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https://www.readbyqxmd.com/read/28329187/bumped-kinase-inhibitors-for-therapy-of-cryptosporidiosis
#1
Matthew A Hulverson, Sumiti Vinayak, Ryan Choi, Deborah A Schaefer, Alejandro Castellanos-Gonzalez, Rama S R Vidadala, Carrie F Brooks, Gillian T Herbert, Dana P Betzer, Grant R Whitman, Hayley N Sparks, Samuel L M Arnold, Kasey L Rivas, Lynn K Barrett, A Clinton White, Maly Dustin J, Michael W Riggs, Boris Striepen, Wesley C Van Voorhis, Kayode K Ojo
Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) are leading candidates for treatment of cryptosporidiosis diarrhea. Potential cardiotoxicity related to anti-human ether-à-go-go potassium channel (hERG) activity of the first generation anti-Cryptosporidium BKIs triggered further testing for efficacy. A luminescence assay adapted for high-throughput screening was used to measure inhibitory activities of BKIs on in vitro C. parvum. Furthermore, neonatal and interferon-γ knockout mouse models of C...
March 3, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28325761/the-aryl-hydrocarbon-receptor-governs-epithelial-cell-invasion-during-oropharyngeal-candidiasis
#2
Norma V Solis, Marc Swidergall, Vincent M Bruno, Sarah L Gaffen, Scott G Filler
Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C...
March 21, 2017: MBio
https://www.readbyqxmd.com/read/28317151/design-synthesis-and-evaluation-of-the-kinase-inhibition-potential-of-pyridylpyrimidinylaminophenyl-derivatives
#3
Priyanka Manchanda, Badri Parshad, Amit Kumar, Rakesh K Tiwari, Amir N Shirazi, Keykavous Parang, Sunil K Sharma
In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8...
March 20, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28314119/a-combined-in-vitro-assay-for-evaluation-of-neurotrophic-activity-and-cytotoxicity
#4
Narayan D Chaurasiya, Surabhi Shukla, Babu L Tekwani
Neurotrophic assays are phenotypic methods to identify molecules that stimulate differentiation of neuronal cells. Bioactive small molecules with neurotrophic actions hold great promise as therapeutic agents for the treatment of neurodegenerative diseases and neuronal injuries by virtue of their ability to stimulate neuritic outgrowth. A combined in vitro method, which measures neurotrophic activity and cytotoxicity in a single assay, has been described. This assay, performed in 96-well microplates with PC12 and Neuroscreen-1 (NS-1; a subclone of PC12) cells, is a simple tool for identification of new neurotrophic agents...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28306605/hyperalgesic-priming-type-ii-induced-by-repeated-opioid-exposure-maintenance-mechanisms
#5
Dioneia Araldi, Luiz F Ferrari, Jon D Levine
We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin-E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming...
March 14, 2017: Pain
https://www.readbyqxmd.com/read/28302906/distinct-focal-adhesion-protein-modules-control-different-aspects-of-mechanotransduction
#6
Ben Stutchbury, Paul Atherton, Ricky Tsang, De-Yao Wang, Christoph Ballestrem
Focal adhesions (FAs) are macromolecular complexes that regulate cell adhesion and mechanotransduction. Using fluorescence recovery after photobleaching (FRAP) and fluorescence loss after photoactivation (FLAP), we found that the mobility of core FA proteins correlates with protein function. Structural proteins such as tensin, talin and vinculin are significantly less mobile in FAs than signaling proteins such as FAK and paxillin. The mobilities of the structural proteins are directly influenced by substrate stiffness, suggesting they are involved in sensing the rigidity of the extracellular environment...
March 16, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28295507/crocin-suppresses-constitutively-active-stat3-through-induction-of-protein-tyrosine-phosphatase-shp-1
#7
Buyun Kim, Ki Yong Lee, Byoungduck Park
The aim of the present study is to investigate the effect of a natural compound crocin, one of the active components of saffron, on human multiple myeloma cells. Crocin effectively suppressed constitutive STAT3 activation, translocation of STAT3 to the nucleus, and its target gene expression. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases JAK1, JAK2 and c-Src. We found that crocin induced the expression of SHP-1, a tyrosine protein phosphatase, and pervanadate treatment reversed the crocin-induced downregulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase...
March 10, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28295363/angiotensin-ii-activates-cav-1-2-ca-2-channels-through-%C3%AE-arrestin2-and-casein-kinase-2-in-mouse-immature-cardiomyocytes
#8
Toshihide Kashihara, Tsutomu Nakada, Katsuhiko Kojima, Toshikazu Takeshita, Mitsuhiko Yamada
Angiotensin II (AngII), the main effector peptide of the renin-angiotensin system, plays important roles in cardiovascular regulation in the perinatal period. Despite the well-known stimulatory effect of AngII on vascular contraction, little is known about regulation of contraction of the immature heart by AngII. Here we found that AngII significantly increased the peak amplitude of twitch Ca(2+) transients by robustly activating L-type CaV 1.2 Ca(2+) (CaV 1.2) channels in mouse immature but not mature cardiomyocytes...
March 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28294316/knockout-of-atg5-leads-to-malignant-cell-transformation-and-resistance-to-src-family-kinase-inhibitor-pp2
#9
Sung-Hee Hwang, Byeal-I Han, Michael Lee
Autophagy can either promote or inhibit cell death in different cellular contexts. In this study, we investigated the role of autophagy in ATG5 knockout (KO) cell line established using CRISPR/Cas9 system. In ATG5 KO cells, RT-PCR and immunoblot of LC3 confirmed the functional gene knockout. We found that knockout of ATG5 significantly increased proliferation of NIH 3T3 cells. In particular, autophagy deficiency enhanced susceptibility to cellular transformation as determined by an in vitro clonogenic survival assay and a soft agar colony formation assay...
March 15, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28292443/paradox-breaking-raf-inhibitors-that-also-target-src-are-effective-in-drug-resistant-braf-mutant-melanoma
#10
Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M J M Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer
No abstract text is available yet for this article.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28288319/synthesis-of-heterocyclic-ring-fused-tricyclic-diterpene-analogs-as-novel-inhibitors-of-rankl-induced-osteoclastogenesis-and-bone-resorption
#11
Gao Wei, Yalan Wu, Xiao-Long He, Ting Liu, Mingyao Liu, Jian Luo, Wen-Wei Qiu
A series of heterocyclic ring-fused tricyclic diterpene analogs were synthesized and their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated on bone marrow-derived monocytes (BMMs) by a cell based tartrate-resistant acid phosphatase (TRAP) activity assay. Among them, the most potent compound, 37 (QG368), showed 72.3% inhibition even at a low concentration of 0.1 μM, which was about 188-fold more potent than the lead compound. Cytotoxicity test on BMMs indicated that the inhibition on osteoclast differentiation of 37 did not result from its cytotoxicity...
March 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28284718/novel-jak3-activating-mutations-in-extranodal-nk-t-cell-lymphoma-nasal-type
#12
Sung H Sim, Soyeon Kim, Tae M Kim, Yoon K Jeon, Soo J Nam, Yong-Oon Ahn, Bhumsuk Keam, Hyun H Park, Dong-Wan Kim, Chul W Kim, Dae S Heo
Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3(A573V), two JAK3(H583Y), and one JAK3(G589D) mutation...
March 8, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28280091/dual-inhibition-of-egfr-and-c-src-by-cetuximab-and-dasatinib-combined-with-folfox-chemotherapy-in-patients-with-metastatic-colorectal-cancer
#13
Christine Parseghian, Nila U Parikh, Ji Yuan Wu, Zhi-Qin Jiang, Laura D Henderson, Feng Tian, Brice Pastor, Marc Ychou, Kanwal Raghav, Arvind Dasari, David Fogelman, Anastasia Katsiampoura, David G Menter, Robert A Wolff, Cathy Eng, Michael J Overman, Alain R Thierry, Gary E Gallick, Scott Kopetz
BACKGROUND: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab. METHODS: We performed a phase IB/II study of 77 patients with previously-treated mCRC. Primary objectives were to determine the MTD, dose-limiting-toxicities, pharmacodynamics, and efficacy...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28278510/autocrine-vegf-and-il-8-promote-migration-via-src-vav2-rac1-pak1-signaling-in-human-umbilical-vein-endothelial-cells
#14
Li Ju, Zhiwen Zhou, Bo Jiang, Yue Lou, Xirong Guo
BACKGROUND/AIMS: Pro-angiogenic factors VEGF and IL-8 play a major role in modulating the migratory potential of endothelial cells. The goal of this study was to investigate the effect of autocrine VEGF and IL-8 in the form of self-conditioned medium (CM) on human umbilical vein endothelial cells (HUVECs). METHODS: Enzyme-linked immunosorbent assay (ELISA) examined the automatic secretion of VEGF and IL-8 protein by HUVECs. Western blot, small interfering RNA (siRNA), pulldown and Transwell assays were used to explore the role and the mechanism of autocrine VEGF and IL-8 in migration of HUVECs...
March 9, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28266741/signaling-and-targeted-therapy-of-inflammatory-cells-in-epidermolysis-bullosa-acquisita
#15
REVIEW
Ralf J Ludwig
Pemphigoid diseases (PD) are chronic and life-threating autoimmune diseases of the skin and mucous membranes. PD are characterized and caused by autoantibodies targeting components of the basement membrane. In the PD epidermolysis bullosa acquisita (EBA) the target autoantigen is type VII collagen. Current treatment options of PD, especially EBA, are limited and are mostly based on systemic immunosuppression. Animal models of PD have greatly advanced our understanding of PD pathogenesis. This has led to the identification of several novel therapeutic targets, including signaling molecules...
March 7, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/28260800/a-novel-stat3-inhibitor-negatively-modulates-platelet-activation-and-aggregation
#16
Zhuan Xu, Yu-Jia Xu, Ya-Nan Hao, Li-Jie Ren, Zu-Bin Zhang, Xin Xu, Bi-Yin Cao, Ke-Sheng Dai, Li Zhu, Qi Fang, Yan Kong, Xin-Liang Mao
The signal transducer and activator of transcription 3 (STAT3) plays a critical role in platelet functions. This study sought to understand the effects of the STAT3 inhibitor SC99 on platelet activation and aggregation. Immunoblotting assays were applied to measure the effects of SC99 on the STAT3 signaling pathway. A ChronoLog aggregometer was used to evaluate platelet aggregation. A flow cytometer was used to evaluate P-selectin expression in the presence of SC99. AlamarBlue and Annexin-V staining were used to evaluate platelet viability and apoptosis, respectively...
March 6, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28259897/dual-roles-of-protein-tyrosine-phosphatase-kappa-in-coordinating-angiogenesis-induced-by-pro-angiogenic-factors
#17
Ping-Hui Sun, Gang Chen, Malcolm Mason, Wen G Jiang, Lin Ye
A potential role may be played by receptor-type protein tyrosine phosphatase kappa (PTPRK) in angiogenesis due to its critical function in coordinating intracellular signal transduction from various receptors reliant on tyrosine phosphorylation. In the present study, we investigated the involvement of PTPRK in the cellular functions of vascular endothelial cells (HECV) and its role in angiogenesis using in vitro assays and a PTPRK knockdown vascular endothelial cell model. PTPRK knockdown in HECV cells (HECVPTPRKkd) resulted in a decrease of cell proliferation and cell-matrix adhesion; however, increased cell spreading and motility were seen...
February 20, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28258630/everolimus-suppresses-invasion-and-migration-of-renal-cell-carcinoma-by-inhibiting-fak-activity-and-reversing-epithelial-to-mesenchymal-transition-in-vitro-and-in-vivo
#18
Sheng-Wen Wu, Pei-Ni Chen, Chin-Yin Lin, Yih-Shou Hsieh, Horng-Rong Chang
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and the major cause of mortality in urological cancer. Most patients with RCC are asymptomatic until the disease is advanced and unresectable. In this situation, systemic therapy with immunotherapy or molecularly targeted therapy agents play an important role in therapeutic strategy. Everolimus (EVE), an m-TOR inhibitor, has the potential to inhibit tumor progression at multiple levels and is indicated for the treatment of advanced RCC in patients whose disease has metastasis...
March 4, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28254813/microrna-150-modulates-ischemia-induced-neovascularization-in-atherosclerotic-conditions
#19
Michel Desjarlais, Sylvie Dussault, Wahiba Dhahri, Raphael Mathieu, Alain Rivard
OBJECTIVE: Hypercholesterolemia is an atherosclerotic condition that is associated with impaired neovascularization in response to ischemia. This study sought to define the role of microRNAs in that pathophysiology. APPROACH AND RESULTS: Next-generation sequencing and quantitative reverse transcription polymerase chain reaction analyses identified miR-150 as a proangiogenic microRNA, which expression is significantly reduced in the ischemic muscles of hypercholesterolemic apolipoprotein E-deficient (ApoE(-/-)) mice, and in human umbilical vein endothelial cells exposed to oxidized low-density lipoprotein...
March 2, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28250239/src-family-kinases-in-hamster-spermatozoa-evidence-for-the-presence-of-lck
#20
Durgesh Kumar Singh, Rohit Kumar Deshmukh, Praveen Kumar Narayanan, Shivaji Sisinthy, Archana Bharadwaj Siva
Sperm capacitation is a prerequisite for successful fertilization. Increase in tyrosine phosphorylation is considered the hallmark of capacitation and attempts to understand its regulation are ongoing. In this regard, we attempted to study the role of SRC family kinases (SFKs) in the hamster sperm functions. Interestingly, we found the presence of the lymphocyte-specific protein tyrosine kinase, LCK in mammalian spermatozoa and further characterized it in terms of its localization and function. LCK was found in spermatozoa of several species and its transcript was identified in the hamster testis...
March 1, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
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