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Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology.
Yamazaki H, Suemizu H, Mitsui M, Shimizu M, Guengerich FP
(2016) Chem Res Toxicol 29: 1903-1911
MeSH Terms: Activation, Metabolic, Animals, Chimera, Cytochrome P-450 Enzyme System, Humans, Liver, Mass Spectrometry, Mice, Thalidomide, Toxicokinetics
Show Abstract · Added March 14, 2018
Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolically activated C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans.
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10 MeSH Terms
Local effects of human PCSK9 on the atherosclerotic lesion.
Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y, DeVay RM, Hong L, Fan D, Predazzi IM, Rashid S, Linton MF, Fazio S
(2016) J Pathol 238: 52-62
MeSH Terms: Animals, Atherosclerosis, Disease Models, Animal, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Immunoprecipitation, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Serine Endopeptidases, Transplantation Chimera
Show Abstract · Added February 3, 2017
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE(-/-) and LDLR(-/-) mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE(-/-) recipient mice, while increasing the infiltration of Ly6C(hi) inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6C(hi) -positive cell numbers in spleens of apoE(-/-) mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR(-/-) recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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18 MeSH Terms
Genetic chimeras reveal the autonomy requirements for Vsx2 in embryonic retinal progenitor cells.
Sigulinsky CL, German ML, Leung AM, Clark AM, Yun S, Levine EM
(2015) Neural Dev 10: 12
MeSH Terms: Animals, Cell Division, Chimera, Embryo Transfer, Female, Genes, Reporter, Homeodomain Proteins, LIM-Homeodomain Proteins, Male, Mice, Mice, Transgenic, Microphthalmia-Associated Transcription Factor, Mosaicism, Neural Stem Cells, Neurogenesis, Neuroglia, Organ Specificity, Retina, Retinal Ganglion Cells, Transcription Factors
Show Abstract · Added November 2, 2015
BACKGROUND - Vertebrate retinal development is a complex process, requiring the specification and maintenance of retinal identity, proliferative expansion of retinal progenitor cells (RPCs), and their differentiation into retinal neurons and glia. The homeobox gene Vsx2 is expressed in RPCs and required for the proper execution of this retinal program. However, our understanding of the mechanisms by which Vsx2 does this is still rudimentary. To define the autonomy requirements for Vsx2 in the regulation of RPC properties, we generated chimeric mouse embryos comprised of wild-type and Vsx2-deficient cells.
RESULTS - We show that Vsx2 maintains retinal identity in part through the cell-autonomous repression of the retinal pigment epithelium determinant Mitf, and that Lhx2 is required cell autonomously for the ectopic Mitf expression in Vsx2-deficient cells. We also found significant cell-nonautonomous contributions to Vsx2-mediated regulation of RPC proliferation, pointing to an important role for Vsx2 in establishing a growth-promoting extracellular environment. Additionally, we report a cell-autonomous requirement for Vsx2 in controlling when neurogenesis is initiated, indicating that Vsx2 is an important mediator of neurogenic competence. Finally, the distribution of wild-type cells shifted away from RPCs and toward retinal ganglion cell precursors in patches of high Vsx2-deficient cell density to potentially compensate for the lack of fated precursors in these areas.
CONCLUSIONS - Through the generation and analysis of genetic chimeras, we demonstrate that Vsx2 utilizes both cell-autonomous and cell-nonautonomous mechanisms to regulate progenitor properties in the embryonic retina. Importantly, Vsx2's role in regulating Mitf is in part separable from its role in promoting proliferation, and proliferation is excluded as the intrinsic timer that determines when neurogenesis is initiated. These findings highlight the complexity of Vsx2 function during retinal development and provide a framework for identifying the molecular mechanisms mediating these functions.
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20 MeSH Terms
KIM-1-mediated phagocytosis reduces acute injury to the kidney.
Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, Ichimura T, Kuchroo V, Bonventre JV
(2015) J Clin Invest 125: 1620-36
MeSH Terms: Acute Kidney Injury, Animals, Apoptosis, Cisplatin, Cytokines, Epithelial Cells, Extracellular Matrix Proteins, Gene Expression Regulation, Hepatitis A Virus Cellular Receptor 1, Homeodomain Proteins, Immunity, Innate, Inflammation, Intercellular Signaling Peptides and Proteins, Kidney, Kidney Tubules, Proximal, LLC-PK1 Cells, Macrophage Activation, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Phagocytosis, Phosphatidylinositol 3-Kinases, Protein Structure, Tertiary, Radiation Chimera, Reperfusion Injury, Swine
Show Abstract · Added September 12, 2016
Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.
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29 MeSH Terms
Resident progenitors, not exogenous migratory cells, generate the majority of visceral mesothelium in organogenesis.
Winters NI, Williams AM, Bader DM
(2014) Dev Biol 391: 125-32
MeSH Terms: Animals, Cell Differentiation, Cell Movement, Chick Embryo, Chimera, Embryonic Stem Cells, Epithelium, Gastrointestinal Tract, Heart, Organogenesis, Quail, Respiratory System
Show Abstract · Added September 28, 2015
Historically, analyses of mesothelial differentiation have focused on the heart where a highly migratory population of progenitors originating from a localized "extrinsic" source moves to and over the developing organ. This model long stood alone as the paradigm for generation of this cell type. Here, using chick/quail chimeric grafting and subsequent identification of mesothelial cell populations, we demonstrate that a different mechanism for the generation of mesothelia exists in vertebrate organogenesis. In this newly discovered model, mesothelial progenitors are intrinsic to organs of the developing digestive and respiratory systems. Additionally, we demonstrate that the early heart stands alone in its ability to recruit an entirely exogenous mesothelial cell layer during development. Thus, the newly identified "organ intrinsic" model of mesotheliogenesis appears to predominate while the long-studied cardiac model of mesothelial development may be the outlier.
Copyright © 2014 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Chimeric exchange of coronavirus nsp5 proteases (3CLpro) identifies common and divergent regulatory determinants of protease activity.
Stobart CC, Sexton NR, Munjal H, Lu X, Molland KL, Tomar S, Mesecar AD, Denison MR
(2013) J Virol 87: 12611-8
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Chimera, Conserved Sequence, Coronavirus, Coronavirus Infections, Cricetinae, Evolution, Molecular, Humans, Mice, Molecular Sequence Data, Peptide Hydrolases, Phylogeny, Protein Structure, Tertiary, Sequence Alignment, Viral Proteins
Show Abstract · Added February 19, 2015
Human coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) cause epidemics of severe human respiratory disease. A conserved step of CoV replication is the translation and processing of replicase polyproteins containing 16 nonstructural protein domains (nsp's 1 to 16). The CoV nsp5 protease (3CLpro; Mpro) processes nsp's at 11 cleavage sites and is essential for virus replication. CoV nsp5 has a conserved 3-domain structure and catalytic residues. However, the intra- and intermolecular determinants of nsp5 activity and their conservation across divergent CoVs are unknown, in part due to challenges in cultivating many human and zoonotic CoVs. To test for conservation of nsp5 structure-function determinants, we engineered chimeric betacoronavirus murine hepatitis virus (MHV) genomes encoding nsp5 proteases of human and bat alphacoronaviruses and betacoronaviruses. Exchange of nsp5 proteases from HCoV-HKU1 and HCoV-OC43, which share the same genogroup, genogroup 2a, with MHV, allowed for immediate viral recovery with efficient replication albeit with impaired fitness in direct competition with wild-type MHV. Introduction of MHV nsp5 temperature-sensitive mutations into chimeric HKU1 and OC43 nsp5 proteases resulted in clear differences in viability and temperature-sensitive phenotypes compared with MHV nsp5. These data indicate tight genetic linkage and coevolution between nsp5 protease and the genomic background and identify differences in intramolecular networks regulating nsp5 function. Our results also provide evidence that chimeric viruses within coronavirus genogroups can be used to test nsp5 determinants of function and inhibition in common isogenic backgrounds and cell types.
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17 MeSH Terms
The hologenomic basis of speciation: gut bacteria cause hybrid lethality in the genus Nasonia.
Brucker RM, Bordenstein SR
(2013) Science 341: 667-9
MeSH Terms: Animals, Bacteria, Chimera, Gastrointestinal Tract, Germ-Free Life, Hymenoptera, Metagenome, Phylogeny, Species Specificity, Symbiosis
Show Abstract · Added October 8, 2015
Although the gut microbiome influences numerous aspects of organismal fitness, its role in animal evolution and the origin of new species is largely unknown. Here we present evidence that beneficial bacterial communities in the guts of closely related species of the genus Nasonia form species-specific phylosymbiotic assemblages that cause lethality in interspecific hybrids. Bacterial constituents and abundance are irregular in hybrids relative to parental controls, and antibiotic curing of the gut bacteria significantly rescues hybrid survival. Moreover, feeding bacteria to germ-free hybrids reinstates lethality and recapitulates the expression of innate immune genes observed in conventionally reared hybrids. We conclude that in this animal complex, the gut microbiome and host genome represent a coadapted "hologenome" that breaks down during hybridization, promoting hybrid lethality and assisting speciation.
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10 MeSH Terms
In vivo drug interactions of the teratogen thalidomide with midazolam: heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice.
Yamazaki H, Suemizu H, Murayama N, Utoh M, Shibata N, Nakamura M, Guengerich FP
(2013) Chem Res Toxicol 26: 486-9
MeSH Terms: Adjuvants, Anesthesia, Animals, Chimera, Cytochrome P-450 CYP3A, Drug Interactions, Female, Humans, Immunosuppressive Agents, Liver, Male, Mice, Midazolam, Teratogens, Thalidomide
Show Abstract · Added March 26, 2014
In vivo drug interactions of the teratogen thalidomide with the model cytochrome P450 (P450) 3A substrate midazolam were investigated in mice with humanized livers. The clearance of midazolam (administered intravenously, 10 mg kg(-1)) in chimeric mice was enhanced by orally co-administered thalidomide (100 mg kg(-1)). A larger area under the curve of the major metabolite 1'-hydroxymidazolam (1.7-fold) was obtained with thalidomide because of the heterotropic cooperativity of human P450 3A enzymes. A larger area under the curve of the minor metabolite 4-hydroxymidazolam (3.5-fold) was seen with daily pretreatment with thalidomide for 3 days, presumably because of human P450 3A induction. These results demonstrate that livers of humanized mice mediate drug interactions of thalidomide and suggest interactions of therapeutic agents during therapies with thalidomide.
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14 MeSH Terms
Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells.
Parekh VV, Wu L, Olivares-Villagómez D, Wilson KT, Van Kaer L
(2013) J Immunol 190: 1948-60
MeSH Terms: Adoptive Transfer, Animals, Antigen Presentation, Autoimmunity, Cell Communication, Cell Movement, Cell Proliferation, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Female, Galactosylceramides, Granulocyte-Macrophage Colony-Stimulating Factor, Interferon-gamma, Interleukin-4, Mice, Mice, Transgenic, Myeloid Cells, Natural Killer T-Cells, Nitric Oxide Synthase Type II, Spleen, Transplantation Chimera, Whole-Body Irradiation
Show Abstract · Added March 5, 2014
Invariant NKT (iNKT) cells are a subset of T lymphocytes that recognize glycolipid Ags presented by the MHC class I-related protein CD1d. Activation of iNKT cells with glycolipid Ags, such as the marine sponge-derived reagent α-galactosylceramide (α-GalCer), results in the rapid production of a variety of cytokines and activation of many other immune cell types. These immunomodulatory properties of iNKT cells have been exploited for the development of immunotherapies against a variety of autoimmune and inflammatory diseases, but mechanisms by which activated iNKT cells confer disease protection have remained incompletely understood. In this study, we demonstrate that glycolipid-activated iNKT cells cooperate with myeloid-derived suppressor cells (MDSCs) in protecting mice against the development of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis. We show that α-GalCer induced the expansion and immunosuppressive activities of MDSCs in the spleen of mice induced for development of EAE. Disease protection in these animals also correlated with recruitment of MDSCs to the CNS. Depletion of MDSCs abrogated the protective effects of α-GalCer against EAE and, conversely, adoptive transfer of MDSCs from α-GalCer-treated mice ameliorated passive EAE induced in recipient animals. The cytokines GM-CSF, IL-4, and IFN-γ, produced by activated iNKT cells, and inducible NO synthase, arginase-1, and IL-10 produced by MDSCs, contributed to these effects. Our findings have revealed cooperative immunosuppressive interactions between iNKT cells and MDSCs that might be exploited for the development of improved immunotherapies for multiple sclerosis and other autoimmune and inflammatory diseases.
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22 MeSH Terms
Effects of simvastatin on retinoic acid system in primary human endometrial stromal cells and in a chimeric model of human endometriosis.
Sokalska A, Anderson M, Villanueva J, Ortega I, Bruner-Tran KL, Osteen KG, Duleba AJ
(2013) J Clin Endocrinol Metab 98: E463-71
MeSH Terms: Adult, Animals, Apoptosis, Cell Proliferation, Cell Survival, Chimera, Disease Models, Animal, Endometriosis, Endometrium, Fatty Acid-Binding Proteins, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Membrane Proteins, Mice, Mice, Nude, Neoplasm Proteins, Primary Cell Culture, Receptors, Retinoic Acid, Simvastatin, Stromal Cells, Tretinoin
Show Abstract · Added May 29, 2014
CONTEXT - Retinoic acid (RA) may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2), and cell survival-promoting fatty acid binding protein 5 (FABP5). Increased cellular uptake of retinol and altered actions of RA related to reduced expression of CRABP2 may contribute to the development of endometriosis. Recently statins have been shown to inhibit growth of human endometrial stromal (HES) cells and to reduce the number and size of endometriotic implants in experimental models of this disorder.
OBJECTIVE - The objective of the study was to determine whether effects of simvastatin on HES cells and experimental endometriotic implants are related to the modulation of the RA system.
METHODS - Effects of simvastatin and RA on proliferation and apoptosis of HES cells were evaluated. Expression of stimulated by RA 6 (STRA6), CRABP2, and FABP5 was determined by real-time PCR and Western blotting. Effects of simvastatin were also evaluated in a nude mouse model of human endometriosis.
RESULTS - Simvastatin potentiated an inhibitory effect of RA on growth of HES cells. In HES cells, simvastatin induced expression of STRA6 and CRABP2 but not FABP5. Similarly, simvastatin treatment of nude mice bearing human endometrial xenografts led to an increased expression of CRABP2 and STRA6 proteins in ectopic lesions.
CONCLUSIONS - Simvastatin interacts with the RA system, inducing the expression of the key protein regulating the uptake of retinol (STRA6) and the expression of apoptosis-promoting CRABP2. These effects may contribute to cooperative apoptosis-inducing effects of simvastatin and RA and support the examination of these compounds in the treatment of endometriosis.
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22 MeSH Terms