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Hyperacute lung rejection in the pig-to-human model. III. Platelet receptor inhibitors synergistically modulate complement activation and lung injury.
Pfeiffer S, Zorn GL, Zhang JP, Giorgio TD, Robson SC, Azimzadeh AM, Pierson RN
(2003) Transplantation 75: 953-9
MeSH Terms: Acute Disease, Animals, Aurintricarboxylic Acid, Blood Physiological Phenomena, Blood Platelets, Complement Activation, Dipeptides, Drug Synergism, Graft Rejection, Graft Survival, Hematocrit, Histamine, Humans, Lung, Lung Transplantation, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Glycoprotein GPIb-IX Complex, Platelet Membrane Glycoproteins, Swine, Thrombin, Thromboxane B2, Transplantation, Heterologous
Show Abstract · Added March 20, 2014
BACKGROUND - The influence of platelet von Willebrand factor (vWF)-glycoprotein (GP)Ib-V-IX and GPIIb-IIIa receptor interactions in the context of hyperacute rejection (HAR) of pulmonary xenografts has not previously been explored.
METHODS - Aurintricarboxylic acid (ATA, an inhibitor of platelet-GPIb interactions with vWF), SC52012A (SC, a synthetic GPIIb/IIIa inhibiting peptide), or both were added to heparinized whole human blood before perfusion of isolated piglet lungs. Results were compared with unmodified blood ("unmodified").
RESULTS - Perfusion of porcine lungs with unmodified human blood resulted in an immediate rise in pulmonary vascular resistance (PVR), fluid and platelet sequestration in the lung, and, without exception, cessation of function within 15 minutes with a mean survival of 8 minutes. Addition of ATA or SC before lung perfusion significantly decreased the rise in PVR, diminished histamine release, and prolonged survival to 31+/-11 and 31+/-22 minutes, respectively. When the therapies were combined, mean survival was 156+/-77 minutes (P<0.05 vs. either monotherapy). Complement activation was synergistically attenuated only when the drugs were used together.
CONCLUSIONS - Platelet protein receptor adhesive interactions play an important role in amplification of complement activation during hyperacute lung rejection. Inhibiting recruitment of platelets at the site of initial immunologic injury to endothelial cells may protect porcine organs against thrombosis and inflammation during the initial exposure to human blood.
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22 MeSH Terms
Cathepsin L and cathepsin B mediate reovirus disassembly in murine fibroblast cells.
Ebert DH, Deussing J, Peters C, Dermody TS
(2002) J Biol Chem 277: 24609-17
MeSH Terms: Amino Acid Sequence, Animals, Capsid, Cathepsin B, Cathepsin L, Cathepsins, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Dipeptides, Fibroblasts, Gene Deletion, Kinetics, L Cells, Mice, Models, Molecular, Molecular Sequence Data, Orthoreovirus, Mammalian, Protein Conformation, Substrate Specificity, Viral Plaque Assay, Virion
Show Abstract · Added December 10, 2013
After attachment to receptors, reovirus virions are internalized by endocytosis and exposed to acid-dependent proteases that catalyze viral disassembly. Previous studies using the cysteine protease inhibitor E64 and a mutant cell line that does not support reovirus disassembly suggest a requirement for specific endocytic proteases in reovirus entry. This study identifies the endocytic proteases that mediate reovirus disassembly in murine fibroblast cells. Infection of both L929 cells treated with the cathepsin L inhibitor Z-Phe-Tyr(t-Bu)-diazomethyl ketone and cathepsin L-deficient mouse embryo fibroblasts resulted in inefficient proteolytic disassembly of viral outer-capsid proteins and decreased viral yields. In contrast, both L929 cells treated with the cathepsin B inhibitor CA-074Me and cathepsin B-deficient mouse embryo fibroblasts support reovirus disassembly and growth. However, removal of both cathepsin B and cathepsin L activity completely abrogates disassembly and growth of reovirus. Concordantly, cathepsin L mediates reovirus disassembly more efficiently than cathepsin B in vitro. These results demonstrate that either cathepsin L or cathepsin B is required for reovirus entry into murine fibroblasts and indicate that cathepsin L is the primary mediator of reovirus disassembly. Moreover, these findings suggest that specific endocytic proteases can determine host cell susceptibility to infection by intracellular pathogens.
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21 MeSH Terms
Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease.
Ye J, Davé UP, Grishin NV, Goldstein JL, Brown MS
(2000) Proc Natl Acad Sci U S A 97: 5123-8
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, CCAAT-Enhancer-Binding Proteins, Cell Line, Cell Membrane, Conserved Sequence, Cricetinae, DNA-Binding Proteins, Dipeptides, Endopeptidases, Helix-Loop-Helix Motifs, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Protein Structure, Secondary, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Sterol Regulatory Element Binding Protein 1, Transcription Factors, Transfection
Show Abstract · Added March 5, 2014
The NH(2)-terminal domains of membrane-bound sterol regulatory element-binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH(2)-terminal cap for a portion of the transmembrane alpha-helix of SREBP, allowing the remainder of the alpha-helix to unwind partially to expose the peptide bond for cleavage by S2P.
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23 MeSH Terms
A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor alpha (TNF alpha) and abrogates endotoxin-induced lethality.
Solorzano CC, Ksontini R, Pruitt JH, Auffenberg T, Tannahill C, Galardy RE, Schultz GP, MacKay SL, Copeland EM, Moldawer LL
(1997) Shock 7: 427-31
MeSH Terms: Animals, Dipeptides, Disease Models, Animal, Endotoxins, Female, Humans, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Protease Inhibitors, Shock, Septic, Tumor Necrosis Factor-alpha
Show Abstract · Added March 5, 2014
Excessive tumor necrosis factor alpha (TNF alpha) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNF alpha production rely on monoclonal antibodies or immunoadhesins that bind TNF alpha and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNF alpha processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 microgram/mL endotoxin, GM-6001 at concentrations > 5 micrograms/mL blocked release of TNF alpha, but did not affect the release of either IL-1 beta or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNF alpha. To confirm the role of secreted TNF alpha in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 micrograms/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNF alpha response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1 beta and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNF alpha processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNF alpha both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.
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12 MeSH Terms
Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor.
Solorzano CC, Ksontini R, Pruitt JH, Hess PJ, Edwards PD, Kaibara A, Abouhamze A, Auffenberg T, Galardy RE, Vauthey JN, Copeland EM, Edwards CK, Lauwers GY, Clare-Salzler M, MacKay SL, Moldawer LL, Lazarus DD
(1997) J Immunol 158: 414-9
MeSH Terms: Animals, Chemical and Drug Induced Liver Injury, Concanavalin A, Dipeptides, Drug Synergism, Galactosamine, Lipopolysaccharides, Liver, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Protease Inhibitors, Receptors, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha
Show Abstract · Added March 5, 2014
TNF-alpha is a pleiotropic cytokine that exists both as a 26-kDa cell-associated and a 17-kDa soluble form. Recently, a class of matrix metalloproteinase inhibitors has been identified that can prevent the processing by TNF convertase of 26-kDa TNF-alpha to its 17-kDa form and can reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhibitor, GM-6001, improves survival but does not protect against liver injury from D-GalN/LPS-induced shock in the mouse. In Con A-induced hepatitis, GM-6001 actually exacerbates hepatocellular necrosis and apoptosis despite greater than 90% reduction in plasma TNF-alpha concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-alpha in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), which neutralizes both membrane-associated and soluble TNF-alpha, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-alpha plays a role in the hepatocellular necrosis and apoptosis that accompany D-GalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.
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14 MeSH Terms
SC-49992--a potent and specific inhibitor of platelet aggregation.
Nicholson NS, Panzer-Knodle SG, King LW, Taite BB, Keller BT, Tjoeng FS, Engleman VW, Giorgio TD, Feigen LP
(1994) Thromb Res 74: 523-35
MeSH Terms: Amino Acid Sequence, Animals, Dipeptides, Dogs, Fibrinogen, Humans, Molecular Sequence Data, Molecular Structure, Oligopeptides, Platelet Aggregation Inhibitors, Rats
Show Abstract · Added March 20, 2014
Fibrinogen binding is required for platelet aggregation and subsequent thrombus formation. SC-49992 (SC), an RGDF mimetic, is a potent and specific inhibitor of the binding of fibrinogen to its receptor on activated platelets, glycoprotein IIb/IIIa (IC50 0.7 microM). SC was more potent (1-5 microM) than either RGDS, RGDF or the gamma chain dodecapeptide in blocking platelet aggregation to a variety of agonists in both dog and human platelet rich plasma. SC was more potent as an inhibitor of GP IIb/IIIa on platelets than it was against other integrin and non-integrin receptors, including the RGD-dependent vitronectin receptor and other non-RGD-dependent integrins such as CDII/CD18. SC had little effect on ristocetin induced agglutination. SC blocked ex vivo collagen induced aggregation in dogs and collagen induced thrombocytopenia in rats. These data suggest that elimination of the Arg-NH2 and the Arg-Gly amide bond of RGDF provided increased inhibitory potency and specificity. This structural modification may be of value in the development of other more potent RGDF mimetics for the inhibition of platelet aggregation.
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11 MeSH Terms
Processing of procarboxypeptidase A and other zymogens in murine mast cells.
Dikov MM, Springman EB, Yeola S, Serafin WE
(1994) J Biol Chem 269: 25897-904
MeSH Terms: Amino Acid Sequence, Animals, Carboxypeptidases, Carboxypeptidases A, Cathepsin B, Cathepsin C, Cells, Cultured, Chymases, Diazomethane, Dipeptides, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Enzyme Precursors, Fluorescent Antibody Technique, Humans, Mast Cells, Mice, Molecular Sequence Data, Monocytes, Protein Processing, Post-Translational, Recombinant Proteins, Serine Endopeptidases, Transfection, Tryptases
Show Abstract · Added March 5, 2014
By cDNA sequence analyses the proteases found within the secretory granules of immune/inflammatory cells appear to be translated initially as zymogens, but by amino-terminal sequencing they are stored within the granules in an active form. We now show that murine mast cell carboxypeptidase A (MC-CPA) is produced in a zymogen form (MC-pro-CPA) that is present at approximately 0.5% of the level of MC-CPA. MC-pro-CPA is an inactive precursor of MC-CPA and is located within the secretory granules of the mast cells. We have identified one mast cell line, KiSV-MC9, that produces MC-pro-CPA yet cannot process it to the active form despite the fact that these cells can process prochymase and protryptase to their active forms, indicating that a separate mechanism exists for activation of the serine proteases. We show that dipeptidylpeptidase-I is involved in the processing of murine mast cell prochymase and procathepsin G, but does not process MC-pro-CPA or protryptase. Thus, mast cell carboxypeptidase, tryptase, and chymase zymogens are each processed to their active forms by different mechanisms.
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23 MeSH Terms
A computer-based protocol for semiautomated assignments and 3D structure determination of proteins.
Meadows RP, Olejniczak ET, Fesik SW
(1994) J Biomol NMR 4: 79-96
MeSH Terms: Algorithms, Amino Acid Sequence, Automation, Carrier Proteins, Cell Line, Computer Graphics, Dipeptides, Heat-Shock Proteins, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Protein Conformation, Tacrolimus, Tacrolimus Binding Proteins
Show Abstract · Added March 5, 2014
A strategy is presented for the semiautomated assignment and 3D structure determination of proteins from heteronuclear multidimensional Nuclear Magnetic Resonance (NMR) data. This approach involves the computer-based assignment of the NMR signals, identification of distance restraints from nuclear Overhauser effects, and generation of 3D structures by using the NMR-derived restraints. The protocol is described in detail and illustrated on a resonance assignment and structure determination of the FK506 binding protein (FKBP, 107 amino acids) complexed to the immunosuppressant, ascomycin. The 3D structures produced from this automated protocol attained backbone and heavy atom rmsd of 1.17 and 1.69 A, respectively. Although more highly resolved structures of the complex have been obtained by standard interpretation of NMR data (Meadows et al. (1993) Biochemistry, 32, 754-765), the structures generated with this automated protocol required minimal manual intervention during the spectral assignment and 3D structure calculations stages. Thus, the protocol may yield an approximate order of magnitude reduction in the time required for the generation of 3D structures of proteins from NMR data.
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15 MeSH Terms
Specific alterations in the levels of N-acetyl-aspartyl-glutamate in the nervous system of the dystrophic mouse.
Blakely RD, Ory-Lavollée L, Coyle JT
(1987) Neurosci Lett 79: 223-8
MeSH Terms: Animals, Aspartic Acid, Brain, Dipeptides, Male, Mice, Mice, Mutant Strains, Muscular Dystrophy, Animal, Spinal Cord
Show Abstract · Added July 10, 2013
Determinations of N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG) levels were obtained by ion-exchange HPLC from 10 regions of the male dystrophic mouse brain as well as from those of non-dystrophic littermate controls. Similar to previous studies in the rat, NAA levels in control mice were distributed rather uniformly while NAAG levels exhibited a pronounced rostrocaudal gradient, with highest levels found in the lumbar spinal cord. Contrary to a recent report, we found no significant alterations in gross brain or spinal cord levels of NAA. In contrast, levels of NAAG were substantially and differentially reduced in several regions of the dystrophic mouse nervous system. These results demonstrate a pathological dissociation between NAA and NAAG, whose levels are known to display differential regional, ontogenetic and phylogenetic patterns. In addition, they may represent an ability of neural tissue to differentially regulate their steady-state levels, if indeed they can be shown to be biosynthetically related. The pronounced and non-uniform NAAG reductions observed in the dystrophic CNS underscores recent suggestions of a role for the neuropeptide in central systems involved in the control of motor function.
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9 MeSH Terms
Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-L-glutamate. Identification and characterization of a novel N-acetylated alpha-linked acidic dipeptidase activity from rat brain.
Robinson MB, Blakely RD, Couto R, Coyle JT
(1987) J Biol Chem 262: 14498-506
MeSH Terms: Animals, Brain, Chlorides, Dipeptidases, Dipeptides, Hydrogen-Ion Concentration, Hydrolysis, Kinetics, Metals, Rats, Rats, Inbred Strains, Structure-Activity Relationship
Show Abstract · Added July 10, 2013
High performance liquid chromatography studies documented the presence of an enzyme activity, N-acetylated alpha-linked acidic dipeptidase (NAALA dipeptidase), in rat brain membranes that cleaves the endogenous brain dipeptide, N-acetyl-L-aspartyl-L-glutamate to N-acetyl-aspartate and glutamate. With ion exchange chromatography, which quantitatively separated [3,4-3H]glutamate from N-acetyl-L-aspartyl-L-[3,4-3H]glutamate, we found that NAALA dipeptidase activity was essentially restricted to nervous tissue and kidney. We characterized NAALA dipeptidase activity in lysed synaptosomal membranes obtained from rat forebrain. Membrane-bound NAALA dipeptidase activity was optimal between pH 6.0 and 7.4 at 37 degrees C. Eadie-Hofstee analysis of kinetic data revealed a rather high apparent affinity for N-acetyl-L-aspartyl-L-glutamate with a Km = 540 nM and a Vmax = 180 nM/mg of protein/min. While NAALA dipeptidase showed a requirement for monovalent anions such as Cl-, the polyvalent anions phosphate and sulfate inhibited enzyme activity 50% at 100 microM and 1 mM, respectively. The divalent metal ion chelators EGTA, EDTA, and o-phenanthroline completely abolished activity, which was partially restored by manganese. Treatment of membranes with 1 mM dithiothreitol abolished NAALA dipeptidase activity. NAALA dipeptidase activity was also sensitive to the aminopeptidase inhibitors bestatin and puromycin, although not to the selective aminopeptidase A inhibitor amastatin. Structure-activity relationships inferred from inhibitor studies suggest that this enzyme shows specificity for N-acetylated alpha-linked acidic dipeptides. NAALA dipeptidase was also potently inhibited by the excitatory amino acid agonist L-quisqualate. Comparison of the properties of NAALA dipeptidase to those of previously characterized enzymes suggests that this is a novel peptidase which may be involved in the synaptic degradation of N-acetyl-L-aspartyl-L-glutamate.
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12 MeSH Terms