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Published: 9 March 2023

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1

Bam, Rakesh, Angela Pennisi, Xin Li, Sharmin Khan, Yuping Wang, Wen Ling, Bart Barlogie, John Shaughnessy, and Shmuel Yaccoby. "Bruton's Tyrosine Kinase (BTK) Is Indispensable for Myeloma Cell Migration towards SDF-1 and Induction of Osteoclastogenesis and Osteolytic Bone Disease." Blood 116, no. 21 (November 19, 2010): 447. http://dx.doi.org/10.1182/blood.v116.21.447.447.

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Abstract Abstract 447 Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase of the TEC family of protein tyrosine kinases, is preferentially expressed in the hematopoietic cells and involved in B-lymphocytes survival and differentiation, and their migration towards SDF-1 gradient. BTK is also expressed in osteoclast precursors and plays indispensable role in osteoclastogenesis (Shinohara et al., Cell 2008). LFM-A13 is small molecule inhibitor of BTK and TEC, and can be tolerated even when animals are given daily dose of 100 mg/kg. The aims of the study were to investigate the effect of LFM-A13 on myeloma cell migration and growth in vitro, and on myeloma bone disease and tumor growth in the SCID-rab model. Our clinical gene expression profiling data indicate that in contrast to most myeloma cell lines, primary myeloma cells express BTK and that relative to normal plasma cells, BTK expression is upregulated in myeloma cells molecularly classified in the CD-1, CD-2, HY, LB and MF subtypes. Expression of BTK at the RNA and proteins levels in myeloma cells and osteoclast precursors was validated using qRT-PCR and Western Blot. To test effect on migration, myeloma cells expressing BTK and cell surface CXCR4 (n=5) were placed in the top of transwell inserts in the absence and presence of LFM-A13 (50 μM) and their migration towards SDF-1 (30 nM) was evaluated after 18 hours. SDF-1 induced migration of myeloma cells by >2.5 folds, an effect that was markedly inhibited by LFM-A13 (p<0.01). At similar concentration, this agent modestly reduced growth of BTK-expressing myeloma cells by 20%, assessed by MTT assay. LFM-A13 dose dependently inhibited osteoclast formation by 25% at 10 μM (p<0.0005) and by 80% at 40 μM (p<0.0001). In vivo, SCID-rab mice engrafted with a novel myeloma cell line, DAS, established through sequential passaging in this animal model (Xin et al., BJH 2007). DAS cells do not grow in culture, are molecularly classified as MF subtype and express high level of BTK. Upon establishment of myeloma growth, 2 weeks after tumor cell injection, hosts were intraperitoneally treated with 40 mg/kg LFM-A13 or vehicle (10 mice/group) twice a day for 3 weeks. Myeloma bone disease was evaluated by x-rays and analysis of bone mineral density (BMD). Tumor growth was analyzed by measurement of circulating human Ig and histologically. Whereas in the control group BMD of the implanted bone was reduced by 15±4% from pretreatment levels, it remained unchanged (0.8±4% change from pretreatment level) in the LFM-A13 treated hosts (p<0.01 versus control). X-ray radiographs revealed induction of osteolytic lesions in implanted bones of control hosts and that LFM-A13 effectively prevented these effects. LFM-A13 reduced the number of TRAP-expressing osteoclasts in myelomatous bones by >43% (p<0.004). At the end of the experiment, tumor burden was insignificantly lower in hosts treated with the LFM-A13 (Ig levels 42±15 and 19±5 μg/ml in control and LFM-A13 groups, respectively). We conclude that BTK is indispensable for SDF-1-indcued myeloma cell migration and stimulation of osteoclastogenesis, and that pharmacologic inhibition of BTK effectively inhibits myeloma-induced bone resorption and may interrupt with myeloma cell homing and metastasis to bone. Disclosures: No relevant conflicts of interest to declare.
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2

Akker, E. van den, T. B. van Dijk, U. Schmidt, L. Felida, H. Beug, B. Löwenberg, and M. von Lindern. "The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity." Biological Chemistry 385, no. 5 (May 14, 2004): 409–13. http://dx.doi.org/10.1515/bc.2004.045.

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AbstractLFMA13, or α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide, was shown to inhibit Brutons tyrosine kinase (Btk). Here we show that LFM-A13 efficiently inhibits erythropoietin (Epo)-induced phosphorylation of the erythropoietin receptor, Janus kinase 2 (Jak2) and downstream signalling molecules. However, the tyrosine kinase activity of immunoprecipitated or in vitro translated Btk and Jak2 was equally inhibited by LFM-A13 in in vitro kinase assays. Finally, Epo-induced signal transduction was also inhibited in cells lacking Btk. Taken together, we conclude that LFM-A13 is a potent inhibitor of Jak2 and cannot be used as a specific tyrosine kinase inhibitor to study the role of Btk in Jak2-dependent cytokine signalling.
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3

Zhang, Wei, Ping Zhou, Xiao Jiang, Zhe Fan, Xingxin Xu, and Fei Wang. "Negative Regulation of Tec Kinase Alleviates LPS-Induced Acute Kidney Injury in Mice via theTLR4/NF-κB Signaling Pathway." BioMed Research International 2020 (June 20, 2020): 1–15. http://dx.doi.org/10.1155/2020/3152043.

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Tec kinase is an important mediator in inflammatory immune response that enhances the activity of neutrophils and macrophages. However, information on its function in lipopolysaccharide- (LPS-) induced acute kidney injury (AKI) is limited. This study is aimed at determining whether Tec kinase was a regulator in AKI. An AKI model in mice was successfully established using intraperitoneal LPS. Results showed that the serum levels of creatinine (Cr), blood urea nitrogen (BUN), and cystatin-C (Cys-C) increased after intraperitoneal LPS injection. Renal tissue sustained significantly severe injury as measured by pathological scores. Pretreatment with LFM-A13 improved the function of the kidney in mice and decreased the renal injury score. Enzyme-linked immunosorbent assay showed that LFM-A13 significantly reduced the release of IL-1β and TNF-α in mice exposed to LPS. LFM-A13 can evidently abrogate the expression of Tec protein, MyD88, TLR4, NF-κB p65, and Tec’s phosphorylated protein as determined by Western blot. Immunohistochemistry analysis revealed that LFM-A13 markedly downregulated the expression of Tec kinase in renal tubular epithelial cells. In vitro, Tec kinase protein was expressed highly in NRK-52E cells after LPS exposure. Tec-siRNA also decreased IL-1β and TNF-α production and obviously abolished phospho-p65 and phospho-IκBα expression in NRK-52E cell stimulated by LPS; however, Tec-siRNA increased the IκBα level. Altogether, these data suggested that Tec kinase can be a modulating protein in AKI through TLR4/NF-κB activation.
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4

Bam, Rakesh, Wen Ling, Sharmin Khan, Angela Pennisi, Sathisha Upparahalli Venkateshaiah, Xin Li, Ryan Williams, et al. "Cell Surface CXCR4 and BTK Expression Are Associated in Myeloma Cells and Osteoclast Precursors and Mediate Myeloma Cell Homing and Clonogenicity, and Osteoclastogenesis." Blood 118, no. 21 (November 18, 2011): 884. http://dx.doi.org/10.1182/blood.v118.21.884.884.

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Abstract Abstract 884 Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Clonal B-lymphocytes and plasma cells harboring lymphocytic phenotypes have a proposed role in sustaining myeloma. Bruton's tyrosine kinase (BTK) is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. The SDF-1/CXCR4 signaling pathway is reportedly involved in homing to bone of myeloma cells and osteoclast precursors. The aims of the study were to investigate the possible association between CXCR4 and BTK signaling in myeloma cells and osteoclast precursors, and the consequences of BTK inhibition on myeloma cell migration and clonogenicity, and osteoclastogenesis. By global gene expression profiling (GEP), BTK expression was moderately higher in clinical myeloma cells (n=559) than normal plasma cells (n=25, p<0.05). BTK was also detected in IL6–dependent cell lines and myeloma cell lines that can passage in vivo (n=7), using GEP, qRT-PCR and Western Blot analyses. Cell surface CXCR4 determined by flow cytometry was variably expressed in myeloma cells (5%–95%) and was significantly correlated with BTK gene expression (r=0.75, p<0.002, n=14). Most myeloma cell lines grown independently in vitro expressed very low levels of BTK; however, even in such cell lines (e.g. CAG), enrichment of myeloma cells expressing cell-surface CXCR4 by FACS analysis resulted in detectable BTK expression. BTK inhibition by shRNA in IL6–dependent INA6 cells inhibited their migration toward SDF-1 by >50% (p<0.006) and diminished their ability to form colonies in a 2-weeks clonogenic assay (p<0.0002). The BTK small molecule inhibitor LFM-A13 (25–50 μM) consistently reduced SDF-1-induced migration of primary myeloma cells and myeloma lines (n=6, p<0.03), and clonogenicity (colonies number and size) of 3 BTK-expressing myeloma lines by >50% (p<0.03). Using kinase immunoprecipitation assay, SDF-1 rapidly induced BTK phosphorylation (activation) in myeloma cells, an effect that was blocked by LFM-A13. In vivo, pretreatment of luciferase-expressing myeloma cells with LFM-A13 lessened their homing to bone following intravenous injection into SCID-rab mice as determined by live-animal imaging. BTK was highly expressed in osteoclast precursors while cell surface CXCR4 was detected in 5% of this cell population. LFM-A13 also reduced osteoclast precursor migration toward SDF-1 and suppressed osteoclast formation and bone resorption activity on dentine slices (p<0.002). In myeloma-bearing SCID-rab mice, LFM-A13 (n=10, 40 mg/kg, twice daily for 3 weeks, i.p.) reduced osteoclast number by 45% (p<0.004), prevented reduction of bone mineral density (BMD, p<0.04) and attenuated myeloma growth at near significant level (p<0.07). These data indicate that CXCR4 and BTK signaling are linked in myeloma cells and osteoclast precursors and that BTK has potential as a targeted myeloma therapy because of its roles in myeloma cell homing and clonogenicity and myeloma-induced osteolysis. Disclosures: Barlogie: Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties. Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties.
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5

Wang, Gaiqing, Zhenni Guo, Lusha Tong, Fang Xue, Paul R. Krafft, Enkhjargal Budbazar, John H. Zhang, and Jiping Tang. "TLR7 (Toll-Like Receptor 7) Facilitates Heme Scavenging Through the BTK (Bruton Tyrosine Kinase)–CRT (Calreticulin)–LRP1 (Low-Density Lipoprotein Receptor–Related Protein-1)–Hx (Hemopexin) Pathway in Murine Intracerebral Hemorrhage." Stroke 49, no. 12 (December 2018): 3020–29. http://dx.doi.org/10.1161/strokeaha.118.022155.

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Background and Purpose— Heme and iron are considered to be key factors responsible for secondary insults after intracerebral hemorrhage (ICH). Our previous study showed that LRP1 (low-density lipoprotein receptor–related protein-1)–Hx (hemopexin) facilitates removal of heme. The TLR7 (Toll-like receptor 7)–BTK (Bruton tyrosine kinase)–CRT (calreticulin) pathway regulates the expression of LRP1-Hx. This study is designed to clarify whether TLR7 activation facilitates heme scavenging and to establish the potential role of the BTK-CRT-LRP1-Hx signaling pathway in the pathophysiology of ICH. Methods— ICH was induced by stereotactic, intrastriatal injection of type VII collagenase. Mice received TLR7 agonist (imiquimod) via intraperitoneal injection after ICH induction. TLR7 inhibitor (ODN2088), BTK inhibitor (LFM-A13), and CRT agonist (thapsigargin) were given in different groups to further evaluate the underlying pathway. Mice were randomly divided into sham, ICH+vehicle (normal saline), ICH+Imiquimod (2.5, 5, and 10 μg/g), ICH+ODN2088, ICH+LFM-A13, ICH+thapsigargin, and ICH+ODN2088+thapsigargin. Imiquimod was administered twice daily starting at 6 hours after ICH; ODN2088 was administered by intracerebroventricular injection at 30 minutes, and LFM-A13 or thapsigargin was administered by intraperitoneal injection at 3 hours after ICH induction. Neurological scores, cognitive abilities, as well as brain edema, blood-brain barrier permeability, hemoglobin level, brain expression of TLR7/BTK/CRT/LRP1/Hx were analyzed. Results— Low dosage imiquimod significantly attenuated hematoma volume, brain edema, BBB permeability, and neurological deficits after ICH. Imiquimod also increased protein expressions of TLR7, BTK, CRT, LRP1, and Hx; ODN2088 reduced TLR7, BTK, CRT, LRP1, and Hx expressions. Conclusions— TLR7 plays an important role in heme scavenging after ICH by modulating the BTK-CRT-LRP1-Hx pathway. TLR7 may offer protective effects by promoting heme resolution and reduction of brain edema after ICH.
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6

Vijayan, Vijith, Eveline Baumgart-Vogt, Srivatsava Naidu, Guofeng Qian, and Stephan Immenschuh. "Bruton's Tyrosine Kinase and Nrf2 mediate TLR-induced activation of Heme oxygenase-1 gene expression in macrophages (116.16)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 116.16. http://dx.doi.org/10.4049/jimmunol.186.supp.116.16.

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Abstract The inducible isoform of heme oxygenase (HO)-1, is involved in heme degradation producing CO and biliverdin, mediating cytoprotection against oxidative stress. Recently, HO-1 has been shown to evoke potent anti-inflammatory and immunomodulatory effects in macrophages. Here we demonstrate that Bruton's tyrosine kinase (Btk), the gene of which is mutated in human immunodeficiency X-linked agammaglobulinemia, is involved in toll-like receptor (TLR)-induced gene expression of HO-1 in macrophages. The Btk inhibitor LFM-A13 blocked the induction of HO-1 by LPS (TLR4 ligand) in RAW264.7 macrophages and primary mouse alveolar macrophages. Furthermore, LPS-stimulated up-regulation of HO-1 gene expression was abrogated in alveolar macrophages from Btk-/- mice. In addition, inhibition of Btk with LFM-A13 attenuated the LPS-induced luciferase activity of the HO-1 promoter in transfection studies in RAW264.7 cells. This effect was mediated by the transcription factor Nrf2, which is a master regulator of the cellular antioxidant defense. Immunofluorescence studies revealed that the nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. Moreover, the generation of reactive oxygen species (ROS), but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression via Nrf2 was also observed upon stimulation by TLR7 and TLR9 ligands, suggesting Btk to be generally involved in TLR-mediated HO-1 gene activation.
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7

Tankiewicz-Kwedlo, Anna, Justyna Magdalena Hermanowicz, Tomasz Domaniewski, Krystyna Pawlak, Małgorzata Rusak, Anna Pryczynicz, Arkadiusz Surazynski, Tomasz Kaminski, Adam Kazberuk, and Dariusz Pawlak. "Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer." British Journal of Pharmacology 175, no. 5 (January 25, 2018): 743–62. http://dx.doi.org/10.1111/bph.14099.

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8

Uckun, Fatih M. "Chemosensitizing Anti-Cancer Activity of LFM-A13, a Leflunomide Metabolite Analog Targeting Polo-like Kinases." Cell Cycle 6, no. 24 (December 15, 2007): 3021–26. http://dx.doi.org/10.4161/cc.6.24.5096.

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9

Hermanowicz, J. M., A. Tankiewicz-Kwedlo, A. Surażyński, K. Pawlak, and D. A. Pawlak. "Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer." Annals of Oncology 29 (March 2018): iii17. http://dx.doi.org/10.1093/annonc/mdy047.030.

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10

Uckun, Fatih M., Ilker Dibirdik, Sanjive Qazi, Alexei Vassilev, Hong Ma, Chen Mao, Alexey Benyumov, and Katayoon H. Emami. "Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK)." Bioorganic & Medicinal Chemistry 15, no. 2 (January 2007): 800–814. http://dx.doi.org/10.1016/j.bmc.2006.10.050.

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11

Tibbles, Heather, Peter Samuel, Doug Erbeck, Sandeep Mahajan, and Fatih Uckun. "In vivo Toxicity and Antithrombotic Profile of the Oral Formulation of the Antileukemic Agent, LFM-A13-F." Arzneimittelforschung 54, no. 06 (December 25, 2011): 330–39. http://dx.doi.org/10.1055/s-0031-1296980.

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Tankiewicz-Kwedlo, Anna, Justyna Hermanowicz, Krystyna Pawlak, Robert Czarnomysy, Krzysztof Bielawski, Izabela Prokop, and Dariusz Pawlak. "Erythropoietin Intensifies the Proapoptotic Activity of LFM-A13 in Cells and in a Mouse Model of Colorectal Cancer." International Journal of Molecular Sciences 19, no. 4 (April 23, 2018): 1262. http://dx.doi.org/10.3390/ijms19041262.

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13

Rozkiewicz, Dariusz, Justyna Magdalena Hermanowicz, Anna Tankiewicz-Kwedlo, Beata Sieklucka, Krystyna Pawlak, Robert Czarnomysy, Krzysztof Bielawski, et al. "The intensification of anticancer activity of LFM-A13 by erythropoietin as a possible option for inhibition of breast cancer." Journal of Enzyme Inhibition and Medicinal Chemistry 35, no. 1 (January 1, 2020): 1697–711. http://dx.doi.org/10.1080/14756366.2020.1818738.

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Wang, Fei, Wei Zhang, Chao Wang, Xu Fang, Hao Cheng, Sheng Liu, and Xu-Lin Chen. "Inhibitor of Tec kinase, LFM-A13, decreases pro-inflammatory mediators production in LPS-stimulated RAW264.7 macrophages via NF-κB pathway." Oncotarget 8, no. 21 (March 15, 2017): 34099–110. http://dx.doi.org/10.18632/oncotarget.16212.

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15

Chu, Charles C., Lu Zhang, Xiaoxuan Cui, Amanda R. Magli, Xiao-Jie Yan, Jonathan E. Kolitz, Steven L. Allen, Jacqueline C. Barrientos, Kanti R. Rai, and Nicholas Chiorazzi. "CLL Cell Viability Promoted by Myosin Heavy Chain IIA Exposed Apoptotic Cells is BTK-dependent." Blood 120, no. 21 (November 16, 2012): 1767. http://dx.doi.org/10.1182/blood.v120.21.1767.1767.

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Abstract Abstract 1767 B-cell chronic lymphocytic leukemia (CLL) is a clonal CD5+CD19+ B-lymphocyte cancer with a B cell receptor (BCR) immunoglobulin heavy chain variable (IGHV) gene sequence that may be classified as unmutated (U-CLL) or mutated (M-CLL) depending on the level of IGHV mutation. Because U-CLL patients have a worse clinical prognosis than M-CLL patients, the structure of the BCR and the signaling consequences of BCR occupancy by antigen are considered crucial to disease development and possibly progression. Moreover, nearly one third of CLL patients express a CLL BCR that is virtually identical in sequence (stereotyped) to other CLL patient subgroups, an incidence that is extraordinarily unlikely by random chance, suggesting that common antigens could bind to these CLL BCRs and initiate signaling. Apoptotic autoantigens may be a source of such antigens. Indeed, CLL BCRs expressed as native or recombinant monoclonal antibodies (mAbs) can recognize autoantigens, such as nonmuscle myosin heavy chain IIA (myosin), actin, vimentin, cofilin-1, filamin B, insulin, DNA, IgG, myoglobin, thyroglobulin, cardiolipin, and oxidized low-density lipoprotein. These molecules are generally intracellular and may be exposed on the cell surface during apoptosis, permitting binding to CLL BCRs. Indeed, intracellular myosin is exposed on the surface of a subset of apoptotic cells, termed MEACs (myosin exposed apoptotic cells). Furthermore, MEACs bind to over 60% of CLL mAbs tested, supporting the idea that multiple autoantigens exposed on MEACs may stimulate CLL cells. This binding may furnish signals beneficial to the leukemic cell, because MEAC binding correlates with shorter patient survival. To test this hypothesis, the effect of MEAC binding on spontaneous CLL cell apoptosis was tested after co-culture of CLL peripheral blood mononuclear cells from a large patient cohort with MEACs (3:1–5:1 ratio) for 2–4 days using flow cytometry and AnnexinV and 7-actinomycin D staining to measure apoptosis in CD19+CD3− cells. A typical wide range of spontaneous apoptosis was observed (median = 26.98% (5.93%–91.35%) AnnexinV+). In this large patient cohort (n=64, with some patient samples tested 2–8 times), co-culture of CLL cells with MEACs resulted in a decrease in apoptosis in all patient samples as compared to cultures without MEACs (median = 18.58% (2.49%–76.35%) AnnexinV+), a highly significant result (P=0.0001, two-tailed paired t-test). In this cohort, U-CLL patients (n=23) had a slightly higher median decrease in apoptosis (30.39%) than M-CLL patients (n=33, 22.69%), but this was not significant (P=0.3940, two-tailed unpaired t-test with Welch's correction). Furthermore, no apparent correlation between MEAC co-culture responsiveness and in vitro MEAC binding was observed in the 9 CLL patient samples exhibiting stereotyped CLL BCR. Finding that MEAC co-culture affects all CLL cells regardless of IGHV mutation status or stereotypy contrasts with MEAC binding to CLL mAbs in vitro, for which there is a marked preference for U-CLL and stereotyped mAbs. One possible explanation for the conflicting result is that CLL cells with BCRs that do not bind MEACs well receive an additional non-Ig receptor signal that boosts the BCR signal to make it near equivalent to the signal from BCRs on cells that bind MEACs well. In this model, inhibition of BCR signaling would abrogate the decrease in apoptosis produced by MEAC co-culture in all CLL cases. To test this, Bruton tyrosine kinase (BTK) inhibitors, ibrutinib or LFM-A13, were added to these co-cultures (n=12 and 18, respectively). Both inhibitors significantly abrogated the MEAC co-culture increase in viability (ibrutinib, P=0.0005; LFM-A13, P=0.0007; two-tailed paired t-test). Ibrutinib and LFM-A13 inhibited all samples regardless of IGHV mutation status (stereotyped BCR samples were not tested). In conclusion, these results are consistent with the theory that antigenic stimulation of CLL cells via the BCR promotes CLL cell viability and may influence the level of disease activity. MEACs may be a source of such antigenic stimulation. Interference with BCR signaling via BTK inhibition prevents this stimulation and may be one of the explanations for the clinical success of BCR signaling inhibitors in treating CLL. Disclosures: Barrientos: Gilead and Pharmacyclics: Research Funding.
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16

Redondo, Pedro C., Matthew T. Harper, Juan A. Rosado, and Stewart O. Sage. "A role for cofilin in the activation of store-operated calcium entry by de novo conformational coupling in human platelets." Blood 107, no. 3 (February 1, 2006): 973–79. http://dx.doi.org/10.1182/blood-2005-05-2015.

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AbstractStore-operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ influx in platelets and other cells. De novo conformational coupling between elements in the plasma membrane and Ca2+ stores, where the actin cytoskeleton plays an important regulatory role, has been proposed as the most likely mechanism to activate SOCE in platelets. Here we have examined for the first time changes in platelet F-actin levels on a subsecond time scale. Using stopped-flow fluorimetry and a quenched-flow approach, we provide evidence for the involvement of cofilin in actin filament reorganization and SOCE in platelets. Thrombin (0.1 U/mL) evoked an initial decrease in F-actin that commenced within 0.1 second and reached a minimum 0.9 second after stimulation, prior to the activation of SOCE. F-actin then increased, exceeding basal levels approximately 2.5 seconds after stimulation. Thrombin also induced cofilin dephosphorylation and activation, which paralleled the changes observed in F-actin, and rapid Btk activation. Inhibition of cofilin dephosphorylation by LFM-A13 resulted in the loss of net actin depolymerization and an increased delay in SOCE initiation. These results suggest that cofilin is important for the rapid actin remodeling necessary for the activation of SOCE in platelets through de novo conformational coupling.
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Gilbert, Caroline, Sylvain Levasseur, Philippe Desaulniers, Andrée-Anne Dusseault, Nathalie Thibault, Sylvain G. Bourgoin, and Paul H. Naccache. "Chemotactic Factor-Induced Recruitment and Activation of Tec Family Kinases in Human Neutrophils. II. Effects of LFM-A13, a Specific Btk Inhibitor." Journal of Immunology 170, no. 10 (May 15, 2003): 5235–43. http://dx.doi.org/10.4049/jimmunol.170.10.5235.

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18

Uckun, Fatih M., Alexei Vassilev, Steve Bartell, Yaguo Zheng, Sandeep Mahajan, and Heather E. Tibbles. "The Anti-leukemic Bruton's Tyrosine Kinase Inhibitor α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl) Propenamide (LFM-A13) Prevents Fatal Thromboembolism." Leukemia & Lymphoma 44, no. 9 (January 1, 2003): 1569–77. http://dx.doi.org/10.1080/1042819031000097447.

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19

Uckun, Fatih M., Alexei Vassilev, Steve Bartell, Yaguo Zheng, Sandeep Mahajan, and Heather E. Tibbles. "The Anti-leukemic Bruto n's Tyrosine Kinase Inhibitor α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl) Propenamide (LFM-A13) Prevents Fatal Thromboembolism." Leukemia & Lymphoma 44, no. 9 (January 2003): 1569–77. http://dx.doi.org/10.3109/10428190309178781.

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20

Bouaziz, Aicha, Nidhal Ben Amor, Geoffrey Woodard, Hanen Zibidi, José López, Ahgleb Bartegi, Ginés Salido, and Juan Rosado. "Tyrosine phosphorylation / dephosphorylation balance is involved in thrombin-evoked microtubular reorganisation in human platelets." Thrombosis and Haemostasis 98, no. 08 (2007): 375–84. http://dx.doi.org/10.1160/th07-01-0061.

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SummaryWe have investigated the intracellular mechanisms involved in microtubular remodelling by thrombin and its possible involvement in platelet aggregation and secretion. Platelet stimulation with thrombin induces a time- and concentration-dependent regulation of the microtubular content, which was found to be maximally effective at the concentration 0.1 U/ml. Thrombin (0.1 U/ml) evoked an initial decrease in the microtubule content detectable at 5 seconds (sec) and reached a minimum 10 sec after stimulation.The microtubular content then increased, exceeding basal levels again approximately 30 sec after stimulation. Inhibition of tyrosine phosphatases using vanadate abolished thrombin-induced microtubular depolymerisation while inhibition of tyrosine kinases by methyl-2,5-dihydroxycinnamate prevented microtubule polymerisation.Thrombin activates the cytosolic Brutons tyrosine kinase (Btk) and Src proteins. Inhibition of Btk or Src by LFM-A13 or PP1, respectively, abolished thrombin-induced microtubular polymerisation, while maintaining intact its ability to induce initial depolymerisation. Microtubular disruption by colchicine significantly reduced thrombin induced platelet aggregation and ATP secretion. Similar results were observed after inhibition of microtubular disassembly by paclitaxel.These findings indicate that thrombin induces microtubular remodelling by modifying the balance between protein tyrosine phosphorylation and dephosphorylation. The former seems to be required for microtubular polymerisation, while tyrosine dephosphorylation is required for microtubular depolymerisation. Both, initial microtubular disassembly and subsequent polymerisation are required for thrombin-induced platelet aggregation and secretion in human platelets.
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DuMez, Darin, Taracad Venkatachalam, and Fatih Uckun. "Large-scale Synthesis of GMP Grade α-Cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13), a New Anti-cancer Drug Candidate." Arzneimittelforschung 57, no. 03 (December 21, 2011): 155–63. http://dx.doi.org/10.1055/s-0031-1296599.

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22

Sahin, Kazim, Mehmet Tuzcu, Mehmet Yabas, Cemal Orhan, Nurhan Sahin, and Ibrahim H. Ozercan. "LFM-A13, a potent inhibitor of polo-like kinase, inhibits breast carcinogenesis by suppressing proliferation activity and inducing apoptosis in breast tumors of mice." Investigational New Drugs 36, no. 3 (November 15, 2017): 388–95. http://dx.doi.org/10.1007/s10637-017-0540-2.

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23

Uckun, Fatih, Heather Tibbies, Taracad Venkatachalam, Darin DuMez, and Douglas Erbeck. "Preclinical Toxicity and Pharmacokinetics of the Bruton's Tyrosine Kinase-Targeting Anti-leukemic Drug Candidate, α-Cyano-β-Hydroxy-β-Methyl-N-(2,5-Dibromophenyl) Propenamide (LFM-A13)." Arzneimittelforschung 57, no. 01 (December 21, 2011): 31–46. http://dx.doi.org/10.1055/s-0031-1296583.

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24

Susaki, Kentaro, Akira Kitanaka, Hiroaki Dobashi, Katsuharu Kittaka, Hiroyuki Mano, Yoshitsugu Kubota, and Terukazu Tanaka. "Tec Kinase Inhibits the Expression of IL-2 Receptor Alpha (CD25) in Human T-Lymphocyte." Blood 112, no. 11 (November 16, 2008): 1545. http://dx.doi.org/10.1182/blood.v112.11.1545.1545.

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Abstract Activation and development of lymphocytes is regulated by the engagement of cell surface immune cell antigen receptors. Following receptor engagement, these receptors transmit signals by the activation of cytoplasmic protein tyrosine kinases (PTKs). The Tec PTK belongs to a group of structurally related nonreceptor PTKs that also includes Btk, Itk (Emt), Rlk (Txk), and Bmx (Etk). We have found the contribution of Tec in the antigen receptor signaling in B-lymphoid cells in the previous studies. Despite the presence of evidences suggesting the involvement of Tec in T-lymphocyte activation pathway via T-cell receptor (TCR) and CD28, the role of Tec in T-lymphocyte still remains unclear because of the lack of apparent defects in T-lymphocyte function in Tec-deficient mice. In this study, we investigated the role of Tec in T-lymphocyte using Jurkat human T-lymphoid cell line stably transfected with a cDNA encoding Tec. We found that the expression of wild type Tec but not kinase-deleted Tec inhibited the expression of IL-2 receptor alpha (CD25) induced by TCR cross-linking. The percentage of CD25 expressing cells after TCR cross-linking was 41.7% in mock-transfected cells, 18.3% in the wild type Tec expressing cells and 41.3% in the kinase-deleted Tec expressing cells. Second, the selective inhibitor of Tec family PTK, LFM-A13, rescued the suppression of TCR-induced CD25 expression observed in the wild type Tec-expressing Jurkat cells. We conclude that Tec PTK mediates signals that negatively regulate CD25 expression induced by TCR cross-linking, implying that this PTK plays a role in the attenuation of the IL-2 activity in human T-lymphocytes.
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Uckun, Fatih, Ilker Dibirdik, Aniee Sarkissian, and Sanjive Qazi. "In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors." Arzneimittelforschung 61, no. 04 (November 27, 2011): 252–59. http://dx.doi.org/10.1055/s-0031-1296196.

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26

Mahajan, Sandeep, Sutapa Ghosh, Elise A. Sudbeck, Yaguo Zheng, Suzanne Downs, Michael Hupke, and Fatih M. Uckun. "Rational Design and Synthesis of a Novel Anti-leukemic Agent Targeting Bruton′s Tyrosine Kinase (BTK), LFM-A13 [α-Cyano-β-Hydroxy-β-Methyl-N-(2,5-Dibromophenyl)Propenamide]." Journal of Biological Chemistry 274, no. 14 (April 2, 1999): 9587–99. http://dx.doi.org/10.1074/jbc.274.14.9587.

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27

Chau, Cindy H., Carlos A. Clavijo, Hong-Tao Deng, Qunzhou Zhang, Kwang-Jin Kim, Yun Qiu, Anh D. Le, and David K. Ann. "Etk/Bmx mediates expression of stress-induced adaptive genes VEGF, PAI-1, and iNOS via multiple signaling cascades in different cell systems." American Journal of Physiology-Cell Physiology 289, no. 2 (August 2005): C444—C454. http://dx.doi.org/10.1152/ajpcell.00410.2004.

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We recently showed that Etk/Bmx, a member of the Tec family of nonreceptor protein tyrosine kinases, promotes tight junction formation during chronic hypoxic exposure and augments normoxic VEGF expression via a feedforward mechanism. Here we further characterized Etk's role in potentiating hypoxia-induced gene expression in salivary epithelial Pa-4 cells. Using transient transfection in conditionally activated Etk (ΔEtk:ER) cells, we demonstrated that Etk enhances hypoxia-response element-dependent reporter activation in normoxia and hypoxia. This Etk-driven reporter activation is ameliorated by treatment with wortmannin or LFM-A13. Using lentivirus-mediated gene delivery and small interfering RNA, we provided direct evidence that hypoxia leads to transient Etk and Akt activation and hypoxia-mediated Akt activation is Etk dependent. Northern blot analyses confirmed that Etk activation led to induction of steady-state mRNA levels of endogenous VEGF and plasminogen activator inhibitor (PAI)-1, a hallmark of hypoxia-mediated gene regulation. We also demonstrated that Etk utilizes a phosphatidylinositol 3-kinase/Akt pathway to promote reporter activation driven by NF-κB, another oxygen-sensitive transcription factor, and to augment cytokine-induced inducible nitric oxide synthase expression in endothelial cells. To establish the clinical relevance of Etk-induced, hypoxia-mediated gene regulation, we examined Etk expression in keloid, which has elevated VEGF and PAI-1. We found that Etk is overexpressed in keloid (but not normal skin) tissues. The differential steady-state Etk protein levels were further confirmed in primary fibroblast cultures derived from these tissues, suggesting an Etk role in tissue fibrosis. Our results provide further understanding of Etk function within multiple signaling cascades to govern adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts.
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Wan, Jia, Xi Yu, Jia-Qi Niu, Le Qiu, Fei Wang, and Xu-Lin Chen. "Inhibition of Bruton's Tyrosine Kinase Protects Against Burn Sepsis-Induced Intestinal Injury." Frontiers in Medicine 9 (February 24, 2022). http://dx.doi.org/10.3389/fmed.2022.809289.

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This study aimed to investigate the role and molecular mechanisms of Bruton's tyrosine kinase (BTK), a member of the Tec family in burn sepsis-induced intestinal injury. Eighty C57BL/6 mice were randomly divided into four groups: the sham group, the burn group, the burn + sepsis group, and the burn + sepsis + LFM-A13 (a selective BTK inhibitor) group. The dynamic expression profiles of BTK and p-BTK in the intestine were measured by Western blot analysis. Intestinal histopathological changes and cellular apoptosis were determined. Inflammatory cytokines in serum and intestinal tissue were examined through enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity was determined via a colorimetric assay. Intestinal p-BTK expression in the burn+sepsis group was significantly increased compared with that in the sham and burn groups. In the burn + sepsis group, the p-BTK expression level increased over time, peaked at 12, and then decreased at 24 h. LFM-A13 administration significantly inhibited p-BTK expression in the intestine. In contrast to the sham and burn groups, the burn + sepsis group exhibited obvious histopathological changes, which gradually aggravated over time. LFM-A13 also reduced the histopathological changes and cellular apoptosis in intestinal tissues, inhibited the inflammatory cytokines IL-4, IL-6, and TNF-α in serum and intestinal tissues, and significantly inhibited the increase in intestinal MPO activity induced by burn sepsis. BTK activation is one important aspect of the signaling event that may mediate the release of the anti-inflammatory cytokine IL-4 and the pro-inflammatory cytokines IL-6 and TNF-α; oxidative stress; and intestinal cell apoptosis. Thus, it contributes to burn sepsis-induced intestinal injury.
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Ghosh, Simantini, Zaidan Mohammed, and Itender Singh. "Bruton’s tyrosine kinase drives neuroinflammation and anxiogenic behavior in mouse models of stress." Journal of Neuroinflammation 18, no. 1 (December 2021). http://dx.doi.org/10.1186/s12974-021-02322-9.

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Abstract Background Current therapies targeting several neurotransmitter systems are only able to partially mitigate the symptoms of stress- and trauma-related disorder. Stress and trauma-related disorders lead to a prominent inflammatory response in humans, and in pre-clinical models. However, mechanisms underlying the induction of neuroinflammatory response in PTSD and anxiety disorders are not clearly understood. The present study investigated the mechanism underlying the activation of proinflammatory NLRP3 inflammasome and IL1β in mouse models of stress. Methods We used two mouse models of stress, i.e., mice subjected to physical restraint stress with brief underwater submersion, and predator odor stress. Mice were injected with MCC950, a small molecule specific inhibitor of NLRP3 activation. To pharmacologically inhibit BTK, a specific inhibitor ibrutinib was used. To validate the observation from ibrutinib studies, a separate group of mice was injected with another BTK-specific inhibitor LFM-A13. Seven days after the induction of stress, mice were examined for anxious behavior using open field test (OFT), light–dark test (LDT), and elevated plus maze test (EPM). Following the behavior tests, hippocampus and amygdale were extracted and analyzed for various components of NLRP3–caspase 1–IL1β pathway. Plasma and peripheral blood mononuclear cells were also used to assess the induction of NLRP3–Caspase 1–IL-1β pathway in stressed mice. Results Using two different pre-clinical models of stress, we demonstrate heightened anxious behavior in female mice as compared to their male counterparts. Stressed animals exhibited upregulation of proinflammatory IL1β, IL-6, Caspase 1 activity and NLRP3 inflammasome activation in brain, which were significantly higher in female mice. Pharmacological inhibition of NLRP3 inflammasome activation led to anxiolysis as well as attenuated neuroinflammatory response. Further, we observed induction of activated Bruton’s tyrosine kinase (BTK), an upstream positive-regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with ibrutinib and LFM-A13. In both sets of experiments, we found BTK inhibition led to anxiolysis and attenuated neuroinflammation, as indicated by significant reduction of NLRP3 inflammasome and proinflammatory IL-1β in hippocampus and amygdala. Analysis of plasma and peripheral blood mononuclear cells indicated peripheral induction of NLRP3–caspase 1–IL1β pathway in stressed mice. Conclusion Our study identified BTK as a key upstream regulator of neuroinflammation, which drives anxiogenic behavior in mouse model of stress. Further, we demonstrated the sexually divergent activation of BTK, providing a clue to heightened neuroinflammation and anxiogenic response to stress in females as compared to their male counterparts. Our data from the pharmacological inhibition studies suggest BTK as a novel target for the development of potential clinical treatment of PTSD and anxiety disorders. Induction of pBTK and NLRP3 in peripheral blood mononuclear cells of stressed mice suggest the potential effect of stress on systemic inflammation.
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DuMez, Darin, Taracad K. Venkatachalam, and Fatih M. Uckun. "Large-Scale Synthesis of GMP Grade α-Cyano-β-hydroxy-β-methyl-N- (2,5-dibromophenyl)propenamide (LFM-A13), a New Anticancer Drug Candidate." ChemInform 38, no. 30 (July 24, 2007). http://dx.doi.org/10.1002/chin.200730051.

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