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https://www.readbyqxmd.com/read/28646470/apobec3b-and-il-6-form-a-positive-feedback-loop-in-hepatocellular-carcinoma-cells
#1
Shuran Li, Xueyang Bao, Duowei Wang, Linjun You, Xianjing Li, Hongbao Yang, Jinsong Bian, Yun Wang, Yong Yang
APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma (HCC) and APOBEC3B (A3B) remains unknown. It has been confirmed that interleukin-6 (IL-6) has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3B in HepG2 cells. A3B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3B and IL-6, and thereby promoted the prolonged non-resolving inflammation...
May 29, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28645562/anti-myeloma-effects-of-ruxolitinib-combined-with-bortezomib-and-lenalidomide-a-rationale-for-jak-stat-pathway-inhibition-in-myeloma-patients
#2
Mariana B de Oliveira, Veruska L Fook-Alves, Angela I P Eugenio, Rodrigo C Fernando, Luiz Felipe G Sanson, Mariana F de Carvalho, Walter M T Braga, Faith E Davies, Gisele W B Colleoni
JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase...
June 20, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28645489/effects-of-hypnotic-bromovalerylurea-on-microglial-bv2-cells
#3
Shun Kawasaki, Naoki Abe, Fumito Ohtake, Afsana Islam, Mohammed Emamussalehin Choudhury, Ryo Utsunomiya, Satoshi Kikuchi, Tasuku Nishihara, Jun Kuwabara, Hajime Yano, Yuji Watanabe, Mayuki Aibiki, Toshihiro Yorozuya, Junya Tanaka
An old sedative and hypnotic bromovalerylurea (BU) has anti-inflammatory effects. BU suppressed nitric oxide (NO) release and proinflammatory cytokine expression by lipopolysaccharide (LPS)-treated BV2 cells, a murine microglial cell line. However, BU did not inhibit LPS-induced nuclear translocation of nuclear factor-κB and subsequent transcription. BU suppressed LPS-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1)...
June 8, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28634059/a-pumpkin-polysaccharide-induces-apoptosis-by-inhibiting-the-jak2-stat3-pathway-in-human-hepatoma-hepg2-cells
#4
Weixi Shen, Chunhong Chen, Yuanyuan Guan, Xiaowei Song, Yinghua Jin, Jingfang Wang, Yu Hu, Tao Xin, Qiuying Jiang, Li Zhong
The purpose of this study is to investigate the effect of a purified polysaccharide (PPPF) from pumpkin fruit on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. The results showed that PPPF or STAT3 siRNA inhibits the cell growth of HepG2 cells via induction of apoptosis. Moreover, PPPF is able to suppress both constitutive and IL-6-induced phosphorylation of STAT3 (on Tyr705) and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through down-regulation of constitutive phosphorylation of JAK2, but not JAk1, c-Src, ERK1/2, and Akt, which means STAT3 tyrosine phosphorylation in HepG2 cells following PPPF treatment is associated with a reduction in JAK2 activity...
June 17, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28626517/janus-associated-kinase-1-jak1-inhibitors-as-potential-treatment-for-immune-disorders
#5
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28622623/a-phase-2-study-of-momelotinib-a-potent-jak1-and-jak2-inhibitor-in-patients-with-polycythemia-vera-or-essential-thrombocythemia
#6
Srdan Verstovsek, Stephane Courby, Martin Griesshammer, Ruben A Mesa, Carrie Baker Brachmann, Jun Kawashima, Julia D Maltzman, Lixin Shao, Yan Xin, Daniel Huang, Ashish Bajel
Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100mg and 200mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10×10(9)/L, platelet count ≤400×10(9)/L, and resolution of palpable splenomegaly, each lasting ≥4 weeks...
May 30, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28622463/efficacy-safety-pharmacokinetics-and-pharmacodynamics-of-filgotinib-a-selective-janus-kinase-1-inhibitor-after-short-term-treatment-of-rheumatoid-arthritis-results-of-two-randomized-phase-iia-trials
#7
Frédéric Vanhoutte, Minodora Mazur, Oleksandr Voloshyn, Mykola Stanislavchuk, Annegret Van der Aa, Florence Namour, René Galien, Luc Meuleners, Gerben van 't Klooster
OBJECTIVE: Janus kinase (JAK) inhibitors have shown efficacy in rheumatoid arthritis (RA). We hypothesized that selective inhibition of JAK1 would combine good efficacy with a differentiated safety profile versus less selective JAK inhibitors. METHODS: In two 4-week exploratory, double-blind, placebo-controlled Phase IIA trials, 127 RA patients with insufficient response to methotrexate received filgotinib (GLPG0634, GS-6034) oral capsules (twice-daily 100 mg, or once-daily 30, 75, 150, 200, or 300 mg) or placebo, added on to a stable regimen of methotrexate, to evaluate safety, efficacy, pharmacokinetics and pharmacodynamics of filgotinib...
June 16, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#8
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28612527/-the-effect-of-p-jak1-p-stat3-signaling-way-in-intervening-nafld-by-blueberry-probiotic-serum
#9
Juan-Juan Zhu, Ming-Liang Cheng, Ming-Yu Zhou, Xue-Ke Zhao
OBJECTIVES: To explore the mechanism of interlukin-22 (IL-22)-mediated phosphor-Janus kinase-1(p-JAK1)/phosphor-signal transducer and activator of transcription 3 (p-STAT3) signaling way in the experiment of improving non-alcholic fatty liver disease (NAFLD) by blueberry probiotic serum. METHODS: The rat serums with low-, medium-, and high-dose of 10% blueberry probiotics, as well as saline were prepared. NAFLD model was built by inducing normal liver cell line L-02 with free fatty acid (FFA)...
March 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28602585/janus-kinase-2-inhibitor-fedratinib-in-patients-with-myelofibrosis-previously-treated-with-ruxolitinib-jakarta-2-a-single-arm-open-label-non-randomised-phase-2-multicentre-study
#10
Claire N Harrison, Nicolaas Schaap, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Ramon V Tiu, Pierre Zachee, Eric Jourdan, Elliott Winton, Richard T Silver, Harry C Schouten, Francesco Passamonti, Sonja Zweegman, Moshe Talpaz, Joanne Lager, Zhenming Shun, Ruben A Mesa
BACKGROUND: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT...
June 8, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28597963/mir-181a-and-mir-150-regulate-dendritic-cell-immune-inflammatory-responses-and-cardiomyocyte-apoptosis-via-targeting-jak1-stat1-c-fos-pathway
#11
Jianbing Zhu, Kang Yao, Junjie Guo, Hongtao Shi, Leilei Ma, Qian Wang, Haibo Liu, Wei Gao, Aijun Sun, Yunzeng Zou, Junbo Ge
The immune inflammatory response plays a crucial role in many cardiac pathophysiological processes, including ischaemic cardiac injury and the post-infarction repair process. MicroRNAs (miRNAs) regulate the development and function of dendritic cells (DCs), which are key players in the initiation and regulation of immune responses; however, the underlying regulatory mechanisms remain unclear. Here, we used the supernatants of necrotic primary cardiomyocytes (Necrotic-S) to mimic the myocardial infarction (MI) microenvironment to investigate the role of miRNAs in the regulation of DC-mediated inflammatory responses...
June 9, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28593745/ox-ldl-increases-microrna-29a-transcription-through-up-regulating-yy1-and-stat1-in-macrophages
#12
Dongdong Jian, Bing Dai, Xiaotong Hu, Qiang Yao, Li Zhang, Jianhua Zhu
Macrophages and oxidized low-density lipoprotein (ox-LDL) have been verified playing vital roles in the pathogenesis of atherosclerosis (AS). Previous studies demonstrated that microRNA-29a (miR-29a) was up-regulated in many atherogenic process and cells thus acting as an important participant in AS. But the detailed regulation mechanism of miR-29a in AS has not been fully understood. In our study, we demonstrated a positive feedback loop ox-LDL-SRA-miR-29a. Furthermore, we found that YY1 and STAT1 were up-regulated in ox-LDL stimulating macrophages followed by translocating in the nucleus and binding to the transcriptional promoter region of miR-29a thus leading to the increase of miR-29a expression...
June 7, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28586756/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#13
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
May 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28580640/region-based-association-tests-for-sequencing-data-on-survival-traits
#14
Li-Chu Chien, Donald W Bowden, Yen-Feng Chiu
Family-based designs enriched with affected subjects and disease associated variants can increase statistical power for identifying functional rare variants. However, few rare variant analysis approaches are available for time-to-event traits in family designs and none of them applicable to the X chromosome. We developed novel pedigree-based burden and kernel association tests for time-to-event outcomes with right censoring for pedigree data, referred to FamRATS (family-based rare variant association tests for survival traits)...
June 4, 2017: Genetic Epidemiology
https://www.readbyqxmd.com/read/28580587/heme-oxygenase-1-directly-binds-stat3-to-control-the-generation-of-pathogenic-th17-cells-during-neutrophilic-airway-inflammation
#15
Xiaoliang Lin, Jiajia Lv, Jie Lv, Caixia Di, Yanjie Zhang, Tong Zhou, Junling Liu, Zhenwei Xia
BACKGROUND: Specific JAK/STAT pathways play a critical role in the functional differentiation of distinct Th subsets. Previously, we showed that HO-1, a stress-inducible protein, inhibits Th17 cell differentiation and alleviates neutrophilic airway inflammation, but the responsible molecular basis remains unclear. METHODS: We employed Th17-skewing differentiation and NEA mouse models to study the role of HO-1 regulating IL-6-STAT3-RORγt/SOCS3 signaling pathway to control Th17 cell-mediated neutrophilic airway inflammation...
June 5, 2017: Allergy
https://www.readbyqxmd.com/read/28579852/treatment-of-myelofibrosis-old-and-new-strategies
#16
REVIEW
Alessandra Iurlo, Daniele Cattaneo
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy...
2017: Clinical Medicine Insights. Blood Disorders
https://www.readbyqxmd.com/read/28561041/acquired-ifn%C3%AE-resistance-impairs-anti-tumor-immunity-and-gives-rise-to-t-cell-resistant-melanoma-lesions
#17
Antje Sucker, Fang Zhao, Natalia Pieper, Christina Heeke, Raffaela Maltaner, Nadine Stadtler, Birgit Real, Nicola Bielefeld, Sebastian Howe, Benjamin Weide, Ralf Gutzmer, Jochen Utikal, Carmen Loquai, Helen Gogas, Ludger Klein-Hitpass, Michael Zeschnigk, Astrid M Westendorf, Mirko Trilling, Susanne Horn, Bastian Schilling, Dirk Schadendorf, Klaus G Griewank, Annette Paschen
Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8(+) T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28560434/mir-30e-acts-as-a-tumor-suppressor-in-hepatocellular-carcinoma-partly-via-jak1-stat3-pathway
#18
Junjie Mao, Xiaojun Hu, Pengfei Pang, Bin Zhou, Dan Li, Hong Shan
Hepatocellular carcinoma (HCC) is the leading cause of cancer-associated mortalities. The effective diagnostic and therapeutic targets for HCC are still unclear. miR-30e was differentially expressed in the majority of HCC tissues and cell lines. The aim of this study was to investigate the functional roles of miR-30e and their modulation of cancer networks in HCC cells. We determined the expression of miR-30e by quantitative real-time polymerase chain reaction, and found downregulation of miR-30e in HepG2 and HuH7 cells...
May 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28559991/exogenous-mscs-ameliorate-hypoxia-reoxygenation-injury-in-renal-tubular-epithelial-cells-through-jak-stat-signaling-pathway-mediated-regulation-of-hmgb1
#19
Lei Zhang, Yan Wang, Junjie Ma, Xingqiang Lai, Jiali Fang, Guanghui Li, Lu Xu, Guanghui Pan, Zheng Chen
This study was conducted to investigate the repair mechanism of hypoxia/reoxygenation injury (HRI) in renal tubular epithelial cells (HK-2) by exogenous mesenchymal stem cells (MSCs). The activation of the JAK/STAT pathway in HK-2 cells after HRI and treatment of MSCs, JAK inhibitor WP1066 and STAT inhibitor SOCS3 was investigated using Western blot analysis. HK-2 cells were transfected with siRNA STAT3 and analyzed for expression of STAT3, JAK2 and HMGB1 using fluorescence quantitative PCR and Western blot...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28554737/podocyte-specific-jak2-overexpression-worsens-diabetic-kidney-disease-in-mice
#20
Hongyu Zhang, Viji Nair, Jharna Saha, Kevin B Atkins, Jeffrey B Hodgin, Thomas L Saunders, Martin G Myers, Thomas Werner, Matthias Kretzler, Frank C Brosius
Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease...
May 26, 2017: Kidney International
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