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https://www.readbyqxmd.com/read/28088907/tofacitinib-an-oral-janus-kinase-inhibitor-perspectives-in-dermatology
#1
Kresimir Kostovic, Sandra Jerkovic Gulin, Zrinka Bukvic Mokos, Romana Ceovic
BACKGROUND: Tofacitinib (formerly known as CP-690,550, CP690550, tasocitinib), a novel selective immunosuppressant, is a small molecule classified as Janus kinase inhibitor. The aim of this review article is to present updated data summary on the tofacitinib in the field of dermatology. METHOD: We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria...
January 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28088788/dual-syk-jak-inhibition-overcomes-ibrutinib-resistance-in-chronic-lymphocytic-leukemia-cerdulatinib-but-not-ibrutinib-induces-apoptosis-of-tumor-cells-protected-by-the-microenvironment
#2
Ailin Guo, Pin Lu, Greg Coffey, Pamela Conley, Anjali Pandey, Y Lynn Wang
Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#3
Elena Calama, Isabel Ramis, Anna Domènech, Cristina Carreño, Jorge De Alba, Neus Prats, Montserrat Miralpeix
BACKGROUND: and purpose: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor...
January 10, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28081143/engineered-aedes-aegypti-jak-stat-pathway-mediated-immunity-to-dengue-virus
#4
Natapong Jupatanakul, Shuzhen Sim, Yesseinia I Angleró-Rodríguez, Jayme Souza-Neto, Suchismita Das, Kristin E Poti, Shannan L Rossi, Nicholas Bergren, Nikos Vasilakis, George Dimopoulos
We have developed genetically modified Ae. aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue, by overexpressing either the receptor Dome or the Janus kinase Hop by the blood feeding-induced vitellogenin (Vg) promoter. Transgene expression inhibits infection with several dengue virus (DENV) serotypes in the midgut as well as systemically and in the salivary glands. The impact of the transgenes Dome and Hop on mosquito longevity was minimal, but it resulted in a compromised fecundity when compared to wild-type mosquitoes...
January 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28077574/platelet-activating-factor-mediates-endotoxin-tolerance-by-regulating-indoleamine-2-3-dioxygenase-dependent-expression-of-the-suppressor-of-cytokine-signaling-3
#5
Kyung Tae Noh, In Duk Jung, Gil Sun Cha, Myung-Kwan Han, Yeong-Min Park
Indoleamine 2, 3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We previously determined plateletactivating factor (PAF) protects mice against lipopolysaccharide (LPS)-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments in IDO+/+ and IDO-/- mice using an LPSinduced endotoxemia model and rated organ injury (neutrophil infiltration, and liver function)...
January 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28077314/biological-or-pharmacological-activation-of-protein-kinase-c-alpha-constrains-hepatitis-e-virus-replication
#6
Wenshi Wang, Yijin Wang, Yannick Debing, Xinying Zhou, Yuebang Yin, Lei Xu, Elena Herrera Carrillo, Johannes H Brandsma, Raymond A Poot, Ben Berkhout, Johan Neyts, Maikel P Peppelenbosch, Qiuwei Pan
Although hepatitis E has emerged as a global health issue, there is limited knowledge of its infection biology and no FDA-approved medication is available. Aiming to investigate the role of protein kinases in hepatitis E virus (HEV) infection and to identify potential antiviral targets, we screened a library of pharmacological kinase inhibitors in a cell culture model, a subgenomic HEV replicon containing luciferase reporter. We identified protein kinase C alpha (PKCα) as an essential cell host factor restricting HEV replication...
January 8, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28077299/anaplastic-lymphoma-kinase-alk-inhibitors-in-the-treatment-of-alk-driven-lung-cancers
#7
REVIEW
Robert Roskoski
Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors...
January 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28072602/-janus-kinase-ing-up-the-treatment-of-primary-myelofibrosis-building-better-combination-strategies
#8
Rita Assi, Srdan Verstovsek, Naval Daver
PURPOSE OF REVIEW: The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting. RECENT FINDINGS: Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK-inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up...
January 7, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28069988/exposure-to-concentrated-ambient-pm2-5-shortens-lifespan-and-induces-inflammation-associated-signaling-and-oxidative-stress-in-drosophila
#9
Xiaoke Wang, Minjie Chen, Mianhua Zhong, Ziying Hu, Lianglin Qiu, Sanjay Rajagopalan, Nancy G Fossett, Lung-Chi Chen, Zhekang Ying
BACKGROUND: Exposure to ambient PM2.5 is associated with human premature mortality. However, it has not yet been toxicologically replicated, likely due to the lack of suitable animal models. Drosophila is frequently used in longevity research due to many incomparable merits. OBJECTIVE: The present study aims to validate Drosophila models for PM2.5 toxicity study through characterizing their biological responses to exposure to concentrated ambient PM2.5 (CAP). RESULTS: The survivorship curve demonstrated that exposure to CAP markedly reduced lifespan of Drosophila...
January 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28069291/antagonizing-cytokine-mediated-jak-stat-signaling-by-porcine-reproductive-and-respiratory-syndrome-virus
#10
REVIEW
Liping Yang, Yan-Jin Zhang
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is activated by myriad cytokines, which are involved in regulation of cell growth, proliferation, differentiation, apoptosis, angiogenesis, immunity and inflammatory response. Because of its significance in immune response, JAK-STAT pathway is often targeted by pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV causes reproductive failure in sows and respiratory disease in pigs of all ages...
December 30, 2016: Veterinary Microbiology
https://www.readbyqxmd.com/read/28068330/loss-of-p53-induces-leukemic-transformation-in-a-murine-model-of-jak2-v617f-driven-polycythemia-vera
#11
T Tsuruta-Kishino, J Koya, K Kataoka, K Narukawa, Y Sumitomo, H Kobayashi, T Sato, M Kurokawa
As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28067377/luteolin-suppresses-the-jak-stat-pathway-in-a-cellular-model-of-intestinal-inflammation
#12
Carla Nunes, Leonor Almeida, Rui M Barbosa, João Laranjinha
Current treatment strategies for inflammatory bowel diseases (IBDs) are associated with a lower efficacy and with several side effects that strongly affect the quality of life of IBD patients. Consequently, the development of new therapies, combining efficacy and safety is an important goal in the field of intestinal inflammation. In this context, evidence supports that polyphenols can be promising candidates due to their ability to modulate intracellular inflammatory signalling cascades. Luteolin, a naturally occurring flavonoid, exhibits anti-inflammatory properties in several models of inflammation...
January 9, 2017: Food & Function
https://www.readbyqxmd.com/read/28063952/transcriptome-profiling-of-spleen-provides-insights-into-the-antiviral-mechanism-in-schizothorax-prenanti-after-poly-i-c-challenge
#13
Xiaogang Du, Yunkun Li, Dong Li, Fangliang Lian, Shiyong Yang, Jiayun Wu, Hanmei Liu, Guixian Bu, Fengyan Meng, Xiaohan Cao, Xianyin Zeng, Huaiyu Zhang, Zhiyu Chen
Schizothorax prenanti (S. prenanti) is an important economical cold-water fish species in southwestern China, but it is susceptible to various pathogens infection. In order to clearly elucidate the antiviral mechanism, in this study, we have analyzed the transcriptome of S. prenanti spleen after challenge with the virus mimic, poly (I:C) (pIC), using next generation sequencing technology (RNA-seq). A total of 313 differential expressed genes (DEGs) in spleen at 24 h were obtained after pIC treatment, including 268 significantly up-regulated unigenes (fold change > 2) and 45 significantly down-regulated unigenes (fold change > 2)...
January 4, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28063793/interleukin-6-increases-the-expression-of-key-proteins-associated-with-steroidogenesis-in-human-nci-h295r-adrenocortical-cells
#14
Janae Strickland, Stephen McIlmoil, Brice J Williams, Dennis C Seager, James P Porter, Allan M Judd
Mechanisms of interleukin-6 (IL-6)-induced cortisol release (CR) were investigated by exposing H295R cells to IL-6 and determining mRNA/protein expression (PCR/western blots) for steroidogenic enzymes (SE), steroidogenic acute regulatory protein (StAR), steroidogenic factor-1 (SF-1)(enhances SE/StAR expression), activator protein 1 (AP-1)(regulates SE/StAR expression) and adrenal hypoplasia congenita-like protein (DAX-1)(inhibits SE/StAR expression). Promoter activity of StAR (SPA) was measured by a luciferase-coupled promoter...
January 4, 2017: Steroids
https://www.readbyqxmd.com/read/28062444/robust-parameter-estimation-for-dynamical-systems-from-outlier-corrupted-data
#15
Corinna Maier, Carolin Loos, Jan Hasenauer
MOTIVATION: Dynamics of cellular processes are often studied using mechanistic mathematical models. These models possess unknown parameters which are generally estimated from experimental data assuming normally distributed measurement noise. Outlier corruption of datasets often cannot be avoided. These outliers may distort the parameter estimates, resulting in incorrect model predictions. Robust parameter estimation methods are required which provide reliable parameter estimates in the presence of outliers...
January 6, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28061797/natural-compounds-targeting-major-cell-signaling-pathways-a-novel-paradigm-for-osteosarcoma-therapy
#16
REVIEW
Pablo Angulo, Gaurav Kaushik, Dharmalingam Subramaniam, Prasad Dandawate, Kathleen Neville, Katherine Chastain, Shrikant Anant
Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival...
January 7, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28057939/activating-jak2-mutants-reveal-cytokine-receptor-coupling-differences-that-impact-outcomes-in-myeloproliferative-neoplasm
#17
H Yao, Y Ma, Z Hong, L Zhao, S A Monaghan, M-C Hu, Lj-S Huang
Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs. granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals...
January 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28057869/leptin-stimulates-bone-formation-in-ob-ob-mice-at-doses-having-minimal-impact-on-energy-metabolism
#18
Kenneth A Philbrick, Carmen P Wong, Adam J Branscum, Russell T Turner, Urszula T Iwaniec
Leptin, the protein product of the ob gene, is essential for normal bone growth, maturation, and turnover. Peripheral actions of leptin occur at lower serum levels of the hormone than central actions because entry of leptin into the central nervous system (CNS) is limited due to its saturable transport across the blood brain barrier (BBB). We performed a study in mice to model the impact of leptin production associated with different levels of adiposity on bone formation and compared the response with well-established centrally-mediated actions of the hormone on energy metabolism...
January 5, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28057797/prmt2-interacts-with-splicing-factors-and-regulates-the-alternative-splicing-of-bcl-x
#19
Mynol I Vhuiyan, Magnolia L Pak, Margaret A Park, Dylan Thomas, Ted M Lakowski, Charles E Chalfant, Adam Frankel
Protein arginine N-methyltransferase 2 (PRMT2) functions in JAK-STAT and Wnt/β-catenin signaling pathways, serves as a nuclear receptor-dependent transcriptional co-activator, and represses NF-κB and E2F1 transcription factor activities to promote apoptosis. We have previously demonstrated that PRMT2 interacts with PRMT1 and increases its activity. Here, we reveal associations using proteomics between the PRMT2 SH3 domain and splicing factors including Src-associated in mitosis 68 kDa protein (SAM68), a PRMT1 substrate and trans-acting factor that mediates BCL-X alternative splicing...
January 5, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28057739/aberrant-let7a-hmga2-signaling-activity-with-unique-clinical-phenotype-in-jak2-mutated-myeloproliferative-neoplasms
#20
Chih-Cheng Chen, Jie-Yu You, Jrhau Lung, Cih-En Huang, Yi-Yang Chen, Yu-Wei Leu, Hsing-Ying Ho, Chian-Pei Li, Chang-Hsien Lu, Kuan-Der Lee, Chia-Chen Hsu, Jyh-Pyng Gau
High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA through binding to its 3-untranslated region (3-UTR). Transgenic mice expressing HMGA2 with a truncation of its 3-UTR has been shown to exhibit a myeloproliferative phenotype. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed up-regulation of HMGA2 with concurrent let-7a repression...
January 5, 2017: Haematologica
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