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https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#1
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/28077574/platelet-activating-factor-mediates-endotoxin-tolerance-by-regulating-indoleamine-2-3-dioxygenase-dependent-expression-of-the-suppressor-of-cytokine-signaling-3
#2
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/28077299/anaplastic-lymphoma-kinase-alk-inhibitors-in-the-treatment-of-alk-driven-lung-cancers
#3
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/28067377/luteolin-suppresses-the-jak-stat-pathway-in-a-cellular-model-of-intestinal-inflammation
#4
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
#5
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/28057939/activating-jak2-mutants-reveal-cytokine-receptor-coupling-differences-that-impact-outcomes-in-myeloproliferative-neoplasm
#6
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/28057797/prmt2-interacts-with-splicing-factors-and-regulates-the-alternative-splicing-of-bcl-x
#7
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
#8
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
https://www.readbyqxmd.com/read/28049849/cd4-t-cell-cytokines-synergize-to-induce-proliferation-of-malignant-and-nonmalignant-innate-intraepithelial-lymphocytes
#9
Yvonne M C Kooy-Winkelaar, Dagmar Bouwer, George M C Janssen, Allan Thompson, Martijn H Brugman, Frederike Schmitz, Arnoud H de Ru, Tom van Gils, Gerd Bouma, Jon J van Rood, Peter A van Veelen, M Luisa Mearin, Chris J Mulder, Frits Koning, Jeroen van Bergen
Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin(-)IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin(-)IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin(-)IELs is driven by epithelial cell-derived IL-15...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28043820/kinase-signaling-and-targeted-therapy-for-primary-myelofibrosis
#10
REVIEW
Qiong Yang, John D Crispino, Qiang Jeremy Wen
The myeloproliferative neoplasms (MPNs) are somatic mutation-driven hematological malignancies characterized by bone marrow fibrosis and the accumulation of atypical megakaryocytes with reduced polyploidization in the primary myelofibrosis (PMF) subtype of the MPNs. Increasing evidence points to a dominant role of abnormal megakaryocytes (MK) in disease initiation and progression. Here we review the literature related to kinase signaling pathways relevant to megakaryocyte differentiation and proliferation, including Aurora A kinase, RhoA/ROCK and JAK/STAT, as well as the activities of their targeted inhibitors in models of the disease...
December 30, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/28039266/malignant-astrocytic-tumor-progression-potentiated-by-jak-mediated-recruitment-of-myeloid-cells
#11
Prajwal Rajappa, William S Cobb, Emma Vartanian, Yujie Huang, Laura Daly, Caitlin Hoffman, Jane Zhang, Beiyi Shen, Rachel Yanowitch, Kunal Garg, Babacar Cisse, Sara Haddock, Jason T Huse, David J Pisapia, Timothy A Chan, David Lyden, Jacqueline Bromberg, Jeffrey P Greenfield
PURPOSE: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of non-resident bone marrow-derived cells (BMDCs) remains to be determined in neurological tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas. EXPERIMENTAL DESIGN: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression...
December 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28038963/phosphorylated-cis-suppresses-the-epo-or-jak2-v617f-mutant-triggered-cell-proliferation-through-binding-to-epor
#12
Megumi Funakoshi-Tago, Takuro Moriwaki, Fumihito Ueda, Hiroomi Tamura, Tadashi Kasahara, Kenji Tago
The JAK2 V617F mutant-mediated aberrant signaling pathway is a hallmark of myeloproliferative neoplasms (MPNs). Although cytokine-inducible Src homology 2 protein (CIS) and suppressors of cytokine signaling (SOCS) are negative regulators of the JAK-STAT pathway, the functional role of CIS/SOCS family members in the JAK2 V617F mutant-induced oncogenic signaling pathway has not yet been elucidated. In this study, we found that the expression of CIS and SOCS1 was induced through the activation of signal transducer and activator of transcription 5 (STAT5) in not only the cells stimulated with Epo or IL-3 but also the cells transformed by the JAK2 V617F mutant...
December 28, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/28035374/activation-of-oncogenic-pathways-in-classical-hodgkin-lymphoma-by-decitabine-a-rationale-for-combination-with-small-molecular-weight-inhibitors
#13
Tatjana Maria Swerev, Thomas Wirth, Alexey Ushmorov
DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis...
December 30, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/28035365/matrine-induces-the-apoptosis-of-fibroblast-like-synoviocytes-derived-from-rats-with-collagen-induced-arthritis-by-suppressing-the-activation-of-the-jak-stat-signaling-pathway
#14
Yongsheng Yang, Qiumei Dong, Rongheng Li
The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen‑induced arthritis (CIA)...
December 29, 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28028720/liuwei-dihuang-pill-treats-postmenopausal-osteoporosis-with-shen-kidney-yin-deficiency-via-janus-kinase-signal-transducer-and-activator-of-transcription-signal-pathway-by-up-regulating-cardiotrophin-like-cytokine-factor-1-expression
#15
Ji-Rong Ge, Li-Hua Xie, Juan Chen, Sheng-Qiang Li, Hui-Juan Xu, Yu-Lian Lai, Long-Long Qiu, Chen-Bo Ni
OBJECTIVES: To investigate the mechanism of Liuwei Dihuang Pill (, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency. METHODS: In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group (Group A), PMOP Shen-yang deficiency group (Group B), PMOP without Shen deficiency group (Group C), and control group (Group N). Real-time polymerase chain reaction (RT-PCR) and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 (CLCF1), ankyrin repeat and SOCS box containing 1 (ASB1), and prokineticin 2 (PROK2) genes and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway...
December 27, 2016: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/28025811/neurocognition-in-ptsd-treatment-insights-and-implications
#16
Amy J Jak, Laura D Crocker, Robin L Aupperle, Ashley Clausen, Jessica Bomyea
Post-traumatic stress disorder (PTSD) is classified as a traumatic stress-related condition and is most often discussed in terms of emotional dysfunction. However, given that cognitive and emotional processes are intricately intertwined, implemented by overlapping brain networks, and effectively integrated in at least some of the same regions (e.g., prefrontal cortex, for a review, see [1]), an abundance of literature now highlights the key role that cognitive functioning plays in both the development and maintenance (or exacerbation) of PTSD symptoms [2, 3]...
December 27, 2016: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/28011622/microrna-194-promotes-prostate-cancer-metastasis-by-inhibiting-socs2
#17
Rajdeep Das, Phillip A Gregory, Rayzel C Fernandes, Iza Denis, Qingqing Wang, Scott L Townley, Shuang G Zhao, Adrienne Hanson, Marie A Pickering, Heather K Armstrong, Noor A Lokman, Esmaeil Ebrahimie, Elai Davicioni, Robert B Jenkins, R Jeffrey Karnes, Ashley E Ross, Robert B Den, Eric A Klein, Kim N Chi, Hayley S Ramshaw, Elizabeth D Williams, Amina Zoubedi, Gregory J Goodall, Felix Y Feng, Lisa M Butler, Wayne D Tilley, Luke A Selth
Serum levels of microRNA-194 (miR-194) have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion and epithelial-mesenchymal transition (EMT) in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts...
December 23, 2016: Cancer Research
https://www.readbyqxmd.com/read/27998802/janus-kinase-inhibition-for-immunosuppression-in-solid-organ-transplantation-is-there-a-role-in-complex-immunologic-challenges
#18
REVIEW
Cody A Moore, Carlo J Iasella, Raman Venkataramanan, Fadi G Lakkis, Randall B Smith, John F McDyer, Adriana Zeevi, Christopher R Ensor
Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γc). The γc is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family...
December 18, 2016: Human Immunology
https://www.readbyqxmd.com/read/27995459/epac-activation-inhibits-il-6-induced-cardiac-myocyte-dysfunction
#19
Huiling Jin, Takayuki Fujita, Meihua Jin, Reiko Kurotani, Yuko Hidaka, Wenqian Cai, Kenji Suita, Rajesh Prajapati, Chen Liang, Yoshiki Ohnuki, Yasumasa Mototani, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Satoshi Okumura, Yoshihiro Ishikawa
Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism...
December 19, 2016: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/27993641/as2553627-a-novel-jak-inhibitor-prevents-chronic-rejection-in-rat-cardiac-allografts
#20
Koji Nakamura, Masamichi Inami, Hiroki Morio, Kenji Okuma, Misato Ito, Takahisa Noto, Shohei Shirakami, Jun Hirose, Tatsuaki Morokata
Janus family kinases (JAKs) are essential molecules for cytokine responses and attractive targets for the treatment of transplant rejection and autoimmune diseases. Several JAK inhibitors have shown demonstrable effects on acute rejection in experimental cardiac transplant models. However, little is known about the potential benefits of JAK inhibitors on chronic rejection outcomes such as vasculopathy and fibrosis. Here, we examined the pharmacological profile of a novel JAK inhibitor, AS2553627, and explored its therapeutic potential in chronic rejection as well as acute rejection in a rat cardiac transplant model...
December 16, 2016: European Journal of Pharmacology
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