAM maintains beta cell mtDNA vital for ATP production and normal GSIS.
0 Communities
2 Members
0 Resources
22 MeSH Terms
An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice.
Traykova-Brauch M, Schönig K, Greiner O, Miloud T, Jauch A, Bode M, Felsher DW, Glick AB, Kwiatkowski DJ, Bujard H, Horst J, von Knebel Doeberitz M, Niggli FK, Kriz W, Gröne HJ, Koesters R
(2008) Nat Med 14: 979-84
MeSH Terms: Animals, Disease Models, Animal, Doxycycline, Fibrosis, Immunohistochemistry, Kidney Tubules, Mice, Mice, Transgenic, PAX8 Transcription Factor, Paired Box Transcription Factors, Polycystic Kidney Diseases, Promoter Regions, Genetic, Trans-Activators, Transforming Growth Factor beta1, Tuberous Sclerosis Complex 1 Protein, Tumor Suppressor Proteins
Show Abstract · Added September 9, 2013
We describe a transgenic mouse line, Pax8-rtTA, which, under control of the mouse Pax8 promoter, directs high levels of expression of the reverse tetracycline-dependent transactivator (rtTA) to all proximal and distal tubules and the entire collecting duct system of both embryonic and adult kidneys. Using crosses of Pax8-rtTA mice with tetracycline-responsive c-MYC mice, we established a new, inducible model of polycystic kidney disease that can mimic adult onset and that shows progression to renal malignant disease. When targeting the expression of transforming growth factor beta-1 to the kidney, we avoided early lethality by discontinuous treatment and successfully established an inducible model of renal fibrosis. Finally, a conditional knockout of the gene encoding tuberous sclerosis complex-1 was achieved, which resulted in the early outgrowth of giant polycystic kidneys reminiscent of autosomal recessive polycystic kidney disease. These experiments establish Pax8-rtTA mice as a powerful tool for modeling renal diseases in transgenic mice.
0 Communities
0 Members
1 Resources
16 MeSH Terms