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Dennis J Grab - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms for the elimination of potentially lytic complement-fixing variable surface glycoprotein antibody-complexes inTrypanosoma brucei
Parasitology Research, 1994Co-Authors: D. C. W. Russo, D J L Williams, Dennis J GrabAbstract:Live antibody-coated Trypanosoma brucei parasites remove variable surface glycoprotein (VSG)-antibody complexes from their surface upon warming to 37° C and evade antibody-activated complement lysis by both protein synthesis-Dependent and protein synthesis-inDependent mechanisms. The protein synthesis-Dependent Process follows antibody-mediated trypanosome agglutination, whereas the protein synthesis-inDependent mechanism can occur in the absence of trypanosome agglutination. The latter Process leads to a more rapid climination of complement-fixing VSG-antibody complexes.
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mechanisms for the elimination of potentially lytic complement fixing variable surface glycoprotein antibody complexes in trypanosoma brucei
Parasitology Research, 1994Co-Authors: D. C. W. Russo, D J L Williams, Dennis J GrabAbstract:Live antibody-coatedTrypanosoma brucei parasites remove variable surface glycoprotein (VSG)-antibody complexes from their surface upon warming to 37° C and evade antibody-activated complement lysis by both protein synthesis-Dependent and protein synthesis-inDependent mechanisms. The protein synthesis-Dependent Process follows antibody-mediated trypanosome agglutination, whereas the protein synthesis-inDependent mechanism can occur in the absence of trypanosome agglutination. The latter Process leads to a more rapid climination of complement-fixing VSG-antibody complexes.
Christopher R Parish - One of the best experts on this subject based on the ideXlab platform.
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immunotherapy of cytotoxic t cell resistant tumors by t helper 2 cells an eotaxin and stat6 Dependent Process
Journal of Experimental Medicine, 2003Co-Authors: Joerg Mattes, Mark D Hulett, Simon P Hogan, Marc E Rothenberg, Paul S Foster, Christopher R ParishAbstract:Currently most attempts at cancer immunotherapy involve the generation of CD8+ cytotoxic T lymphocytes (CTLs) against tumor-associated antigens. Many tumors, however, have been immunoselected to evade recognition by CTLs and thus alternative approaches to cancer immunotherapy are urgently needed. Here we demonstrate that CD4+ T cells that recognize a secreted tumor-specific antigen and exhibit a cytokine secretion profile characteristic of Th2 cells, are capable of clearing established lung and visceral metastases of a CTL-resistant melanoma. Clearance of lung metastases by the Th2 cells was found to be totally Dependent on the eosinophil chemokine, eotaxin, and partially Dependent on the transcription activator signal transducer and activator of transcription 6 (STAT6), with degranulating eosinophils within the tumors inducing tumor regression. In contrast, tumor-specific CD4+ Th1 cells, that recruited macrophages into the tumors, had no effect on tumor growth. This work provides the basis for a new approach to adoptive T cell immunotherapy of cancer.
D. C. W. Russo - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms for the elimination of potentially lytic complement-fixing variable surface glycoprotein antibody-complexes inTrypanosoma brucei
Parasitology Research, 1994Co-Authors: D. C. W. Russo, D J L Williams, Dennis J GrabAbstract:Live antibody-coated Trypanosoma brucei parasites remove variable surface glycoprotein (VSG)-antibody complexes from their surface upon warming to 37° C and evade antibody-activated complement lysis by both protein synthesis-Dependent and protein synthesis-inDependent mechanisms. The protein synthesis-Dependent Process follows antibody-mediated trypanosome agglutination, whereas the protein synthesis-inDependent mechanism can occur in the absence of trypanosome agglutination. The latter Process leads to a more rapid climination of complement-fixing VSG-antibody complexes.
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mechanisms for the elimination of potentially lytic complement fixing variable surface glycoprotein antibody complexes in trypanosoma brucei
Parasitology Research, 1994Co-Authors: D. C. W. Russo, D J L Williams, Dennis J GrabAbstract:Live antibody-coatedTrypanosoma brucei parasites remove variable surface glycoprotein (VSG)-antibody complexes from their surface upon warming to 37° C and evade antibody-activated complement lysis by both protein synthesis-Dependent and protein synthesis-inDependent mechanisms. The protein synthesis-Dependent Process follows antibody-mediated trypanosome agglutination, whereas the protein synthesis-inDependent mechanism can occur in the absence of trypanosome agglutination. The latter Process leads to a more rapid climination of complement-fixing VSG-antibody complexes.
Steven Grant - One of the best experts on this subject based on the ideXlab platform.
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inhibition of bcl 2 antiapoptotic members by obatoclax potently enhances sorafenib induced apoptosis in human myeloid leukemia cells through a bim Dependent Process
Blood, 2012Co-Authors: Mohamed Rahmani, Mandy Mayo Aust, Elisa Attkisson, David C Williams, Andrea Ferreiragonzalez, Steven GrantAbstract:Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34+ cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 Processing and LC3–green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML.
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Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-Dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-κB-Dependent Process
Oncogene, 2003Co-Authors: Mohamed Rahmani, Steven GrantAbstract:Interactions between proteasome and cyclin-Dependent kinase inhibitors have been examined in human leukemia cells in relation to induction of apoptosis. Simultaneous exposure (24 h) of U937 myelomonocytic leukemia cells to 100 n M flavopiridol and 300 n M MG-132 resulted in a marked increase in mitochondrial injury (cytochrome c , Smac/DIABLO release, loss of Δ Ψ _m), caspase activation, and synergistic induction of cell death, accompanied by a marked decrease in clonogenic potential. Similar effects were observed with other proteasome inhibitors (e.g., Bortezomib (VELCADE™ bortezomib or injection), lactacystin, LLnL) and cyclin-Dependent kinase inhibitors (e.g., roscovitine), as well as other leukemia cell types (e.g., HL-60, Jurkat, Raji). In U937 cells, synergistic interactions between MG-132 and flavopiridol were associated with multiple perturbations in expression/activation of signaling- and survival-related proteins, including downregulation of XIAP and Mcl-1, activation of JNK and p34^cdc2, and diminished expression of p21^CIP1. The lethal effects of MG-132/flavopiridol were not reduced in leukemic cells ectopically expressing Bcl-2, but were partially attenuated in cells ectopically expressing dominant-negative caspase-8 or CrmA. Flavopiridol/proteasome inhibitor-mediated lethality was also significantly diminished by agents and siRNA blocking JNK activation. Lastly, coadministration of MG-132 with flavopiridol resulted in diminished DNA binding of NF- κ B. Notably, pharmacologic interruption of the NF- κ B pathway (e.g., by BAY 11-7082, PDTC, or SN-50) or molecular dysregulation of NF- κ B (i.e., in cells ectopically expressing an I κ B α super-repressor) mimicked the actions of proteasome inhibitors in promoting flavopiridol-induced mitochondrial injury, JNK activation, and apoptosis. Together, these findings indicate that proteasome inhibitors strikingly lower the apoptotic threshold of leukemic cells exposed to pharmacologic CDK inhibitors, and suggest that interruption of the NF- κ B cytoprotective pathway and JNK activation both play key roles in this phenomenon. They also raise the possibility that combining proteasome and CDK inhibitors could represent a novel antileukemic strategy.
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the lethal effects of pharmacological cyclin Dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3 kinase akt Dependent Process
Cancer Research, 2003Co-Authors: Mohamed Rahmani, Yun Dai, Daniel H Conrad, Geoffrey W Krystal, Paul Dent, Steven GrantAbstract:ABSTRACT The impact of disruption of the PI3K (phosphatidylinositol 3-kinase)pathway on the response of human leukemia cells to pharmacologicalcyclin-Dependent kinase (CDK) inhibitors has been examined. Exposure ofU937 monocytic leukemia cells to minimally toxic concentrations of fla-vopiridol (FP), roscovitine, or CGP74514A for3hinconjunction with thePI3K inhibitor LY294002 (abbreviated LY in the article) resulted in amarked decrease in Akt phosphorylation. Coexposure of cells to LY andCDK inhibitors also resulted in an early (i.e., within 3 h) and strikingincrease in mitochondrial damage [e.g., cytochrome c, second mitochon-dria-derived activator of caspases/direct inhibitor of apoptosis (IAP)-binding protein with low isoelectric point (Smac/DIABLO), and apoptosis-initiating factor (AIF) release], caspase activation, and apoptosis. Similarinteractions were observed in a variety of other leukemia cell types (e.g.,HL-60, Jurkat, Raji, and NB4). Apoptosis, induced by FP/LY, was sub-stantially blocked by ectopic expression of Bcl-2, but to a considerablylesser extent by dominant-negative caspase-8. FP-induced apoptosis wasnot enhanced by agents that inhibited protein kinase (PK) A (H89), PKC(GFX), mitogen-activated protein (MAP)/extracellular signal-regulatedkinase (ERK) kinase (MEK1/2; U0126), p38 MAP kinase (MAPK;SB202190), m-target of rapamycin (TOR; rapamycin), or ataxia-telangi-ectasia mutation (ATM; caffeine), whereas the PI3K inhibitor wortman-nin exerted effects similar to those of LY. The dramatic potentiation ofCDK inhibitor-induced apoptosis by LY was accompanied by diminishedBad phosphorylation, induction of Bcl-2 cleavage, and down-regulation ofX-linked IAP (XIAP) and Mcl-1. Cells exposed to CDK inhibitors LYalso exhibited reduced phosphorylation of glycogen synthase kinase(GSK)-3, forkhead transcription factor (FKHR), p70
Theoharis C Theoharides - One of the best experts on this subject based on the ideXlab platform.
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corticotropin releasing hormone induces skin vascular permeability through a neurotensin Dependent Process
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: J Donelan, William Boucher, Nikoletta Papadopoulou, Michael Lytinas, Dean Papaliodis, Paul R Dobner, Theoharis C TheoharidesAbstract:Many skin disorders are associated with increased numbers of activated mast cells and are worsened by stress; however, the mechanism underlying these Processes is not understood. Corticotropin-releasing hormone (CRH) is secreted under stress from the hypothalamus, but also in the skin, where it induces mast cell activation and vascular permeability. We investigated the effect of CRH in a number of animal models by using i.v. Evans blue extravasation as a marker of vascular permeability. Intradermal CRH is among the most potent peptides at 100 nM, its effect being nearly comparable to that of neurotensin (NT). Pretreatment of skin injection sites with the NT receptor antagonist SR48692 blocks CRH-induced vascular permeability, which is diminished in NT−/− mice, implying that NT is necessary for the effect of CRH. CRH and NT precursor mRNA are shown to be expressed in both dorsal root ganglia and skin, whereas the latter also expresses mRNA for prohormone convertase 5, an enzyme that cleaves pro-NT into its active form. We also show that the effect of both CRH and NT is absent in W/Wv mast cell-deficient mice; however, only a fraction of skin mast cells express CRH receptors, as shown by FACS analysis of CRH receptor (CRHR) and c-kit double-positive disaggregated mouse skin mast cells. These findings suggest that CRH induces skin vascular permeability through NT acting on mast cells and that both peptides should be considered in the pathogenesis of skin disorders exacerbated by stress.
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A Neurotensin Receptor Antagonist Inhibits Acute Immobilization Stress-Induced Cardiac Mast Cell Degranulation, a Corticotropin-Releasing Hormone-Dependent Process
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Xinzhu Pang, Nicholas Alexacos, Dimitri Seretakis, William Boucher, David E. Cochrane, Richard Letourneau, Theoharis C TheoharidesAbstract:Stress worsens certain disorders such as migraines or asthma, and has also been implicated in sudden myocardial arrest. It was previously shown that acute psychological stress by immobilization results in dura mast cell degranulation, an effect blocked by pretreatment with antiserum against corticotropin-releasing hormone (CRH). Moreover, CRH was recently shown to induce skin mast cell degranulation. The effect of psychological stress was investigated on rat cardiac mast cells, because their release of coronary constrictive and proinflammatory molecules contributes to myocardial ischemia and possibly arrhythmias. Immobilization of rats for 30 min induced maximal cardiac mast cell degranulation as evidenced by light and electron microscopy. This effect was inhibited by pretreatment with the “antiallergic” drug sodium cromoglycate (cromolyn), which is thought to act primarily through mast cell stabilization. Mast cell degranulation was also blocked by preincubation with antiserum against CRH and was partially inhibited by a CRH type-1 receptor selective antagonist. Sensory neuropeptides did not appear to influence this effect, but a nonpeptide neurotensin receptor antagonist blocked stress-induced cardiac mast cell degranulation. This finding supports the involvement of neuropeptide neurotensin which is present in the heart and is known to trigger mast cell degranulation. These results indicate acute stress could result in local CRH and nonpeptide neurotensin release which could contribute to myocardial pathophysiology through direct or indirect release of cardiac mast cell mediators.