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- Type:
- Article
- Descripción/Resumen:
- Organovanadium compounds have been shown to be insulin sensitizers in vitro and in vivo. One potential biochemical mechanism for insulin sensitization by these compounds is that they inhibit protein tyrosine phosphatases (PTPs) that negatively regulate insulin receptor activation and signaling. In this study, bismaltolato oxovanadium (BMOV), a potent insulin sensitizer, was shown to be a reversible, competitive phosphatase inhibitor that inhibited phosphatase activity in cultured cells and enhanced insulin receptor activation in vivo. NMR and X-ray crystallographic studies of the interaction of BMOV with two different phosphatases, HCPTPA (human low molecular weight cytoplasmic protein tyrosine phosphatase) and PTP1B (protein tyrosine phosphatase 1B), demonstrated uncomplexed vanadium (VO ) in the active site. Taken together, these findings support phosphatase inhibition as a mechanism for insulin sensitization by BMOV 4 and other organovanadium compounds and strongly suggest that uncomplexed vanadium is the active component of these compounds.
- Creador/Autor:
- Diven, Conrad; Peters, Kevin G.; Evdokimov, Artem; Howard, Brian W.; Soper, Shari; Genbauffe, Frank; Greis, Kenneth D.; Rastogi, Vinit; Eby-Wilkens, Elaine; Pokross, Matthew, and Maier, Matthew
- Peticionario:
- Kenneth Greis
- Fecha modificada:
- 03/01/2017
- Fecha modificada:
- 04/07/2017
- Fecha de creacion:
- 2003-09
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- Background: Role of apolipoprotein (apo) A-II on metabolism of high density lipoproteins (HDLs) is unknown. Results: Conformational changes of apoA-I, the major apolipoprotein of HDL, caused by apoA-II in discoidal HDL are confined to two regions of apoA-I. Conclusion: Interactions between the two major apolipoproteins in discoidal HDL are site specific. Significance: Functional implications of HDL complexes will significantly benefit from such structural information.
- Creador/Autor:
- Gauthamadasa, Kekulawalage; Vaitinadin, Nataraja Sarma; Homan, Reyn; Macha, Stephen; Dresman, James L.; D. Silva, R. A. Gangani, and Greis, Kenneth D.
- Peticionario:
- Kenneth Greis
- Fecha modificada:
- 03/01/2017
- Fecha modificada:
- 04/07/2017
- Fecha de creacion:
- 2012-03
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- The primary structure of the major surface glycoconjugate of Leishmania donovani parasites, a lipophosphoglycan, has been further characterized. The repeating PO4-6Galp beta 1-4Man disaccharide units, which are a salient feature of the molecule, are shown to terminate with one of several neutral structures, the most abundant of which is the branched trisaccharide Galp beta 1-4(Manp alpha 1-2)Man. The phosphosaccharide core of lipophosphoglycan, which links the disaccharide repeats to a lipid anchor, contains 2 phosphate residues. One of the core phosphates has previously been localized on O-6 of the galactosyl residue distal to the lipid anchor; the second phosphate is now shown to be on O-6 of the mannosyl residue distal to the anchor and to bear an alpha-linked glucopyranosyl residue. Also, the anomeric configuration of the unusual 3-substituted Galf residue in the phosphosaccharide core is established as beta. The complete structure of the core is thus PO4-6Galp alpha 1-6Galp alpha 1-3Galf beta 1-3[Glcp alpha 1-PO4-6]Manp alpha 1-3Manp alpha 1-4GlcN alpha 1-. This further clarification of the structure of lipophosphoglycan may prove beneficial in determining the structure-function relationships of this highly unusual glycoconjugate.
- Creador/Autor:
- Ferguson, Michael A. J.; Turco, Salvatore J.; Thomas, Jerry R.; Gorin, Philip A. J.; Homans, Steven W.; McConville, Malcom J.; Greis, Kenneth D., and Thomas-Oates, Jane E.
- Peticionario:
- Kenneth Greis
- Fecha modificada:
- 03/01/2017
- Fecha modificada:
- 04/07/2017
- Fecha de creacion:
- 1992-05
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- An extracellular phosphoglycan (exPG), present in the culturem edium of the promastigote form L oefi shmania donovani, was purified and structurally characterized. The purification scheme included ethanol precipitation of the culture medium, anion exchange chromatography, hydrophobic chromatography on phenyl-Sepharose, and preparative polyacrylamgeild e electrophoresis. Structural analysis by ‘H-’H NMR, methylation linkage analysis, and glycosidase digestion revealed that the exPG consisted of thfoel lowing structure: (CAP)+[P04-6Galp@1-4Manpal]lo-11-POr6GalpB1-4Man. The capw as found to be ones eovf eral small, neutral oligosaccharides, the most abundant of which was the trisaccharide Galp@l-4(Manpal-2)Man. The results indicated structural analogy to the cellular-derived lipophosphoglycan (LPG) from L. donovani. The important exceptions are a lacko f the lipid anchor, the entire phosphosaccharide core, and several of the repeating disaccharide units. Although the function of exPGis presently unknowni,t may play a protective role for the promastigote in the insect vector or during infection of a mammalian host
- Creador/Autor:
- Turco, Salvatore J.; Thomas, Jerry R.; Homans, Steven W.; Ferguson, Michael A.; McConville, Malcolm J., and Greis, Kenneth D.
- Peticionario:
- Kenneth Greis
- Fecha modificada:
- 03/01/2017
- Fecha modificada:
- 04/07/2017
- Fecha de creacion:
- 1992-04
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- Proteomic analysis of biological samples in disease models or therapeutic intervention studies requires the ability to detect and identify biologically relevant proteins present in relatively low concentrations. The detection and analysis of these low-level proteins is hindered by the presence of a few proteins that are expressed in relatively high concentrations. In the case of muscle tissue, highly abundant structural proteins, such as actin, myosin, and tropomyosin, compromise the detection and analysis of more biologically relevant proteins. We have developed a practical protocol which exploits high-pH extraction to reduce or remove abundant structural proteins from skeletal muscle crude membrane preparations in a manner suitable for two dimensional gel electrophoresis. An initial whole-cell muscle lysate is generated by homogenization of powdered tissue in Tris-base. This lysate is subsequently partitioned into a supernatant and pellet containing the majority of structural proteins. Treatment of the pellet with high-pH conditions effectively releases structural proteins from membrane compartments which are then removed through ultracentrifugation. Mass spectrometric identification shows that the majority of protein spots reduced or removed by high-pH treatment were contractile proteins or contractile-related proteins. Removal of these proteins enabled successful detection and identification of minor proteins. Structural protein removal also results in significant improvement of gel quality and the ability to load higher amounts of total protein for the detection of lower abundant protein classes.
- Creador/Autor:
- Wang, Feng; Jarrold, Bradley; Burt, Thomas; DeMuth, Jeffrey, and Greis, Kenneth D.
- Peticionario:
- Kenneth Greis
- Fecha modificada:
- 03/01/2017
- Fecha modificada:
- 04/07/2017
- Fecha de creacion:
- 2005-06
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- Not Available.
- Creador/Autor:
- Cancelas, Jose A. and Taniguchi, E.
- Peticionario:
- Jose Cancelas
- Fecha modificada:
- 02/08/2017
- Fecha modificada:
- 04/10/2017
- Fecha de creacion:
- 2012-09-01
- Licencia:
- All rights reserved
-
Insertional Mutagenesis Identifies a STAT3/Arid1b/ b-catenin Pathway Driving Neurofibroma Initiation
- Type:
- Article
- Descripción/Resumen:
- Wu et al. map an Nf1-Stat3-Arid1b/ b-catenin pathway that initiates Neurofibromatosis type 1 (Nf1) neurofibromas, using unbiased insertional mutagenesis screening. Stat3 transcriptionally represses Gsk3b and Arid1b, thereby activating b-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance. Stat3-mediated modification plays a role in early tumorigenesis.
- Creador/Autor:
- Spinner, R. J.; Ratner, N.; Largaespada, D. A.; Keng, V.; Patmore, D. M.; Wu, J., and Cancelas, Jose A.
- Peticionario:
- Jose Cancelas
- Fecha modificada:
- 02/08/2017
- Fecha modificada:
- 04/10/2017
- Fecha de creacion:
- 2016-02
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE Nancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1, Edwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James R. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose A. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David A. Largaespada2; 1 Cincinnati Children’s, Cincinnati, OH, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3 Mayo Clinic, Rochester, MN, USA; 4 Massachusetts General Hospital, Boston, MA, USA; 5 National Cancer Institute Pediatric Branch, Bethesda, MD, USA; 6 New York University School of Medicine, New York, NY, USA To identify genes and signaling pathways that drive peripheral nerve tumor initiationand growth beyond the Ras-MAPK pathwaywe used unbiased insertional mutagenesis screening. We identified Stat3 as a potential driver of Neurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented neurofibroma formation, and self-renewal of tumor initiating cells. Genetic gain- and loss-of-function identified EGFR as the major upstream regulator of P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation; IL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/ Stat3 inhibitor reduced established neurofibroma growth, supporting an additional role for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream of Stat3, we identified b-catenin, and b-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and b-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ b-catenin pathway inhibition in neurofibroma therapeutic trials. Supported by: NIH R01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a DAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.). The American Cancer Society (IRG-67-003-44) supported J.R.F.
- Creador/Autor:
- Schwartz, E. B.; Ratner, N.; Largaespada, D. A.; Cancelas, Jose A., and Stemmer-Rachamimov, A. O.
- Peticionario:
- Jose Cancelas
- Fecha modificada:
- 02/08/2017
- Fecha modificada:
- 04/10/2017
- Fecha de creacion:
- 2014-11
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- Overnight, room temperature hold (ONH) of whole blood before component processing offers several benefits. This study evaluated the storage and in vivo recovery characteristics of ONH red blood cells (RBCs) stored in additive solution-7 (AS-7).
- Creador/Autor:
- Szczerpiorkowski, Z. M.; Whitley, P.; Maes, L. A.; Dumont, L. J.; Cancelas, Jose A.; Zia, M.; Hess, J. R.; Rugg, N., and Herschel, L.
- Peticionario:
- Jose Cancelas
- Fecha modificada:
- 02/08/2017
- Fecha modificada:
- 04/10/2017
- Fecha de creacion:
- 2014-10
- Licencia:
- All rights reserved
-
- Type:
- Article
- Descripción/Resumen:
- Patients in organ failure of vascular origin have increased circulating hematopoietic stem cells and progenitors (HSC/P). Plasma levels of angiotensin II (Ang-II), are commonly increased in vasculopathies. Hyperangiotensinemia results in activation of a very distinct Ang-II receptor set, Rho-family GTPase members, and actin in bone marrow endothelial cells (BMEC) and HSC/P, which results in decreased membrane integrin activation in both BMEC and HSC/P, and in HSC/P de-adhesion and mobilization. The Ang-II effect can be reversed pharmacologically and genetically by inhibiting Ang-II production or signaling through BMEC AT2R, HSCP AT1R/ AT2R or HSC/P RhoA, but not by interfering with other vascular tone mediators. Hyperangiotensinemia and high counts of circulating HSC/P seen in sickle cell disease (SCD) as a result of vascular damage, is significantly decreased by Ang-II inhibitors. Our data define for the first time the role of Ang-II HSC/P traffic regulation and redefine the hematopoietic consequences of anti-angiotensin therapy in SCD.
- Creador/Autor:
- Inagami, T.; Hill, S. E.; Wellendorf, A. M.; Perumbeti, A.; Nayak, R. C.; Bezold, K. Y.; Zheng, Y.; Chang, K. H.; Pirman, M.; Loberg, A.; Cancelas, Jose A.; Roy, S.; Malik, P.; Starnes, J., and Zhou, X.
- Peticionario:
- Jose Cancelas
- Fecha modificada:
- 02/08/2017
- Fecha modificada:
- 04/10/2017
- Fecha de creacion:
- 2015-01
- Licencia:
- All rights reserved
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