49 results on '"Physiology"'
Search Results
2. H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition.
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Nancy, Patrice, Siewiera, Johan, Rizzuto, Gabrielle, Tagliani, Elisa, Osokine, Ivan, Manandhar, Priyanka, Dolgalev, Igor, Clementi, Caterina, Tsirigos, Aristotelis, and Erlebacher, Adrian
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PREGNANCY complications , *DECIDUA , *MYOMETRIUM , *STROMAL cells , *DEMETHYLATION , *GENE silencing , *PROTEIN metabolism , *ANIMAL experimentation , *BIOCHEMISTRY , *COMPARATIVE studies , *ENDOMETRIUM , *GENES , *LABOR (Obstetrics) , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *METHYLATION , *MICE , *PREGNANCY , *PROTEINS , *RESEARCH , *RESEARCH funding , *EVALUATION research , *PHYSIOLOGY - Abstract
Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a noncontractile state until term and then surmounts this state to enter labor. Here, we show that dynamic generation and erasure of the repressive histone modification tri-methyl histone H3 lysine 27 (H3K27me3) in decidual stromal cells dictate both elements of pregnancy success in mice. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets ensured uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and most unexpectedly, generating myofibroblasts and associated wound-healing responses. In late gestation, genome-wide H3K27 demethylation allowed for target gene upregulation, decidual activation, and labor entry. Pharmacological inhibition of H3K27 demethylation in late gestation not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a noninflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders. [ABSTRACT FROM AUTHOR]
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- 2018
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3. TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury.
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Peixiang Lan, Yihui Fan, Yue Zhao, Xiaohua Lou, Monsour, Howard P., Xiaolong Zhang, Yongwon Choi, Yaling Dou, Naoto Ishii, Ghobrial, Rafik M., Xiang Xiao, Xian Chang Li, Lan, Peixiang, Fan, Yihui, Zhao, Yue, Lou, Xiaohua, Zhang, Xiaolong, Choi, Yongwon, Dou, Yaling, and Ishii, Naoto
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KILLER cells , *LIVER injuries , *IMMUNE response , *IMMUNOPATHOLOGY , *HOMEOSTASIS , *CELL death , *PROTEIN metabolism , *T cells , *CELL receptors , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL transport , *CELL lines , *PHENOMENOLOGY , *MICE , *PROTEOLYTIC enzymes , *PHYSIOLOGY , *CELL physiology - Abstract
Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A-induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro-IL-1β to mature IL-1β as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore-forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies. [ABSTRACT FROM AUTHOR]
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- 2017
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4. Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling.
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Ansa-Addo, Ephraim A., Yongliang Zhang, Yi Yang, Hussey, George S., Howley, Breege V., Salem, Mohammad, Riesenberg, Brian, Shaoli Sun, Rockey, Don C., Karvar, Serhan, Howe, Philip H., Bei Liu, Zihai Li, Zhang, Yongliang, Yang, Yi, Sun, Shaoli, Liu, Bei, and Li, Zihai
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MOESIN , *MICROFILAMENT proteins , *IMMUNOLOGY , *IMMUNOLOGIC diseases , *C-terminal binding proteins , *MELANOMA treatment , *T cells , *ANIMALS , *BIOCHEMISTRY , *BIOLOGICAL transport , *CELL culture , *CELL differentiation , *CELL membranes , *CELL receptors , *CELLULAR signal transduction , *EPITHELIAL cells , *GENES , *GROWTH factors , *IMMUNITY , *IMMUNIZATION , *PHENOMENOLOGY , *MELANOMA , *MICE , *PROTEINS , *RESEARCH funding , *SKIN tumors , *TRANSFERASES , *TUMOR treatment , *PHYSIOLOGY - Abstract
Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β-induced Tregs (iTregs) is unknown. Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs. Loss of moesin impaired the development and function of both peripherally derived iTregs and in vitro-induced Tregs. Mechanistically, we identified an interaction between moesin and TGF-β receptor II (TβRII) that allows moesin to control the surface abundance and stability of TβRI and TβRII. We also found that moesin is required for iTreg conversion in the tumor microenvironment, and the deletion of moesin from recipient mice supported the rapid expansion of adoptively transferred CD8+ T cells against melanoma. Our study establishes moesin as an important regulator of the surface abundance and stability of TβRII and identifies moesin's role in facilitating the efficient generation of iTregs. It also provides an advancement to our understanding about the role of the ERM proteins in regulating signal transduction pathways and suggests that modulation of moesin is a potential therapeutic target for Treg-related immune disorders. [ABSTRACT FROM AUTHOR]
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- 2017
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5. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients.
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Chauvin, Joe-Marc, Pagliano, Ornella, Fourcade, Julien, Sun, Zhaojun, Wang, Hong, Sander, Cindy, Kirkwood, John M, Chen, Tseng-Hui Timothy, Maurer, Mark, Korman, Alan J, and Zarour, Hassane M
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LYMPHOCYTE metabolism , *ANTIGEN presenting cells , *ANTIGENS , *BIOCHEMISTRY , *CELL lines , *CELL receptors , *CYTOKINES , *GENES , *IMMUNITY , *IMMUNOLOGY technique , *IMMUNOPHENOTYPING , *INTERLEUKIN-2 , *LYMPHOCYTES , *PHENOMENOLOGY , *MELANOMA , *MONOCLONAL antibodies , *PROTEINS , *RESEARCH funding , *T cells , *TUMOR antigens , *CHEMICAL inhibitors , *PHYSIOLOGY , *CELL physiology - Abstract
T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen-specific (TA-specific) CD8⁺ T cells and CD8⁺ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8⁺ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8⁺ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1⁺TIM-3⁺ TA-specific CD8⁺ T cells. PD-1⁺TIGIT⁺, PD-1⁻TIGIT⁺, and PD-1⁺TIGIT⁻ CD8⁺ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8⁺ T cells and CD8⁺ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8⁺ T cells and CD8⁺ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8⁺ T cell responses in patients with advanced melanoma. [ABSTRACT FROM AUTHOR]
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- 2015
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6. Myeloid cell-specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis.
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Chakraborty, Mahua, Lou, Caixia, Huan, Chongmin, Kuo, Ming-Shang, Park, Tae-Sik, Cao, Guoqing, and Jiang, Xian-Cheng
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LIPID metabolism , *MACROPHAGES , *PROTEIN metabolism , *ANIMAL experimentation , *ATHEROSCLEROSIS , *BIOCHEMISTRY , *BONE marrow transplantation , *CELL membranes , *CELL receptors , *CELL motility , *CHOLESTEROL , *INFLAMMATORY mediators , *LIPIDS , *PHENOMENOLOGY , *MICE , *GENETIC mutation , *PROTEINS , *RESEARCH funding , *TRANSFERASES , *THORACIC aorta , *PHYSIOLOGY - Abstract
Serine palmitoyltransferase (SPT) is the first and rate-limiting enzyme of the de novo biosynthetic pathway of sphingomyelin (SM). Both SPT and SM have been implicated in the pathogenesis of atherosclerosis, the development of which is driven by macrophages; however, the role of SPT in macrophage-mediated atherogenesis is unknown. To address this issue, we have analyzed macrophage inflammatory responses and reverse cholesterol transport, 2 key mediators of atherogenesis, in SPT subunit 2-haploinsufficient (Sptlc2(+/-)) macrophages. We found that Sptlc2(+/-) macrophages have significantly lower SM levels in plasma membrane and lipid rafts. This reduction not only impaired inflammatory responses triggered by TLR4 and its downstream NF-κB and MAPK pathways, but also enhanced reverse cholesterol transport mediated by ABC transporters. LDL receptor-deficient (Ldlr(-/-)) mice transplanted with Sptlc2(+/-) bone marrow cells exhibited significantly fewer atherosclerotic lesions after high-fat and high-cholesterol diet feeding. Additionally, Ldlr(-/-) mice with myeloid cell-specific Sptlc2 haploinsufficiency exhibited significantly less atherosclerosis than controls. These findings suggest that SPT could be a novel therapeutic target in atherosclerosis. [ABSTRACT FROM AUTHOR]
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- 2013
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7. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice.
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Weiguo Zou, Greenblatt, Matthew B., Jae-Hyuck Shim, Kant, Shashi, Bo Zhai, Lotinun, Sutada, Brady, Nicholas, Zhang Hu, Dorothy, Gygi, Steven P., Baron, Roland, Davis, Roger J., Jones, Dallas, Glimcher, Laurie H., Zou, Weiguo, Shim, Jae-Hyuck, Zhai, Bo, and Hu, Dorothy Zhang
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CELLULAR signal transduction , *DYSPLASIA , *PROTEIN kinases , *BONE growth , *GENETIC mutation , *BONE diseases , *LABORATORY mice , *FACIAL abnormalities , *PROTEIN metabolism , *DWARFISM , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL models , *COMPARATIVE studies , *CONGENITAL heart disease , *FACE , *MALE reproductive organs , *GENETIC techniques , *HAND abnormalities , *PHENOMENOLOGY , *RESEARCH methodology , *X-linked genetic disorders , *MEDICAL cooperation , *MICE , *PROTEINS , *RESEARCH , *TRANSFERASES , *EVALUATION research , *OSTEOBLASTS , *PHYSIOLOGY - Abstract
Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients. [ABSTRACT FROM AUTHOR]
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- 2011
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8. A mystery unfolds: Franz-Ulrich Hartl and Arthur L. Horwich win the 2011 Albert Lasker Basic Medical Research Award.
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Claiborn, Kathryn
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AWARDS , *PROTEINS , *PHYSIOLOGY , *DISEASES , *HISTORY of medical research , *BIOCHEMISTRY , *BIOLOGICAL transport , *HISTORY , *PHENOMENOLOGY - Abstract
The article reports on scientists Franz-Ulrich Hartl and Arthur L. Horwich, who are awarded the 2011 Albert Lasker Basic Medical Research Award for revealing secrets of basic protein chemistry. It states the research of Hartl and Horwich provide a new understanding of human physiology and disease. The research focused on the mechanism of protein folding and its impact on human disease.
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- 2011
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9. The LRF transcription factor regulates mature B cell development and the germinal center response in mice.
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Sakurai, Nagisa, Maeda, Manami, Sung-Uk Lee, Ishikawa, Yuichi, Min Li, Williams, John C., Lisheng Wang, Leila Su, Suzuki, Mai, Saito, Toshiki I., Shigeru Chiba, Casola, Stefano, Yagita, Hideo, Teruya-Feldstein, Julie, Tsuzuki, Shinobu, Bhatia, Ravi, Maeda, Takahiro, Lee, Sung-Uk, Li, Min, and Wang, Lisheng
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TRANSCRIPTION factors , *INTERLEUKIN-4 , *GERMINAL centers , *LABORATORY mice , *AUTOIMMUNE diseases , *IMMUNE response , *RNA metabolism , *ANIMAL experimentation , *B cells , *BIOCHEMISTRY , *CELL differentiation , *COMPARATIVE studies , *GENES , *LYMPHOID tissue , *MATHEMATICAL models , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *MOLECULAR structure , *PROTEINS , *RESEARCH , *RNA , *SPLEEN , *DNA-binding proteins , *THEORY , *EVALUATION research , *MICROARRAY technology , *PHYSIOLOGY - Abstract
B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies. Employing B cell-specific conditional knockout mice, we have demonstrated here that the transcription factor leukemia/lymphoma-related factor (LRF) forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms. Moreover, LRF inactivation in transformed B cells attenuated their growth rate. These studies identify what we believe to be a new key factor for mature B cell development and provide a rationale for targeting LRF dimers for the treatment of autoimmune diseases and B cell malignancies. [ABSTRACT FROM AUTHOR]
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- 2011
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10. From probiotics to therapeutics: another step forward?
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Ghishan, Fayez K. and Kiela, Pawel R.
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COLITIS treatment , *GASTROINTESTINAL disease prevention , *GASTROINTESTINAL disease treatment , *INFLAMMATORY bowel disease treatment , *OPPORTUNISTIC infection prevention , *COLITIS prevention , *THERAPEUTIC use of probiotics , *LACTOBACILLUS , *ANIMALS , *BACTERIAL proteins , *BIOCHEMISTRY , *COLITIS , *DRUG design , *CLINICAL drug trials , *EPIDERMAL growth factor , *FOOD microbiology , *GASTROINTESTINAL diseases , *GENOMES , *PHENOMENOLOGY , *MICE , *PROTEIN kinases , *RECOMBINANT proteins , *RESEARCH funding , *PHYSIOLOGY , *THERAPEUTICS - Abstract
Preclinical studies with probiotics continue to unravel mechanisms of cytoprotection and suggest that approaches utilizing microbial products as therapeutics in acute and chronic gastrointestinal disorders could be effective. However, clinical trials using these bacteria have thus far been inconsistent. In this issue of the JCI, Yan et al. describe a novel mechanism of cytoprotection by p40, a soluble product of Lactobacillus rhamnosus GG, mediated via EGFR. The efficacy of p40 in three models of chemically induced colitis indicates tremendous therapeutic potential, though this finding will need to be verified in human patients. [ABSTRACT FROM AUTHOR]
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- 2011
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11. Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque.
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Rotger, Margalida, Dalmau, Judith, Rauch, Andri, McLaren, Paul, Bosinger, Steven E., Martinez, Raquel, Sandler, Netanya G., Roque, Annelys, Liebner, Julia, Battegay, Manuel, Bernasconi, Enos, Descombes, Patrick, Erkizia, Itziar, Fellay, Jacques, Hirschel, Bernard, Miró, Jose M., Palou, Eduard, Hoffmann, Matthias, Massanella, Marta, and Julià Blanco
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PHENOTYPES , *HIV , *SIMIAN immunodeficiency virus , *IMMUNODEFICIENCY , *T cells , *AIDS , *ANIMAL experimentation , *BIOCHEMISTRY , *COMPARATIVE studies , *DISEASE susceptibility , *GENES , *HIV infections , *IMMUNITY , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *PRIMATES , *RESEARCH , *RESEARCH funding , *VIRAL load , *EVALUATION research , *VIREMIA , *DISEASE progression , *GENE expression profiling , *RNA virus infections , *PHYSIOLOGY - Abstract
High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4⁺ and CD8⁺ T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4⁺ T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2011
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12. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism.
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Fang Yan, Hanwei Cao, Cover, Timothy L., Washington, M. Kay, Yan Shi, LinShu Liu, Chaturvedi, Rupesh, Peek Jr., Richard M., Wilson, Keith T., Polk, D. Brent, Yan, Fang, Cao, Hanwei, Shi, Yan, Liu, LinShu, and Peek, Richard M Jr
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EPITHELIAL cells , *ANIMAL models of colitis , *LABORATORY mice , *EPIDERMAL growth factor , *PROBIOTICS , *CYTOKINES , *COLITIS prevention , *ANIMAL experimentation , *APOPTOSIS , *BACTERIAL proteins , *BIOCHEMISTRY , *CELLULAR signal transduction , *COLITIS , *DEXTRAN , *DRUG design , *CLINICAL drug trials , *PHARMACEUTICAL gels , *HETEROCYCLIC compounds , *INTESTINAL mucosa , *LACTOBACILLUS , *LATEX , *PHENOMENOLOGY , *MICE , *PERMEABILITY , *RECOMBINANT proteins , *RECTAL medication , *RESEARCH funding , *TRANSFERASES , *CHEMICAL inhibitors , *PHYSIOLOGY , *THERAPEUTICS - Abstract
Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria-derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40's effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation. [ABSTRACT FROM AUTHOR]
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- 2011
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13. Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice.
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Park, Cheryl J., Zhen Zhao, Glidewell-Kenney, Christine, Lazic, Milos, Chambon, Pierre, Krust, Andrée, Weiss, Jeffrey, Clegg, Deborah J., Dunaif, Andrea, Jameson, J. Larry, Levine, Jon E., Zhao, Zhen, and Krust, Andrée
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BIOENERGETICS , *ENERGY metabolism , *CELLULAR signal transduction , *MAMMAL body composition , *METABOLIC disorders , *OBESITY , *BIOCHEMISTRY , *PHYSIOLOGY , *PROTEIN metabolism , *ANIMALS , *BODY weight , *CARRIER proteins , *HOMEOSTASIS , *INGESTION , *MICE , *MOTOR ability , *PROTEINS , *LEPTIN - Abstract
In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null (Erα-/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in Erα-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women. [ABSTRACT FROM AUTHOR]
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- 2011
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14. Pain imaging in health and disease--how far have we come?
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Schweinhardt, Petra and Bushnell, M. Catherine
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BRAIN physiology , *MEDICAL imaging systems , *NEURAL transmission , *NEURAL circuitry , *CHRONIC pain , *BIOCHEMISTRY , *BRAIN anatomy , *PAIN & psychology , *SPINAL cord physiology , *BRAIN , *BRAIN mapping , *COMPARATIVE studies , *DIAGNOSTIC imaging , *DIGITAL image processing , *RESEARCH methodology , *MEDICAL cooperation , *PAIN , *RESEARCH , *EVALUATION research , *SPINAL cord , *ANATOMY , *NEURAL pathways , *PHYSIOLOGY - Abstract
Since modern brain imaging of pain began 20 years ago, networks in the brain related to pain processing and those related to different types of pain modulation, including placebo, have been identified. Functional and anatomical connectivity of these circuits has begun to be analyzed. Imaging in patients suggests that chronic pain is associated with altered function and structural abnormalities in pain modulatory circuits. Moreover, biochemical alterations associated with chronic pain are being identified that provide information on cellular correlates as well as potential mechanisms of structural changes. Data from these brain imaging studies reinforce the idea that chronic pain leads to brain changes that could have functional significance. [ABSTRACT FROM AUTHOR]
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- 2010
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15. Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways.
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Timmins, Jenelle M., Ozcan, Lale, Seimon, Tracie A., Gang Li, Malagelada, Cristina, Backs, Johannes, Backs, Thea, Bassel-Duby, Rhonda, Olson, Eric N., Anderson, Mark E., Tabas, Ira, and Li, Gang
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PROTEIN kinases , *ENDOTHELIAL seeding , *MITOCHONDRIAL pathology , *EXFOLIATIVE cytology , *APOPTOSIS , *CELL death , *EPITHELIAL cells , *BIOLOGICAL transport , *CALCIUM metabolism , *RNA metabolism , *CHOLESTEROL metabolism , *HYDROCARBON metabolism , *ANIMAL experimentation , *ANTIGENS , *BIOCHEMISTRY , *CARRIER proteins , *CELL culture , *COMPARATIVE studies , *CYTOPLASM , *KIDNEY tubules , *MACROPHAGES , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *MITOCHONDRIA , *PHOSPHOTRANSFERASES , *RESEARCH , *RESEARCH funding , *RNA , *PHYSIOLOGICAL stress , *TRANSFERASES , *EVALUATION research , *PHYSIOLOGY , *CELL physiology - Abstract
ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma) and JNK. Remarkably, CaMKIIgamma was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKIIgamma-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis. [ABSTRACT FROM AUTHOR]
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- 2009
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16. Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice.
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Ling, Haiyun, Zhang, Tong, Pereira, Laetitia, Means, Christopher Kable, Cheng, Hongqiang, Gu, Yusu, Dalton, Nancy D., Peterson, Kirk L., Chen, Ju, Bers, Donald, Heller^Brown, Joan, and Brown, Joan Heller
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HEART dilatation , *HEART diseases , *CALCIUM-binding proteins , *CHEMICAL reactions , *GENE expression , *SARCOPLASMIC reticulum , *BODY fluid disorders , *AORTA surgery , *CALCIUM metabolism , *HEART anatomy , *HEART metabolism , *HEART physiology , *HEART ventricles , *PROTEIN metabolism , *ANIMAL experimentation , *BIOCHEMISTRY , *BLOOD pressure , *CELLULAR signal transduction , *COMPARATIVE studies , *CARDIAC hypertrophy , *HEART failure , *HYDROLASES , *LUNGS , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *MYOCARDIUM , *PHOSPHORYLATION , *PHOSPHOTRANSFERASES , *RESEARCH , *TRANSFERASES , *EVALUATION research , *STENOSIS , *DISEASE complications , *PHYSIOLOGY - Abstract
Ca2+/calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIdelta, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIdelta deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP3R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca2+ spark frequency only in WT mice. We suggest that CaMKIIdelta contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKIIdelta activation can limit the progression to heart failure. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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17. Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition.
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Fetalvero, Kristina M., Zhang, Peisheng, Shyu, Maureen, Young, Benjamin T., Hwa, John, Young, Roger C., and Martin, Kathleen A.
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UTERINE contraction , *PROSTACYCLIN , *PARTURITION grounds , *SMOOTH muscle , *LABOR (Obstetrics) , *ARACHIDONIC acid , *BIOCHEMISTRY , *CELL membranes , *CELL receptors , *CELLULAR signal transduction , *CYCLIC adenylic acid , *PHENOMENOLOGY , *MEMBRANE proteins , *MYOMETRIUM , *OXIDOREDUCTASES , *OXYTOCIN , *PREGNANCY , *RESEARCH funding , *TRANSFERASES , *OXYTOCICS , *PHARMACODYNAMICS , *PHYSIOLOGY - Abstract
An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI2), a smooth muscle relaxant. However, here we have shown that activation of PGI2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI2-mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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18. Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1.
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Weinman, Edward J., Biswas, Rajat S., Quihong Peng, Shen, Lily, Turner, Christina L., Xiaofei E., Steplock, Deborah, Shenolikar, Shirish, Cunningham, Rochelle, Peng, Guihong, Peng, Quihong, and E, Xiaofei
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PARATHYROID hormone , *CALCIUM regulating hormones , *PHOSPHORYLATION , *SERINE proteinases , *CARRIER proteins , *SODIUM metabolism , *SERINE metabolism , *PHOSPHATE metabolism , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL transport , *CELL culture , *CELLULAR signal transduction , *ENZYME inhibitors , *KIDNEYS , *PHENOMENOLOGY , *MICE , *MOLECULAR structure , *PHOSPHOPROTEINS , *RECOMBINANT proteins , *RESEARCH funding , *TRANSFERASES , *PHYSIOLOGY - Abstract
Parathyroid hormone (PTH), via activation of PKC and/or protein kinase A, inhibits renal proximal tubular phosphate reabsorption by facilitating the internalization of the major sodium-dependent phosphate transporter, Npt2a. Herein, we explore the hypothesis that the effect of PTH is mediated by phosphorylation of serine 77 (S77) of the first PDZ domain of the Npt2a-binding protein sodium-hydrogen exchanger regulatory factor-1 (NHERF-1). Using recombinant polypeptides representing PDZ I, S77 of NHERF-1 is phosphorylated by PKC but not PKA. When expressed in primate kidney epithelial cells (BSC-1 cells), however, activation of either protein kinase phosphorylates S77, suggesting that the phosphorylation of PDZ I by PKC and PKA proceeds by different biochemical pathways. PTH and other activators of PKC and PKA dissociate NHERF-1/Npt2a complexes, as assayed using quantitative coimmunoprecipitation, confocal microscopy, and sucrose density gradient ultracentrifugation in mice. Murine NHERF-1-/- renal proximal tubule cells infected with adenovirus-GFP-NHERF-1 containing an S77A mutation showed significantly increased phosphate transport compared with a phosphomimetic S77D mutation and were resistant to the inhibitory effect of PTH compared with cells infected with wild-type NHERF-1. These results indicate that PTH-mediated inhibition of renal phosphate transport involves phosphorylation of S77 of the NHERF-1 PDZ I domain and the dissociation of NHERF-1/Npt2a complexes. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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19. Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo.
- Author
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Ouedraogo, Raogo, Gong, Yulan, Berzins, Brett, Xiandong Wu, Mahadev, Kalyankar, Hough, Kelly, Chan, Lawrence, Goldstein, Barry J., Scalia, Rosario, and Wu, Xiandong
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CELL adhesion molecules , *CELL membranes , *VASCULAR diseases , *LEUCOCYTES , *GLUTAMATE decarboxylase , *BIOAVAILABILITY , *ANTI-inflammatory agents , *ANIMAL experimentation , *ANTIGENS , *BIOCHEMISTRY , *CELL physiology , *EPITHELIAL cells , *PHENOMENOLOGY , *MICE , *NITRIC oxide , *PROTEINS , *RECOMBINANT proteins , *RESEARCH funding , *ADIPONECTIN , *IN vitro studies , *PHARMACODYNAMICS , *PHYSIOLOGY - Abstract
This study reports on what we believe are novel mechanism(s) of the vascular protective action of adiponectin. We used intravital microscopy to measure leukocyte-endothelium interactions in adiponectin-deficient (Ad(-/-)) mice and found that adiponectin deficiency was associated with a 2-fold increase in leukocyte rolling and a 5-fold increase in leukocyte adhesion in the microcirculation. Measurement of endothelial NO (eNO) revealed that adiponectin deficiency drastically reduced levels of eNO in the vascular wall. Immunohistochemistry demonstrated increased expression of E-selectin and VCAM-1 in the vascular endothelium of Ad(-/-) mice. Systemic administration of the recombinant globular adiponectin domain (gAd) to Ad(-/-) mice significantly attenuated leukocyte-endothelium interactions and adhesion molecule expression in addition to restoring physiologic levels of eNO. Importantly, prior administration of gAd also protected WT mice against TNF-alpha-induced leukocyte-endothelium interactions, indicating a pharmacologic action of gAd. Mechanistically, blockade of eNOS with N(omega)-nitro-L-arginine methyl ester ( L-NAME) abolished the inhibitory effect of gAd on leukocyte adhesion, demonstrating the obligatory role of eNOS signaling in the antiinflammatory action of gAd. We believe this is the first demonstration that gAd protects the vasculature in vivo via increased NO bioavailability with suppression of leukocyte-endothelium interactions. Overall, we provide evidence that loss of adiponectin induces a primary state of endothelial dysfunction with increased leukocyte-endothelium adhesiveness. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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20. CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells.
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Si, Jutong, Mueller, LeMoyne, and Collins, Steven J
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BIOCHEMISTRY , *CELL differentiation , *CELL receptors , *CELLULAR signal transduction , *COMPARATIVE studies , *GENES , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *PHOSPHOTRANSFERASES , *RESEARCH , *RESEARCH funding , *TRETINOIN , *EVALUATION research , *ACUTE promyelocytic leukemia , *PHYSIOLOGY - Abstract
Retinoic acid receptors (RARs) are members of the nuclear hormone receptor family and regulate the proliferation and differentiation of multiple different cell types, including promyelocytic leukemia cells. Here we describe a biochemical/functional interaction between the Ca(2+)/calmodulin-dependent protein kinases (CaMKs) and RARs that modulates the differentiation of myeloid leukemia cells. We observe that CaMKIIgamma is the CaMK that is predominantly expressed in myeloid cells. CaMKII inhibits RAR transcriptional activity, and this enzyme directly interacts with RAR through a CaMKII LxxLL binding motif. CaMKIIgamma phosphorylates RARalpha both in vitro and in vivo, and this phosphorylation inhibits RARalpha activity by enhancing its interaction with transcriptional corepressors. In myeloid cell lines, CaMKIIgamma localizes to RAR target sites within myeloid gene promoters but dissociates from the promoter upon retinoic acid-induced myeloid cell differentiation. KN62, a pharmacological inhibitor of the CaMKs, enhances the terminal differentiation of myeloid leukemia cell lines, and this is associated with a reduction in activated (autophosphorylated) CaMKII in the terminally differentiating cells. These observations reveal a significant cross-talk between Ca(2+) and retinoic acid signaling pathways that regulates the differentiation of myeloid leukemia cells, and they suggest that CaMKIIgamma may provide a new therapeutic target for the treatment of certain human myeloid leukemias. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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21. Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways.
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Dasgupta, Piyali, Rastogi, Shipra, Pillai, Smitha, Ordonez-Ercan, Dalia, Morris, Mark, Haura, Eric, and Chellappan, Srikumar
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PROTEIN metabolism , *BIOCHEMISTRY , *CHOLINERGIC receptors , *CELL division , *CELL lines , *GENES , *LUNG cancer , *LUNG tumors , *PHENOMENOLOGY , *MEMBRANE proteins , *NICOTINE , *PROTEINS , *RESEARCH funding , *TRANSFERASES , *CHEMICAL inhibitors , *PHARMACODYNAMICS , *PHYSIOLOGY - Abstract
Recent studies have shown that nicotine, a component of cigarette smoke, can stimulate the proliferation of non-neuronal cells. While nicotine is not carcinogenic by itself, it has been shown to induce cell proliferation and angiogenesis. Here we find that mitogenic effects of nicotine in non-small cell lung cancers (NSCLCs) are analogous to those of growth factors and involve activation of Src, induction of Rb-Raf-1 interaction, and phosphorylation of Rb. Analysis of human NSCLC tumors show enhanced levels of Rb-Raf-1 complexes compared with adjacent normal tissue. The mitogenic effects of nicotine were mediated via the alpha7-nAChR subunit and resulted in enhanced recruitment of E2F1 and Raf-1 on proliferative promoters in NSCLC cell lines and human lung tumors. Nicotine stimulation of NSCLC cells caused dissociation of Rb from these promoters. Proliferative signaling via nicotinic acetylcholine receptors (nAChRs) required the scaffolding protein beta-arrestin; ablation of beta-arrestin or disruption of the Rb-Raf-1 interaction blocked nicotine-induced proliferation of NSCLCs. Additionally, suppression of beta-arrestin also blocked activation of Src, suppressed levels of phosphorylated ERK, and abrogated Rb-Raf-1 binding in response to nicotine. It appears that nicotine induces cell proliferation by beta-arrestin-mediated activation of the Src and Rb-Raf-1 pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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22. Antisense oligonucleotide therapy for neurodegenerative disease.
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Smith, Richard A., Miller, Timothy M., Yamanaka, Koji, Monia, Brett P., Condon, Thomas P., Hung, Gene, Lobsiger, Christian S., Ward, Chris M., McAlonis-Downes, Melissa, Wei, Hongbing, Wancewicz, Ed V., Bennett, C. Frank, and Cleveland, Don W.
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NUCLEOTIDE metabolism , *ANIMAL experimentation , *BIOCHEMISTRY , *COMPARATIVE studies , *FIBROBLASTS , *HEART ventricles , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MOTOR neuron diseases , *NEURODEGENERATION , *NUCLEOTIDES , *PRIMATES , *RATS , *RESEARCH , *RNA , *SUPEROXIDE dismutase , *EVALUATION research , *THERAPEUTICS , *PHYSIOLOGY - Abstract
Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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23. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice.
- Author
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Belcher, John D., Mahaseth, Hemachandra, Welch, Thomas E., Otterbein, Leo E., Hebbel, Robert P., and Vercellotti, Gregory M.
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TRANSGENIC mice , *VASCULAR endothelium , *HYPOXEMIA , *HEME oxygenase , *BILIRUBIN , *HAPTOGLOBINS , *ANIMALS , *BIOCHEMISTRY , *BIOLOGICAL models , *IMMUNITY , *INFLAMMATORY mediators , *PHENOMENOLOGY , *MICE , *OXIDOREDUCTASES , *PORPHYRINS , *SICKLE cell anemia , *VASOCONSTRICTION , *METALLOPORPHYRINS , *CHEMICAL inhibitors , *PHYSIOLOGY - Abstract
Transgenic sickle mice expressing betaS hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-kappaB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NF-kappaB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-kappaB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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24. Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP.
- Author
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Kobayashi, Tatsuya, Soegiarto, Desi W., Yang, Yingzi, Lanske, Beate, Schipani, Ernestina, McMahon, Andrew P., and Kronenberg, Henry M.
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CARTILAGE cells , *HEDGEHOG signaling proteins , *PARATHYROID hormone , *CALCIUM regulating hormones , *CHONDROGENESIS , *HETEROZYGOSITY , *CELL differentiation , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL models , *CELL receptors , *COMPARATIVE studies , *EPIPHYSIS , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *MOSAICISM , *PEPTIDE hormones , *PROTEINS , *RESEARCH , *RESEARCH funding , *PHENOTYPES , *EVALUATION research , *GENETIC carriers , *PHYSIOLOGY , *CELL physiology - Abstract
In the developing growth plate, periarticular chondrocytes proliferate, differentiate into columnar chondrocytes, and then further differentiate into postmitotic hypertrophic chondrocytes. Parathyroid hormone-related (PTH-related) protein (PTHrP), regulated by Indian hedgehog (Ihh), prevents premature hypertrophic differentiation, thereby maintaining the length of columns. Ihh regulates cartilage development through PTHrP-independent pathways as well. Here we show that Ihh stimulates differentiation of periarticular to columnar chondrocytes (periarticular chondrocyte differentiation) and thereby regulates the length of columns independently of PTHrP. Mosaic ablation of the PTH/PTHrP receptor in the growth plate caused upregulation of Ihh action, PTHrP upregulation, acceleration of periarticular chondrocyte differentiation, and elongation of the columnar region. Decreasing Ihh action in these mice reduced elongation of columns, whereas decreasing PTHrP showed only a modest effect on column length. Overexpression of Ihh caused PTHrP upregulation, elongation of columns, and acceleration of periarticular chondrocyte differentiation. PTHrP heterozygosity in this model had a minimal effect on the elongation of columns. Moreover, the elongation of columns and stimulation of periarticular chondrocyte differentiation in these models were still observed when PTHrP signaling was maintained so that it remained constant. These results demonstrate that Ihh acts on periarticular chondrocytes to stimulate their differentiation, thereby regulating the columnar cell mass independently of PTHrP. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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25. Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.
- Author
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Yang, Chao-Ling, Zhu, Xiaoman, Wang, Zhaohong, Subramanya, Arohan R., Edison, David H., and Ellison, David H
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KIDNEY tubules , *HIGH-lysine diet , *GENETIC mutation , *LYSINE , *KIDNEYS , *PROTEINS , *BIOLOGICAL transport , *AMINO acids , *ANIMAL experimentation , *BIOCHEMISTRY , *DOCUMENTATION , *DRUG receptors , *HYPERTENSION , *PHENOMENOLOGY , *MICE , *RATS , *RESEARCH funding , *SALT , *TRANSFERASES , *HYPERKALEMIA , *ION transport (Biology) , *PHYSIOLOGY - Abstract
With-no-lysine (WNK) kinases are highly expressed along the mammalian distal nephron. Mutations in either WNK1 or WNK4 cause familial hyperkalemic hypertension (FHHt), suggesting that the protein products converge on a final common pathway. We showed previously that WNK4 downregulates thiazide-sensitive NaCl cotransporter (NCC) activity, an effect suppressed by WNK1. Here we investigated the mechanisms by which WNK1 and WNK4 interact to regulate ion transport. We report that WNK1 suppresses the WNK4 effect on NCC activity and associates with WNK4 in a protein complex involving the kinase domains. Although a kinase-dead WNK1 also associates with WNK4, it fails to suppress WNK4-mediated NCC inhibition; the WNK1 kinase domain alone, however, is not sufficient to block the WNK4 effect. The carboxyterminal 222 amino acids of WNK4 are sufficient to inhibit NCC, but this fragment is not blocked by WNK1. Instead, WNK1 inhibition requires an intact WNK4 kinase domain, the region that binds to WNK1. In summary, these data show that: (a) the WNK4 carboxyl terminus mediates NCC suppression, (b) the WNK1 kinase domain interacts with the WNK4 kinase domain, and (c) WNK1 inhibition of WNK4 is dependent on WNK1 catalytic activity and an intact WNK1 protein. These findings provide insight into the complex interrelationships between WNK1 and WNK4 and provide a molecular basis for FHHt. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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26. Regulation of CD1d expression and function by a herpesvirus infection.
- Author
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Sanchez, David Jesse, Gumperz, Jenny E., and Ganem, Don
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HERPESVIRUS diseases , *INFECTION , *IMMUNE response , *T cells , *VIRAL replication , *CELL physiology , *PROTEIN metabolism , *ANTIGENS , *BIOCHEMISTRY , *COMPARATIVE studies , *HERPESVIRUSES , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *EVALUATION research , *PHYSIOLOGY - Abstract
Little is known about the role of CD1d-restricted T cells in antiviral immune responses. Here we show that the lytic replication cycle of the Kaposi sarcoma-associated herpesvirus (KSHV) promotes downregulation of cell-surface CD1d. This is caused by expression of the 2 modulator of immune recognition (MIR) proteins of the virus, each of which promotes the loss of surface CD1d expression following transfection into uninfected cells. Inhibition of CD1d surface expression is due to ubiquitination of the CD1d alpha-chain on a unique lysine residue in its cytoplasmic tail, which triggers endocytosis. Unlike MIR-mediated MHC class I downregulation, however, CD1d downregulation does not appear to include accelerated lysosomal degradation. MIR2-induced downregulation of CD1d results in reduced activation of CD1d-restricted T cells in vitro. KSHV modulation of CD1d expression represents a strategy for viral evasion of innate host immune responses and implicates CD1d-restricted T cells as regulators of this viral infection. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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27. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis.
- Author
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Zhang, Kezhong, Wong, Hetty N, Song, Benbo, Miller, Corey N, Scheuner, Donalyn, and Kaufman, Randal J
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BONE marrow physiology , *RNA physiology , *B cells , *ANIMAL experimentation , *BIOCHEMISTRY , *BONE marrow transplantation , *CELL differentiation , *CELLULAR signal transduction , *COMPARATIVE studies , *CYTOPLASM , *ESTERASES , *HEMATOPOIESIS , *IMMUNOGLOBULINS , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MEMBRANE proteins , *MICE , *RESEARCH , *RESEARCH funding , *RNA , *TRANSCRIPTION factors , *TRANSFERASES , *DNA-binding proteins , *EVALUATION research , *NUCLEAR proteins , *PHYSIOLOGY - Abstract
B lymphocyte differentiation is coordinated with the induction of high-level Ig secretion and expansion of the secretory pathway. Upon accumulation of unfolded proteins in the lumen of the ER, cells activate an intracellular signaling pathway termed the unfolded protein response (UPR). Two major proximal sensors of the UPR are inositol-requiring enzyme 1alpha (IRE1alpha), an ER transmembrane protein kinase/endoribonuclease, and ER-resident eukaryotic translation initiation factor 2alpha (eIF2alpha) kinase (PERK). To elucidate whether the UPR plays an important role in lymphopoiesis, we carried out reconstitution of recombinase-activating gene 2-deficient (rag2-/-) mice with hematopoietic cells defective in either IRE1alpha- or PERK-mediated signaling. IRE1alpha-deficient (ire1alpha-/-) HSCs can proliferate and give rise to pro-B cells that home to bone marrow. However, IRE1alpha, but not its catalytic activities, is required for Ig gene rearrangement and production of B cell receptors (BCRs). Analysis of rag2-/- mice transplanted with IRE1alpha trans-dominant-negative bone marrow cells demonstrated an additional requirement for IRE1alpha in B lymphopoiesis: both the IRE1alpha kinase and RNase catalytic activities are required to splice the mRNA encoding X-box-binding protein 1 (XBP1) for terminal differentiation of mature B cells into antibody-secreting plasma cells. Furthermore, UPR-mediated translational control through eIF2alpha phosphorylation is not required for B lymphocyte maturation and/or plasma cell differentiation. These results suggest specific requirements of the IRE1alpha-mediated UPR subpathway in the early and late stages of B lymphopoiesis. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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28. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity.
- Author
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Smythies, Lesley E., Sellers, Marty, Clements, Ronald H., Mosteller-Barnum, Meg, Meng, Gang, Benjamin, William H., Orenstein, Jan M., Smith, Phillip O., and Smith, Phillip D
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MACROPHAGES , *INTESTINAL mucosa , *PHAGOCYTES , *INFLAMMATION , *CYTOKINES , *GENETICS , *ESCHERICHIA coli physiology , *ANTIGENS , *BIOCHEMISTRY , *COMPARATIVE studies , *CONNECTIVE tissue cells , *CULTURE media (Biology) , *ESCHERICHIA coli , *GROWTH factors , *JEJUNUM , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *PHAGOCYTOSIS , *RESEARCH , *RESEARCH funding , *PHENOTYPES , *SALMONELLA , *EVALUATION research , *LIPOPOLYSACCHARIDES , *PHYSIOLOGY - Abstract
Intestinal macrophages, which are thought to orchestrate mucosal inflammatory responses, have received little investigative attention compared with macrophages from other tissues. Here we show that human intestinal macrophages do not express innate response receptors, including the receptors for LPS (CD14), Fcalpha (CD89), Fcgamma (CD64, CD32, CD16), CR3 (CD11b/CD18), and CR4 (CD11c/CD18); the growth factor receptors IL-2 (CD25) and IL-3 (CD123); and the integrin LFA-1 (CD11a/CD18). Moreover, resident intestinal macrophages also do not produce proinflammatory cytokines, including IL-1, IL-6, IL-10, IL-12, RANTES, TGF-beta, and TNF-alpha, in response to an array of inflammatory stimuli but retain avid phagocytic and bacteriocidal activity. Thus, intestinal macrophages are markedly distinct in phenotype and function from blood monocytes, although intestinal macrophages are derived from blood monocytes. To explain this paradox, we show that intestinal stromal cell-derived products downregulate both monocyte receptor expression and, via TGF-beta, cytokine production but not phagocytic or bacteriocidal activity, eliciting the phenotype and functional profile of intestinal macrophages. These findings indicate a mechanism in which blood monocytes recruited to the intestinal mucosa retain avid scavenger and host defense functions but acquire profound "inflammatory anergy," thereby promoting the absence of inflammation characteristic of normal intestinal mucosa despite the close proximity of immunostimulatory bacteria. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
29. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin.
- Author
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Ichihara, Atsuhiro, Hayashi, Matsuhiko, Kaneshiro, Yuki, Suzuki, Fumiaki, Nakagawa, Tsutomu, Tada, Yuko, Koura, Yukako, Nishiyama, Akira, Okada, Hirokazu, Uddin, M Nasir, Nabi, A H M Nurun, Ishida, Yuichi, Inagami, Tadashi, and Saruta, Takao
- Subjects
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DIABETES complications , *RENIN-angiotensin system , *ANGIOTENSINS , *ANIMAL experimentation , *BIOCHEMISTRY , *COMPARATIVE studies , *DIABETES , *DIABETIC nephropathies , *IMMUNOGLOBULINS , *KIDNEYS , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MOLECULAR structure , *PEPTIDES , *PROTEIN precursors , *PROTEINS , *RATS , *RENIN , *RESEARCH , *URINE , *ANGIOTENSIN II , *ANGIOTENSIN I , *EVALUATION research , *PREVENTION , *PHYSIOLOGY - Abstract
We found that when a site-specific binding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
30. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes.
- Author
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Hennige, Anita M, Burks, Deborah J, Ozcan, Umut, Kulkarni, Rohit N, Ye, Jing, Park, Sunmin, Schubert, Markus, Fisher, Tracey L, Dow, Matt A, Leshan, Rebecca, Zakaria, Mark, Mossa-Basha, Mahmud, and White, Morris F
- Subjects
- *
ISLANDS of Langerhans transplantation , *TYPE 2 diabetes prevention , *ANIMAL experimentation , *APOPTOSIS , *BIOCHEMISTRY , *CARRIER proteins , *CELL receptors , *CELLULAR signal transduction , *COMPARATIVE studies , *DIABETES , *FAT content of food , *GENES , *INSULIN , *ISLANDS of Langerhans , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *TYPE 2 diabetes , *PHOSPHOPROTEINS , *RESEARCH , *SOMATOMEDIN , *SURVIVAL , *EVALUATION research , *CELL size , *SIGNAL peptides , *PHYSIOLOGY - Abstract
The insulin receptor substrate-2 (Irs2) branch of the insulin/IGF signaling system coordinates peripheral insulin action and pancreatic beta cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that beta cell-specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted beta cell growth, survival, and insulin secretion that prevented diabetes in Irs2-/- mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in beta cells, especially specific cAMP agonists, could be rational treatments for beta cell failure and diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
31. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus.
- Author
-
Bordier, Bruno B., Ohkanda, Junko, Liu, Ping, Lee, So-Young, Salazar, F.H., Marion, Patricia L., Ohashi, Kazuo, Meuse, Leonard, Kay, Mark A., Casey, John L., Sebti, Said M., Hamilton, Andrew D., and Glenn, Jeffrey S.
- Subjects
- *
HEPATITIS D virus , *HEPATITIS viruses , *VIRUSES , *LIVER diseases , *MICROORGANISMS , *ANIMAL experimentation , *ANTIVIRAL agents , *BIOCHEMISTRY , *BIOLOGICAL models , *COMPARATIVE studies , *HEPATITIS D , *ENZYME inhibitors , *HEPATITIS B , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *METHIONINE , *MICE , *OLIGOPEPTIDES , *RESEARCH , *RESEARCH funding , *RNA , *TRANSFERASES , *VIRAL antigens , *DRUG development , *EVALUATION research , *VIREMIA , *DISEASE complications , *PHARMACODYNAMICS , *PHYSIOLOGY - Abstract
Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
32. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II.
- Author
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Wang, Lin, Soroka, Carol J, and Boyer, James L
- Subjects
- *
PROTEIN metabolism , *ENZYMES , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL transport , *CARRIER proteins , *CELL culture , *CHOLESTASIS , *COMPARATIVE studies , *DOGS , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MOTHS , *GENETIC mutation , *PROTEOLYTIC enzymes , *RESEARCH , *EVALUATION research , *PHYSIOLOGY - Abstract
PFIC II is a subtype of progressive familial intrahepatic cholestasis (PFIC) that is associated with mutations in the ABCB11 gene encoding the bile salt export pump (BSEP). However it is not known how these mutations cause this disease. To evaluate these mechanisms, we introduced seven PFIC II-associated missense mutations into rat Bsep and assessed their effects on Bsep membrane localization and transport function in MDCK and Sf9 cells, respectively. Five mutations, G238V, E297G, G982R, R1153C, and R1268Q, prevented the protein from trafficking to the apical membrane, and E297G, G982R, R1153C, and R1268Q also abolished taurocholate transport activity, possibly by causing Bsep to misfold. Mutation C336S affected neither Bsep transport activity nor the apical trafficking of Bsep, suggesting that this mutation alone may not cause this disease. D482G did not affect the apical expression but partially decreased the transport activity of Bsep. Mutant G238V was rapidly degraded in both MDCK and Sf9 cells, and proteasome inhibitor resulted in intracellular accumulation of this and other mutants, suggesting proteasome-mediated degradation plays an important role in expression of these PFIC II mutants. Our studies highlight the heterogeneous nature of PFIC II mutations and illustrate the significance of these mutations in the function and expression of Bsep. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
33. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse.
- Author
-
Saito, Eriko, Fujimoto, Manabu, Hasegawa, Minoru, Komura, Kazuhiro, Hamaguchi, Yasuhito, Kaburagi, Yuko, Nagaoka, Tetsuya, Takehara, Kazuhiko, Tedder, Thomas F., and Sato, Shinichi
- Subjects
- *
PHENOTYPES , *MICE physiology , *IMMUNOGLOBULINS , *AUTOANTIBODIES , *CALCIUM metabolism , *PROLINE metabolism , *TYROSINE metabolism , *ANIMAL experimentation , *ANTIGENS , *B cells , *BIOCHEMISTRY , *BIOLOGICAL models , *CELLULAR signal transduction , *DOSE-effect relationship in pharmacology , *ENZYME-linked immunosorbent assay , *FLOW cytometry , *GLYCOSIDASES , *INTERLEUKINS , *PHENOMENOLOGY , *MICE , *PHOSPHORYLATION , *RESEARCH funding , *SKIN , *SYSTEMIC scleroderma , *TIME , *WESTERN immunoblotting , *FIBROSIS , *MEMBRANE glycoproteins , *PRECIPITIN tests , *PHYSIOLOGY - Abstract
The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca(2+)](i) responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-gamma-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
34. AIP1: a new player in TNF signaling.
- Author
-
Guicciardi, M Eugenia and Gores, Gregory J
- Subjects
- *
ANTIGENS , *APOPTOSIS , *BIOCHEMISTRY , *CELL receptors , *CELLULAR signal transduction , *COMPARATIVE studies , *ENZYME inhibitors , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *PROTEINS , *RESEARCH , *TRANSFERASES , *TUMOR necrosis factors , *EVALUATION research , *PHYSIOLOGY , *CELL physiology - Abstract
Apoptosis signal-regulating kinase 1 (ASK1) is an upstream activator of JNK and p38 MAPK signaling cascades. Evidence now shows that the ASK1-interacting protein, AIP1, plays an important role in TNF-alpha-induced ASK1 activation by facilitating dissociation from its inhibitor. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
35. Kinetic analysis of lead metabolism in healthy humans
- Author
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G W Wetherill, Michael B. Rabinowitz, and Joel D. Kopple
- Subjects
Adult ,Male ,Radioisotope Dilution Technique ,Isotope ,Chemistry ,Urinary system ,Physiology ,General Medicine ,Urine ,Metabolism ,Middle Aged ,Isotope dilution ,Models, Biological ,Intestinal absorption ,SWEAT ,Kinetics ,Intestinal Absorption ,Lead ,Biochemistry ,Humans ,Radioactive Tracers ,Feces ,Research Article - Abstract
The steady state kinetics of lead metabolism were studied in five healthy men with stable isotope tracers. Subjects lived in a metabolic unit and ate constant low lead diets. Their intake was supplemented each day with 79--204 mug of enriched lead-204 as nitrate which was ingested with meals for 1--124 days. The concentration and isotopic composition of lead was determined serially in blood, urine, feces, and diet and less commonly in hair, nails, sweat, bone, and alimentary tract secretions by isotopic dilution, mass spectrometric analysis. The data suggest a three compartmental model for lead metabolism. The first compartment encompasses blood and is 1.5--2.2 times larger than the blood mass. It contains approximately 1.7--2.0 mg of lead and has a mean life of 35 days. This pool is in direct communication with ingested lead, urinary lead, and pools two and three. The second compartment is largely composed of soft tissue, contains about 0.3--0.9 mg of lead, and has a mean life of approximately 40 days. This pool gives rise to lead in hair, nails, sweat, and salivary, gastric, pancreatic, and biliary secretions. Pool three resides primarily in the skeleton, contains the vast quantity of body lead, and has a very slow mean life. Bones appear to differ in their rates of lead turnover. Within the relatively small changes in blood lead observed in the present study, the transfer coefficients between the pools remained constant.
- Published
- 1976
36. CLINICAL STUDIES ON PYRIDOXINE (VITAMIN B6)
- Author
-
James Flexner and Maurice R. Chassin
- Subjects
business.industry ,Physiology ,Renal function ,Articles ,General Medicine ,Urine ,Body weight ,Pyridoxine ,Excretion ,Biochemistry ,medicine ,Vitamin b6 ,business ,medicine.drug - Published
- 1941
37. Utilization of Glycerol-C14 for Intestinal Glyceride Esterification: Studies in a Patient with Chyluria *
- Author
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Peter R. Holt
- Subjects
Glycerol ,Fistula ,Physiology ,Chyluria ,Glyceride ,Urinary Bladder ,Urine ,Glycerides ,Thoracic Duct ,chemistry.chemical_compound ,medicine ,Humans ,Carbon Isotopes ,Esterification ,Urinary Bladder Fistula ,Fatty Acids ,Lymphography ,Articles ,General Medicine ,Chyle ,Lipid Metabolism ,medicine.disease ,Filariasis ,Intestines ,chemistry ,Biochemistry - Published
- 1964
38. STUDIES ON THE CHEMICAL DIAGNOSIS OF PELLAGRA (NICOTINIC ACID DEFICIENCY) 1
- Author
-
Henry Field, Daniel Melnick, William D. Robinson, and Charles F. Wilkinson
- Subjects
Excretion ,Biochemistry ,Nicotinic acid deficiency ,Chemistry ,Pellagra ,medicine ,Physiology ,General Medicine ,Urine ,medicine.disease - Published
- 1941
39. MUSCLE COMPOSITION IN RESPIRATORY ACIDOSIS 1
- Author
-
Frances E. Coville, Robert E. Cooke, William E. Segar, and Frank R. Coughlin
- Subjects
Respiratory acidosis ,Biochemistry ,business.industry ,medicine ,Physiology ,General Medicine ,Muscle composition ,medicine.symptom ,medicine.disease ,business ,Acidosis - Published
- 1952
40. Effect of Erythrocyte Destruction on Carbon Monoxide Production in Man*
- Author
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R. E. Forster, W. J. Williams, and Ronald F. Coburn
- Subjects
Male ,Carbon Monoxide ,Erythrocyte destruction ,Erythrocytes ,Physiology ,Chemistry ,Articles ,General Medicine ,Metabolism ,Hemoglobins ,chemistry.chemical_compound ,Biochemistry ,Humans ,Hemoglobin ,Carbon monoxide - Published
- 1964
41. SERUM CITRIC ACID AFTER INGESTION OF GLUCOSE IN NORMAL AND STARVED SUBJECTS
- Author
-
Knud Lundbæk, Villy Posborg Petersen, and Fritz Schönheyder
- Subjects
business.industry ,Physiology ,Blood sugar ,Articles ,General Medicine ,medicine.disease ,chemistry.chemical_compound ,Blood serum ,Biochemistry ,chemistry ,Blood chemistry ,Oral administration ,Diabetes mellitus ,Ingestion ,Medicine ,business ,Citric acid - Published
- 1950
42. Hemodilution, Tonicity, and Blood Viscosity *
- Author
-
Peter W. Rand and Eleanor H. Lacombe
- Subjects
Osmosis ,Erythrocytes ,Physiology ,Sodium ,Hypertonic Solutions ,Blood viscosity ,chemistry.chemical_element ,Sodium Chloride ,Hematocrit ,chemistry.chemical_compound ,medicine ,Urea ,Mannitol ,Pharmacology ,Hemodilution ,Chromatography ,medicine.diagnostic_test ,Chemistry ,Research ,Dextrans ,Articles ,General Medicine ,Blood Viscosity ,Molecular Weight ,Glucose ,Dextran ,Biochemistry ,Tonicity ,Isotonic Solutions ,medicine.drug - Published
- 1964
43. EXCRETION OF HYDROXYPROLINE IN PATIENTS WITH RHEUMATIC AND NON-RHEUMATIC DISEASES 1
- Author
-
H. Joel Gribetz, Morris Ziff, Andre Kibrick, and Ellis Dresner
- Subjects
Excretion ,Hydroxyproline ,chemistry.chemical_compound ,chemistry ,Biochemistry ,business.industry ,Medicine ,Physiology ,In patient ,General Medicine ,Urine ,business - Published
- 1956
44. The Early Appearing Bilirubin: Evidence for Two Components *
- Author
-
A. Zipursky, Joan Skanderbeg, T. Yamamoto, and Lyonel G. Israels
- Subjects
Biliary Fistula ,Erythrocytes ,Bilirubin ,Glycine ,Physiology ,Heme ,Feces ,chemistry.chemical_compound ,Dogs ,Bone Marrow ,Cholelithiasis ,Anemia, Pernicious ,Animals ,Bile ,Medicine ,Erythropoiesis ,Amino acid metabolism ,Amino Acids ,Hyperbilirubinemia ,Carbon Isotopes ,business.industry ,Anemia ,Articles ,General Medicine ,Levulinic Acids ,Blood ,Metabolism ,Liver ,Biochemistry ,chemistry ,Geriatrics ,business - Published
- 1965
45. ALTERATIONS OF FLUID AND ELECTROLYTE DISTRIBUTION AND RENAL FUNCTION IN DIARRHEA OF INFANCY 1
- Author
-
Avrum L. Katcher, Marvin F. Levitt, Avron Y. Sweet, Herbert Haber, Charlotte Spanier, and Horace L. Hodes
- Subjects
Diarrhea ,Chemistry ,Infant ,Physiology ,Renal function ,Articles ,General Medicine ,Electrolyte ,Body Fluids ,Electrolytes ,Biochemistry ,medicine ,Humans ,Distribution (pharmacology) ,medicine.symptom ,Child - Published
- 1953
46. EXPERIENCES WITH RADIOSULFATE IN THE ESTIMATION OF PHYSIOLOGIC EXTRACELLULAR WATER IN HEALTHY AND ABNORMAL MAN 12
- Author
-
Tohru Inoye, Lionel M. Bernstein, Luke R. Pascal, and Robert J. Ryan
- Subjects
Biochemistry ,Chemistry ,Extracellular fluid ,Water metabolism ,Physiology ,General Medicine ,Body weight - Published
- 1956
47. METABOLIC STUDIES IN PARALYTIC ACUTE ANTERIOR POLIOMYELITIS. II. ALTERATIONS IN CALCIUM AND PHOSPHORUS METABOLISM 1
- Author
-
Vincent Toscani, Estelle Stevens, Ephraim Shorr, and G. Donald Whedon
- Subjects
Calcium metabolism ,chemistry ,Biochemistry ,business.industry ,Phosphorus ,chemistry.chemical_element ,Medicine ,Physiology ,General Medicine ,Calcium ,Acute anterior poliomyelitis ,business ,Phosphorus metabolism - Published
- 1957
48. HEMODYNAMIC RELATIONSHIPS OF ANAEROBIC METABOLISM AND PLASMA FREE FATTY ACIDS DURING PROLONGED, STRENUOUS EXERCISE IN TRAINED AND UNTRAINED SUBJECTS*
- Author
-
Leonard A. Cobb and Willard P. Johnson
- Subjects
Blood Glucose ,business.industry ,Strenuous exercise ,Fatty Acids ,Physical Exertion ,Hemodynamics ,Physiology ,Blood sugar ,Articles ,General Medicine ,Fatty Acids, Nonesterified ,Biochemistry ,Lactates ,Humans ,Medicine ,Exertion ,business ,Anaerobic exercise ,Plasma free fatty acid - Published
- 1963
49. THE INFLUENCE OF VITAMIN A UPON UREA CLEARANCE IN THE HUMAN SUBJECT 1
- Author
-
Henry J. Nicholes and Raymond C. Herrin
- Subjects
Vitamin ,Urea clearance ,business.industry ,Retinol ,Physiology ,General Medicine ,medicine.disease ,Vitamin A deficiency ,chemistry.chemical_compound ,Blood pressure ,Biochemistry ,chemistry ,Urea ,Medicine ,business - Published
- 1940
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