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Signal Transduction Inhibitors (signal + transduction_inhibitor)
Selected AbstractsChronic myelogenous leukaemia , new therapeutic principlesJOURNAL OF INTERNAL MEDICINE, Issue 1 2001Michael E. O'Dwyer O'Dwyer ME, Druker BJ (Oregon Health Sciences University, Portland, USA). Chronic myelogenous leukaemia , new therapeutic principles. J. Intern Med 2001; 250: 3,9 The deregulated tyrosine kinase activity of the BCR-ABL fusion protein is the cause of malignant transformation in almost all cases of chronic myelogenous leukaemia (CML), making BCR-ABL an ideal target for pharmacological inhibition. Signal transduction inhibitor (STI571) (formerly CGP57 148B), is an ABL specific, tyrosine kinase inhibitor. In preclinical studies, it has been shown to selectively kill BCR-ABL expressing cells, both in-vitro and in vivo. The results of clinical studies to date are highly encourageing and STI571 promises to be an important addition to the therapy of CML. [source] Tumor necrosis factor-alpha (TNF-,) regulates Toll-like receptor 2 (TLR2) expression in microgliaJOURNAL OF NEUROCHEMISTRY, Issue 4 2007Mohsin Md. Abstract Microglia represent one effector arm of CNS innate immunity as evident by their role in pathogen recognition. We previously reported that exposure of microglia to Staphylococcus aureus (S. aureus), a prevalent CNS pathogen, led to elevated Toll-like receptor 2 (TLR2) expression, a pattern recognition receptor capable of recognizing conserved structural motifs associated with gram-positive bacteria such as S. aureus. In this study, we demonstrate that the proinflammatory cytokine tumor necrosis factor-, (TNF-,) enhances TLR2 expression in microglia, whereas interleukin-1, has no significant effect. To determine the downstream signaling events responsible for elevated microglial TLR2 expression in response to TNF-,, a series of signal transduction inhibitors were employed. Treatment with caffeic acid phenethyl ester, an inhibitor of redox-mediated nuclear factor-kappa B activation, significantly attenuated TNF-,-induced TLR2 expression. Similar results were observed with the IKK-2 and I,B-, inhibitors SC-514 and BAY 11-7082, respectively. In contrast, no significant alterations in TLR2 expression were observed with protein kinase C or p38 mitogen-activated protein kinase inhibitors. A definitive role for TNF-, was demonstrated by the inability of S. aureus to augment TLR2 expression in microglia isolated from TNF-, knockout mice. In addition, TLR2 expression was significantly attenuated in brain abscesses of TNF-, knockout mice. Collectively, these results indicate that in response to S. aureus, TNF-, acts in an autocrine/paracrine manner to enhance TLR2 expression in microglia and that this effect is mediated, in part, by activation of the nuclear factor-kappa B pathway. [source] CC Chemokine ligand 17 in periodontal diseases: expression in diseased tissues and production by human gingival fibroblastsJOURNAL OF PERIODONTAL RESEARCH, Issue 4 2008Y. Hosokawa Background and Objective:, It has been reported that T helper 2 (Th2) cells are related to exacerbation of periodontal disease. However, it is uncertain how the migration of Th2 cells is controlled. In this study, we examined the expression of CC chemokine ligand 17 (CCL17), which is a Th2 chemokine, in periodontal tissues. Moreover, we investigated the effects of cytokines and toll-like receptor (TLR) ligands on the production of CCL17 by human gingival fibroblasts (HGFs). Material and Methods:, We used immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) to detect CCL17 in periodontal tissues. HGFs were exposed to cytokines and TLR ligands. Expression of CCL17 was examined by RT-PCR and enzyme-linked immunosorbent assay. We used signal transduction inhibitors in some experiments. Results:, Both CCL17 and its receptor, CC chemokine receptor 4 (CCR4), were expressed in diseased periodontal tissues. A combination of tumour necrosis factor , (TNF-,) and interleukin (IL)-4/IL-13 increased CCL17 expression. Moreover, treatment of HGFs with a low dose of interferon-, (IFN-,) in combination with TNF-, and IL-4 or IL-13 had synergistic effects on the production of CCL17, whereas a high dose of IFN-, inhibited CCL17 production. Furthermore, Escherichia coli (E. coli) lipopolysaccharide (TLR4 ligand) and Pam3CSK4 (TLR2 ligand) inhibited CCL17 production by TNF-, + IL-4-stimulated HGFs, while CpG DNA (TLR9 ligand) enhanced TNF-, + IL-4 induced-CCL17 production by HGFs. Furthermore, a c-Jun NH2 terminal kinase (JNK) inhibitor, a phosphatidylinositol-3-kinase (PI3K) inhibitor and a nuclear factor ,B (NF-,B) inhibitor inhibited CCL17 production by HGFs. Conclusion:, These results suggest that the CCL17 produced by HGFs may be involved in the migration of Th2 cells into inflamed tissues, and provide evidence that CCL17 production is controlled by cytokines and TLR ligands in periodontal disease. [source] Macrophage Stimulating Protein (MSP) evokes superoxide anion production by human macrophages of different originBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2001Sandra Brunelleschi Macrophage Stimulating Protein (MSP), a serum factor related to Hepatocyte Growth Factor, was originally discovered to stimulate chemotaxis of murine resident peritoneal macrophages. MSP is the ligand for Ron, a member of the Met subfamily of tyrosine kinase receptors. The effects of MSP on human macrophages and the role played in human pathophysiology have long been elusive. We show here that human recombinant MSP (hrMSP) evokes a dose-dependent superoxide anion production in human alveolar and peritoneal macrophages as well as in monocyte-derived macrophages, but not in circulating human monocytes. Consistently, the mature Ron protein is expressed by the MSP responsive cells but not by the unresponsive monocytes. The respiratory burst evoked by hrMSP is quantitatively higher than the one induced by N-formylmethionyl-leucyl-phenylalanine and similar to phorbol myristate acetate-evoked one. To investigate the mechanisms involved in NADPH oxidase activation, leading to superoxide anion production, different signal transduction inhibitors were used. By using the non selective tyrosine kinase inhibitor genistein, the selective c-Src inhibitor PP1, the tyrosine phosphatase inhibitor sodium orthovanadate, the phosphatidylinositol 3-kinase inhibitor wortmannin, the p38 inhibitor SB203580, the MEK inhibitor PD098059, we demonstrate that hrMSP-evoked superoxide production is mediated by tyrosine kinase activity, requires the activation of Src but not of PI 3-kinase. We also show that MAP kinase and p38 signalling pathways are involved. These results clearly indicate that hrMSP induces the respiratory burst in human macrophages but not in monocytes, suggesting for the MSP/Ron complex a role of activator as well as of possible marker for human mature macrophages. British Journal of Pharmacology (2001) 134, 1285,1295; doi:10.1038/sj.bjp.0704356 [source] Enhancing endocrine response with novel targeted therapies,CANCER, Issue S3 2008Why have the clinical trials to date failed to deliver on the preclinical promise? Abstract Acquired resistance to endocrine therapies has severely limited their long-term effectiveness in breast cancer. In recent years a clear rationale has developed for combining signal transduction inhibitors (STIs) with endocrine therapies to delay the emergence of acquired resistance and enhance endocrine responsiveness. A variety of biologic agents have been developed to target key proteins along the EGFR, HER2, MAPK, and P13K/Akt signal transduction cascades. While several of these agents have shown early promise in selected breast cancer models, translating these data into convincing clinical results has been generally disappointing to date. By applying more rigorous trial design and tumor selection criteria to future trials, it is much more likely that adding the new generation of targeted therapies can fulfill its promise in enhancing endocrine responsiveness and our ability to treat breast cancer patients. Cancer 2008. © 2007 American Cancer Society. [source] | ||||||||||