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https://www.readbyqxmd.com/read/28626342/effects-of-src-kinase-inhibition-on-expression-of-protein-tyrosine-phosphatase-1b-after-brain-hypoxia-in-a-piglet-animal-model
#1
Dimitrios Angelis, Maria Delivoria-Papadopoulos
BACKGROUND: Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28625738/mechanisms-of-paradoxical-activation-of-ampk-by-the-kinase-inhibitors-su6656-and-sorafenib
#2
Fiona A Ross, Simon A Hawley, F Romana Auciello, Graeme J Gowans, Abdelmadjid Atrih, Douglas J Lamont, D Grahame Hardie
SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1...
June 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28624460/identification-of-kx2-391-as-an-inhibitor-of-hbv-transcription-by-a-recombinant-hbv-based-screening-assay
#3
Keisuke Harada, Hironori Nishitsuji, Saneyuki Ujino, Kunitada Shimotohno
Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection...
June 15, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28619847/targeted-activation-of-the-shp-1-pp2a-signalling-axis-elicits-apoptosis-of-chronic-lymphocytic-leukemia-cells
#4
Elena Tibaldi, Mario Angelo Pagano, Federica Frezzato, Valentina Trimarco, Monica Facco, Giuseppe Zagotto, Giovanni Ribaudo, Valeria Pavan, Luciana Bordin, Andrea Visentin, Francesca Zonta, Gianpietro Semenzato, Anna Maria Brunati, Livio Trentin
The Src Family Kinase (SFK) Lyn is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is the spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and the serine/threonine phosphatase 2A, eventually triggering apoptosis...
June 15, 2017: Haematologica
https://www.readbyqxmd.com/read/28618271/lck-hck-fgr-mediated-tyrosine-phosphorylation-negatively-regulates-tbk1-to-restrain-innate-antiviral-responses
#5
Shengduo Liu, Shasha Chen, Xinran Li, Shiying Wu, Qian Zhang, Qiuheng Jin, Lin Hu, Ruyuan Zhou, Zhengyang Yu, Fansen Meng, Siwen Wang, Yaowei Huang, Sheng Ye, Li Shen, Zongping Xia, Jian Zou, Xin-Hua Feng, Pinglong Xu
Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance were substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28618084/ccl20-promotes-migration-and-invasiveness-of-human-cancerous-breast-epithelial-cells-in-primary-culture
#6
Antonella Muscella, Carla Vetrugno, Santo Marsigliante
The relation between the tumor and its microenvironment is one of the most interesting and less understood issues. Recently, we showed a role of CCL20 chemokine in proning the healthy tissue neighbouring the tumor to carcinogenesis. Besides, tumor-secreted CCL20 induced proliferation, migration and EMT of healthy cells. In this context, we have studied here if CCL20 had effects on the migration of cancer cells and the intracellular pathways used in breast epithelial cells in primary culture. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated and involved in CCL20-induced tumor breast cell migration...
June 15, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28615246/src-family-kinases-in-chronic-kidney-disease
#7
Jun Wang, Shougang Zhuang
Src family kinases (SFKs) belong to non-receptor protein tyrosine kinases (PTKs) and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated and some of SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis related chronic diseases (e...
June 14, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28611048/targeting-src-coactivators-blocks-the-tumor-initiating-capacity-of-cancer-stem-like-cells
#8
Aarti D Rohira, Fei Yan, Lei Wang, Jin Wang, Suoling Zhou, Andrew Lu, Yang Yu, Jianming Xu, David M Lonard, Bert W O'Malley
Tumor initiating cells (TICs) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation and, metastasis. Here, we report that SRC-3 supports the TIC/CSC state and induces an epithelial to mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers...
June 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28598023/nintedanib-reduces-ventilation-augmented-bleomycin-induced-epithelial-mesenchymal-transition-and-lung-fibrosis-through-suppression-of-the-src-pathway
#9
Li-Fu Li, Kuo-Chin Kao, Yung-Yang Liu, Chang-Wei Lin, Ning-Hung Chen, Chung-Shu Lee, Chih-Wei Wang, Cheng-Ta Yang
Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear...
June 9, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28597397/protein-kinase-c%C3%AE-gene-depletion-protects-against-methamphetamine-induced-impairments-in-recognition-memory-and-erk1-2-signaling-via-upregulation-of-glutathione-peroxidase-1-gene
#10
The-Vinh Tran, Eun-Joo Shin, Lan Thuy Ty Nguyen, Youngho Lee, Dae-Joong Kim, Ji Hoon Jeong, Choon-Gon Jang, Seung-Yeol Nah, Kazuya Toriumi, Toshitaka Nabeshima, Kiyofumi Yamada, Hyoung-Chun Kim
Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cδ (PKCδ) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKCδ expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCδ expression and phospho-ERK1/2 expression...
June 9, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28594363/alteration-of-shp-1-p-stat3-signaling-a-potential-target-for-anticancer-therapy
#11
REVIEW
Tzu-Ting Huang, Jung-Chen Su, Chun-Yu Liu, Chung-Wai Shiau, Kuen-Feng Chen
The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers...
June 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28592413/recruitment-of-endosomal-signaling-mediates-the-forskolin-modulation-of-guinea-pig-cardiac-neuron-excitability
#12
Jean C Hardwick, Todd A Clason, John D Tompkins, Beatrice M Girard, Caitlin N Baran, Laura A Merriam, Victor May, Rodney L Parsons
Forskolin, a selective activator of adenylyl cyclase (AC), commonly is used to establish actions of G protein coupled receptors (GPCRs) that are initiated primarily through activation of AC/cAMP signaling pathways. In the present study, forskolin was used to evaluate the potential role of AC/cAMP, which is a major signaling mechanism for the pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor, in the regulation of guinea pig cardiac neuronal excitability. Forskolin (5-10 µM) increases excitability in ~60 % of the cardiac neurons...
June 7, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28591164/alamandine-reduces-leptin-expression-through-the-c-src-p38-map-kinase-pathway-in-adipose-tissue
#13
Tsuyoshi Uchiyama, Fumikazu Okajima, Chihiro Mogi, Ayaka Tobo, Shoichi Tomono, Koichi Sato
OBJECTIVE: Obesity is associated with an increased risk of diabetes mellitus, hypertension, and renal dysfunction. Angiotensin 1-7 and alamandine are heptameric renin angiotensin system peptide hormones. Further, alamandine levels increase with renal dysfunction. In the cardiovascular system, angiotensin 1-7 and alamandine produce similar improvements and counterbalance angiotensin II in regulating vascular function. We aimed to determine whether the effect of alamandine on leptin expression and secretion in adipocytes was similar to that of angiotensin 1-7...
2017: PloS One
https://www.readbyqxmd.com/read/28589758/identification-of-type-i-and-type-ii-inhibitors-of-c-yes-kinase-using-in-silico-and-experimental-techniques
#14
Chandrasekaran Ramakrishnan, Anthony Mary Thangakani, Devadasan Velmurugan, Dhanabalan Anantha Krishnan, Masakazu Sekijima, Yutaka Akiyama, M Michael Gromiha
c-Yes kinase is considered as one of the attractive targets for anti-cancer drug design. The DFG (Asp-Phe-Gly) motif present in most of the kinases will adopt active and inactive conformations, known as DFG-in and DFG-out and their inhibitors are classified into type I and type II, respectively. In the present study, two screening protocols were followed for identification of c-Yes kinase inhibitors. (i) Structure-based virtual screening (SBVS) and (ii) Structure-based (SB) and Pharmacophore-based (PB) tandem screening...
June 7, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28585567/role-of-src-family-kinases-in-bdnf-mediated-suppression-of-cocaine-seeking-and-prevention-of-cocaine-induced-erk-glun2a-and-glun2b-dephosphorylation-in-the-prelimbic-cortex
#15
Sarah M Barry, Jacqueline F McGinty
Models of relapse have demonstrated that neuroadaptations in reward circuits following cocaine self-administration underlie reinstatement of drug seeking. Dysregulation of the pathway from the prelimbic cortex to the nucleus accumbens is implicated in reinstatement. A single BDNF infusion into the prelimbic cortex following a final cocaine self-administration session results in attenuation of reinstatement of cocaine-seeking. Inhibiting BDNF's receptor, TrkB, ERK/MAP kinase activation, or NMDA receptors blocks this attenuating effect, indicating that the interaction between glutamate-mediated synaptic activity and TrkB signaling is imperative to BDNF's suppressive effect on drug-seeking...
June 6, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28584020/kit-d816v-induces-src-mediated-tyrosine-phosphorylation-of-mitf-and-altered-transcription-program-in-melanoma
#16
Bengt Phung, Julhash U Kazi, Alicia Lundby, Kristin Bergsteinsdottir, Jianmin Sun, Colin R Goding, Göran Jönsson, Jesper V Olsen, Eiríkur Steingrímsson, Lars Rönnstrand
The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KIT(D816V) has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KIT(D816V) induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell-cycle progression, suppression of senescence, survival, and invasion...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28569781/mitochondrial-akap1-supports-mtor-pathway-and-tumor-growth
#17
Laura Rinaldi, Maria Sepe, Rossella Delle Donne, Kristel Conte, Antonietta Arcella, Domenica Borzacchiello, Stefano Amente, Fernanda De Vita, Monia Porpora, Corrado Garbi, Maria A Oliva, Claudio Procaccini, Deriggio Faicchia, Giuseppe Matarese, Federica Zito Marino, Gaetano Rocco, Sara Pignatiello, Renato Franco, Luigi Insabato, Barbara Majello, Antonio Feliciello
Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells...
June 1, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28559019/il6-is-associated-with-response-to-dasatinib-and-cetuximab-phase-ii-clinical-trial-with-mechanistic-correlatives-in-cetuximab-resistant-head-and-neck-cancer
#18
L P Stabile, A M Egloff, M K Gibson, W E Gooding, J Ohr, P Zhou, N J Rothenberger, L Wang, J L Geiger, J T Flaherty, J R Grandis, J E Bauman
OBJECTIVE: Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. PATIENTS AND METHODS: We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA...
June 2017: Oral Oncology
https://www.readbyqxmd.com/read/28558969/pyrazolo-3-4-d-pyrimidines-loaded-human-serum-albumin-hsa-nanoparticles-preparation-characterization-and-cytotoxicity-evaluation-against-neuroblastoma-cell-line
#19
Anna Lucia Fallacara, Aarianna Mancini, Claudio Zamperini, Elena Dreassi, Stefano Marianelli, Mario Chiariello, Gianni Pozzi, Francesco Santoro, Maurizio Botta, Silvia Schenone
Pyrazolo[3,4-d]pyrimidine derivatives 1-5, active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200nm) and an optimal stability over time, confirmed by an in vitro drug release assay...
May 17, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28550679/downregulation-of-src-kinase-signaling-inhibitor-1-srcin1-expression-by-microrna-32-promotes-proliferation-and-epithelial-mesenchymal-transition-in-human-liver-cancer-cells
#20
Ren Chen, Jin-Yao Liao, Jing Huang, Wen-Li Chen, Xiao-Jun Ma, Xiao-Dan Luo
MicroRNAs play an important role in regulating gene expression by binding to the 3' UTR of target mRNAs. In this studywe have made an attempt to assess the molecular mechanisms by which miR-32 suppresses the expression of SRCIN1, thereby leading to promotion of proliferation and epithelial-mesenchymal transition of human liver cancer cells. Human liver cancer cell lines HepG2 were transfected with miR-32 mimics and its control. The HepG2 cell lines were the assessed for miR-32 expression. The transfected cell lines were then studied for SRCIN1 expression by luciferase assay, effect of transfection on cell proliferation and finally epithelial-mesenchymal transition...
May 22, 2017: Oncology Research
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