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https://www.readbyqxmd.com/read/28644734/high-throughput-phenotypic-screening-of-kinase-inhibitors-to-identify-drug-targets-for-polycystic-kidney-disease
#1
Tijmen H Booij, Hester Bange, Wouter N Leonhard, Kuan Yan, Michiel Fokkelman, Steven J Kunnen, Johannes G Dauwerse, Yu Qin, Bob van de Water, Gerard J P van Westen, Dorien J M Peters, Leo S Price
Polycystic kidney disease (PKD) is a prevalent disorder characterized by renal cysts that lead to kidney failure. Various signaling pathways have been targeted to stop disease progression, but most interventions still focus on alleviating PKD-associated symptoms. The mechanistic complexity of the disease, as well as the lack of functional in vitro assays for compound testing, has made drug discovery for PKD challenging. To identify modulators of PKD, Pkd1(-/-) kidney tubule epithelial cells were applied to a scalable and automated 3D cyst culture model for compound screening, followed by phenotypic profiling to determine compound efficacy...
June 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28634183/syk-inhibitors-interfere-with-erythrocyte-membrane-modification-during-p-falciparum-growth-and-suppress-parasite-egress
#2
Antonella Pantaleo, Kristina R Kesely, Maria Carmina Pau, Ioannis Tsamesidis, Evelin Schwarzer, Oleksii A Skorokhod, Huynh D Chien, Marta Ponzi, Lucia Bertuccini, Philip S Low, Francesco M Turrini
Band 3 (a.k.a. the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intra-erythrocytic stage of Plasmodium falciparum's life cycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization...
June 20, 2017: Blood
https://www.readbyqxmd.com/read/28624575/intestinal-fungal-dysbiosis-associates-with-visceral-hypersensitivity-in-patients-with-irritable-bowel-syndrome-and-rats
#3
Sara Botschuijver, Guus Roeselers, Evgeni Levin, Daisy M Jonkers, Olaf Welting, Sigrid Em Heinsbroek, Heleen H de Weerd, Teun Boekhout, Matteo Fornai, Ad A Masclee, Frank H J Schuren, Wouter J de Jonge, Jurgen Seppen, Rene M van den Wijngaard
BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity. METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity)...
June 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28614370/the-hemagglutinin-neuramidinase-protein-of-newcastle-disease-virus-upregulates-expression-of-the-trail-gene-in-murine-natural-killer-cells-through-the-activation-of-syk-and-nf-%C3%AE%C2%BAb
#4
Ying Liang, De-Zhi Song, Shuang Liang, Zeng-Feng Zhang, Ling-Xi Gao, Xiao-Hui Fan
Newcastle disease virus (NDV) is responsible for tumoricidal activity in vitro and in vivo. However, the mechanisms that lead to this activity are unclear. Natural killer cells are able to induce apoptosis of tumor cells through multiple pathways, including the tumor necrosis factor-related apoptosis-inducing ligand-death receptor pathway. We previously showed that exposure of NK and T cells to NDV resulted in enhanced tumoricidal activity that was mediated by upregulated expression of the TRAIL gene, via an interferon gamma -dependent pathway...
2017: PloS One
https://www.readbyqxmd.com/read/28598382/syk-activity-is-dispensable-for-platelet-gp1b-ix-v-signaling
#5
Rachit Badolia, John C Kostyak, Carol Dangelmaier, Satya P Kunapuli
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation...
June 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28594748/inhibition-of-spleen-tyrosine-kinase-reduces-renal-allograft-injury-in-a-rat-model-of-acute-antibody-mediated-rejection-in-sensitized-recipients
#6
Sharmila Ramessur Chandran, Yingjie Han, Greg H Tesch, Julie Di Paolo, William R Mulley, John Kanellis, Frank Y Ma, David J Nikolic-Paterson
BACKGROUND: Organ transplantation into sensitized patients with preexisting donor-specific antibodies (DSA) is very challenging. Spleen tyrosine kinase (Syk) promotes leukocyte recruitment and activation via signalling through various cell surface receptors. We investigated whether a selective Syk inhibitor (GS-492429) could suppress antibody-mediated rejection (AMR) in a rat model of AMR in sensitized recipients. METHODS: Recipient Lewis rats (RT1) were immunized with donor (Dark Agouti, RT1) spleen cells (day -5)...
June 7, 2017: Transplantation
https://www.readbyqxmd.com/read/28500073/fc%C3%AE-riiia-signaling-modulates-endosomal-tlr-responses-in-human-cd4-t-cells
#7
Anil K Chauhan
Recognition of Ab-opsonized pathogens by immune cells triggers both TLR and Fc receptor signaling. Fc receptors endocytose modified nucleic acids bound to Abs and deliver them to endosomes, where they are recognized by nucleic acid-sensing TLRs (NA-TLRs). We show that in CD4(+) T cells, NA-TLRs, TLR3, TLR8, and TLR9 are upregulated by FcγRIIIa-pSyk cosignaling and localize with FcγRIIIa on the cell surface. TLR9 accumulates on the cell surface, where it recognizes CpG oligonucleotide 2006. Subcellular location of NA-TLRs is a key determinant in discriminating self versus viral nucleic acid...
June 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28479222/effects-of-a-spleen-tyrosine-kinase-inhibitor-on-progression-of-the-lupus-nephritis-in-mice
#8
Maki Kitai, Noboru Fukuda, Takahiro Ueno, Morito Endo, Takashi Maruyama, Masanori Abe, Kazuyoshi Okada, Masayoshi Soma, Koichi Matsumoto
The Fc receptors (FcR) have pivotal roles in the pathogenesis of the autoimmune glomerulonephritis. We therefore investigated the effects of a Syk inhibitor on the progression of lupus nephritis and SH3 domain binding protein 2 and p38MAP kinase signalings in mice. NZB/W F1 mice, a model of lupus nephritis, received a Syk inhibitor R406. Western blotting and immunohistochemistry revealed that R406 treatment significantly delayed the appearance of proteinuria, histologically improved their glomerulosclerosis and inhibited the increased the expression of MCP-1 and TGF-β1 mRNAs and the nephrin and podocin proteins in the kidney...
May 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28462919/targeting-antigen-independent-proliferation-in-chronic-lymphocytic-leukemia-through-differential-kinase-inhibition
#9
E Slinger, R Thijssen, A P Kater, E Eldering
The clinical success of B cell receptor (BCR) signaling pathway inhibitors in chronic lymphocytic leukemia (CLL) is attributed to inhibition of adhesion in and migration towards the lymph node. Proliferation of CLL cells is restricted to this protective niche, but the underlying mechanism(s) is/are not known. Treatment with BCR pathway inhibitors results in rapid reductions of total clone size, while CLL cell survival is not affected, which points towards inhibition of proliferation. However, BCR stimulation does not induce proliferation of CLL in vitro, while triggering via TLR-, TNF- or cytokine- receptors does...
May 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28460620/cx-4945-a-selective-inhibitor-of-casein-kinase-2-synergizes-with-b-cell-receptor-signaling-inhibitors-in-inducing-diffuse-large-b-cell-lymphoma-cell-death
#10
Elisa Mandato, Sara Canovas Nunes, Fortunato Zaffino, Alessandro Casellato, Paolo Macaccaro, Laura Quotti Tubi, Andrea Visentin, Livio Trentin, Gianpietro Semenzato, Francesco Piazza
BACKGROUND: Approximately one third of Diffuse Large B cell Lymphomas (DLBCL) are refractory or relapse. Novel therapeutic approaches under scrutiny include inhibitors of B-cell receptor (BCR) signaling. Protein kinase CK2 propels survival, proliferation and stress response in solid and hematologic malignancies and promotes a "non-oncogene addiction" phenotype. Whether this kinase regulates BCR signaling thus being a suitable pharmacological target in DLBCL is unknown. OBJECTIVE: To establish if CK2 controls DLBCL cell survival and the BCR signaling; to check if the combination of CK2 inhibitor CX-4945 and BCR blockers Ibrutinib and Fostamatinib is more effectively cytotoxic for DLBCL cells than the single agents; to survey the changes in signaling molecules downstream BCR upon CK2 inhibition...
April 26, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28445193/a-pilot-randomized-trial-on-safety-and-efficacy-of-a-novel-topical-combined-inhibitor-of-janus-kinase-1-3-and-spleen-tyrosine-kinase-for-gvhd-associated-ocular-surface-disease
#11
Ahmad Kheirkhah, Antonio Di Zazzo, Vannarut Satitpitakul, Merle Fernandez, Daniel Magilavy, Reza Dana
PURPOSE: Janus kinase (JAK) and spleen tyrosine kinase (SYK) play critical functions in T-cell activation and in inflammation. Because of their antiinflammatory effects, JAK and SYK inhibitors have recently been evaluated in several immunopathogenic disorders. This pilot study was designed to assess the safety and efficacy of a topical combined JAK/SYK inhibitor, R348, ophthalmic solution for treatment of ocular surface disease in graft-versus-host disease (GVHD). METHODS: This phase 2, double-masked, randomized, pilot trial included 30 patients with ocular surface disease due to GVHD who were randomized to receive topical 0...
July 2017: Cornea
https://www.readbyqxmd.com/read/28405610/btk-specific-inhibition-blocks-pathogenic-plasma-cell-signatures-and-myeloid-cell-associated-damage-in-ifn%C3%AE-driven-lupus-nephritis
#12
Arna Katewa, Yugang Wang, Jason A Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D Austin, Meire Bremer, Jacob Zhi Chen, James J Crawford, Kevin S Currie, Peter Blomgren, Jason DeVoss, Julie A DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E DeForge, Zhonghua Lin, Marya Liimatta, Joseph W Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P Lee, Harvey Wong, Wendy B Young, Michael J Townsend, Karin Reif
Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28391340/targeting-the-tyrosine-kinase-signalling-pathways-for-treatment-of-immune-mediated-glomerulonephritis-from-bench-to-bedside-and-beyond
#13
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai Keung Tam
Glomerulonephritis (GN) affects patients of all ages and is an important cause of morbidity and mortality. Non-selective immunosuppressive drugs have been used in immune-mediated GN but often result in systemic side effects and occasionally fatal infective complications. There is increasing evidence from both preclinical and clinical studies that abnormal activation of receptor and non-receptor tyrosine kinase signalling pathways are implicated in the pathogenesis of immune-mediated GN. Activation of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and discoidin domain receptor 1 (DDR1) have been demonstrated in anti-GBM disease...
January 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28385506/divergent-synthesis-of-kinase-inhibitor-derivatives-leading-to-discovery-of-selective-gck-inhibitors
#14
Takanori Matsumaru, Makoto Inai, Kana Ishigami, Toshiki Iwamatsu, Hiroshi Maita, Satoko Otsuguro, Takao Nomura, Akira Matsuda, Satoshi Ichikawa, Masahiro Sakaitani, Satoshi Shuto, Katsumi Maenaka, Toshiyuki Kan
We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.
March 23, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28359287/activity-of-the-novel-bcr-kinase-inhibitor-iqs019-in-preclinical-models-of-b-cell-non-hodgkin-lymphoma
#15
P Balsas, A Esteve-Arenys, J Roldán, L Jiménez, V Rodríguez, J G Valero, A Chamorro-Jorganes, R Puig de la Bellacasa, J Teixidó, A Matas-Céspedes, A Moros, A Martínez, E Campo, A Sáez-Borderías, J I Borrell, P Pérez-Galán, D Colomer, G Roué
BACKGROUND: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. METHODS: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib...
March 31, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28350104/induction-of-galectin-1-by-tlr-dependent-pi3k-activation-enhances-epithelial-mesenchymal-transition-of-metastatic-ovarian-cancer-cells
#16
Ga Bin Park, Yoon Hee Chung, Daejin Kim
The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK‑OV‑3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110α, p110β, and p110δ) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, α-SMA, and TCF) in SK‑OV‑3 cells...
May 2017: Oncology Reports
https://www.readbyqxmd.com/read/28336564/identification-of-a-novel-syk-c-myc-malat1-signaling-pathway-and-its-potential-therapeutic-value-in-ewing-sarcoma
#17
Haibo Sun, De-Chen Lin, Qi Cao, Brendan Pang, David D Gae, Victor Km Lee, Huey Jin Lim, Ngan Doan, Jonathan W Said, Sigal Gery, Marilynn Chow, Anand Mayakonda, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler
PURPOSE: Ewing Sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TKs) and associated pathways are continuously activated in many malignancies including EWS; these enzymes provide candidate therapeutic targets. EXPERIMENTAL DESIGN: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines...
March 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28336561/mice-lacking-the-inhibitory-collagen-receptor-lair-1-exhibit-a-mild-thrombocytosis-and-hyperactive-platelets
#18
Christopher W Smith, Steven G Thomas, Zaher Raslan, Pushpa Patel, Maxwell Byrne, Marie Lordkipanidzé, Danai Bem, Linde Meyaard, Yotis A Senis, Steve P Watson, Alexandra Mazharian
OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif-containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif-containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored...
May 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28335387/dectin-1-mediated-pathway-contributes-to-fusarium-proliferatum-induced-cxcl-8-release-from-human-respiratory-epithelial-cells
#19
Chang-Ching Yeh, Huann-Cheng Horng, Hong Chou, Hsiao-Yun Tai, Horng-Der Shen, Shie-Liang Hsieh, Peng-Hui Wang
Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C-X-C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits...
March 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28326700/-in-vitro-investigation-on-the-mechanism-of-cyclooxygenase-2-upregulation-induced-by-spleen-tyrosine-kinase-nuclear-factor-%C3%AE%C2%BAb-signaling-in-cancer-pain-caused-by-oral-cancer-associated-macrophage
#20
Lin Jie, Wang Miao, Ji Yang, Liu Le, Gao Pan, Li Chunjie
OBJECTIVE: This study explores the mechanism of cyclooxygenase-2 (COX-2) upregulation in oral cancers associated with macrophage by using molecular biology techniques and primary culture of murine macrophage. METHODS: Murine macrophage was induced by macrophage colony-stimulating factor (M-CSF) and Cal27 conditional medium (CM). Purity of the macrophage was detected through CD68 immunofluorescence staining. Inhibitors of spleen tyrosine kinase (Syk) and nuclear factor κB (NFκB) were used to inhibit these pathways...
October 1, 2016: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
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