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Jak2 inhibitor

Yanna Si, Yuan Zhang, Liu Han, Lihai Chen, Yajie Xu, Fan Sun, Muhuo Ji, Jianjun Yang, Hongguang Bao
BACKGROUND: Previous studies showed that isoflurane-induced cognitive deficits could be alleviated by dexmedetomidine in young animal subjects. In the current study, we examine whether dexmedetomidine could also alleviate isoflurane-induced cognitive deficits in senile animals. METHODS: Senile male C57BL/6 mice (20 months) received dexmedetomidine (50 μg/kg, i.p.) or vehicle 30 minutes prior to isoflurane exposure (1.3% for 4 h). Cognitive function was assessed 19 days later using a 5-day testing regimen with Morris water maze...
2016: PloS One
Guoliang Wang, Jingchao Zhang, Danhua Dui, Haoyuan Ren, Jin Liu
The pathogenesis of severe acute pancreatitis (SAP) remains unclear. The Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway is important for various cytokines and growth factors. This study investigated the effect of the late inflammatory factor high mobility group box 1 (HMGB1) on the activation of JAK2/STAT3 in pancreatic acinar cells and the inhibitory effects of AG490 (a JAK2 inhibitor) and rapamycin (a STAT3 inhibitor) on this pathway. Rat pancreatic acinar cells were randomly divided into the control, HMGB1, AG490, and rapamycin groups...
October 18, 2016: Bosnian Journal of Basic Medical Sciences
M S Patton, D J Lodge, D A Morilak, M Girotti
Deficits in cognitive flexibility are prominent in stress-related psychiatric disorders, including depression. Ketamine has rapid antidepressant efficacy, but it is unknown if ketamine improves cognitive symptoms. In rats, 2 weeks chronic intermittent cold (CIC) stress impairs reversal learning, a form of cognitive flexibility mediated by the orbitofrontal cortex (OFC) that we have used previously to model cognitive dysfunction in depression. We have shown that activating JAK2/STAT3 signaling in the OFC rescued the CIC stress-induced reversal learning deficit...
October 17, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Anna Ngo, Ann Koay, Christian Pecquet, Carmen C Diaconu, Yasmine Ould-Amer, Qiwei Huang, Congbao Kang, Anders Poulsen, May Ann Lee, David Jenkins, Andrew Shiau, Stefan N Constantinescu, Meng Ling Choo
BACKGROUND: Rather than a Janus Kinase 2 inhibitor (ruxolitinib), a specific thrombopoietin receptor (TpoR) inhibitor would be more specific for the treatment of myeloproliferative neoplasms due to TpoR mutations. OBJECTIVE: A cell-based phenotypic approach to identify specific TpoR inhibitors was implemented and a library of 505,483 small molecules was screened for inhibitory effects on cells transformed by TpoR mutants. RESULTS: Among the identified hits are two analogs of 3-(4-piperidinyl) indole...
October 10, 2016: Combinatorial Chemistry & High Throughput Screening
K Kollmann, W Warsch, C Gonzalez-Arias, F L Nice, E Avezov, J Milburn, J Li, D Dimitropoulou, S Biddie, M Wang, E Poynton, M Colzani, M R Tijssen, S Anand, U McDermott, B Huntly, T Green
Most MPN patients lacking JAK2 mutations harbour somatic CALR mutations that are thought to activate cytokine signalling although the mechanism is unclear. To identify kinases important for survival of CALR-mutant cells we developed a novel strategy (KISMET) which utilises the full range of kinase selectivity data available from each inhibitor and thus takes advantage of off-target noise that limits conventional siRNA or inhibitor screens. KISMET successfully identified known essential kinases in haematopoietic and non-haematopoietic cell lines and identified the MAPK pathway as required for growth of the CALR-mutated MARIMO cells...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
M Marchetti, G Barosi, F Cervantes, G Birgegård, M Griesshammer, C Harrison, R Hehlmann, J-J Kiladjian, N Kröger, M F McMullin, F Passamonti, A Vannucchi, T Barbui
Ruxolitinib is an oral JAK1/JAK2 inhibitor approved for the treatment of patients with myelofibrosis (MF) based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of three clinical outcomes: a) splenomegaly, b) disease-related symptoms, and c) survival...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Sabine Blum, Filipe Martins, Lorenzo Alberio
The discovery of JAK2 V617F mutation in the mid-2000s started to fill the gap between clinical presentation of polycythemia vera (PV), first described by Vaquez at the end of the 19th century, and spontaneous erythroid colony formation, reported by Prchal and Axelrad in the mid-1970s. The knowledge on this mutation brought an important insight to our understanding of PV pathogenesis and led to a revision of the World Health Organization diagnostic criteria in 2008. JAK-STAT is a major signaling pathway implicated in survival and proliferation of hematopoietic precursors...
2016: Journal of Blood Medicine
Katsuto Takenaka
Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis. The JAK2V617F mutation was identified in 2005, followed by the discovery of the JAK2 exon12, MPNW515 mutation, and CALR mutation. About 90% of patients with BCR/ABL negative MPNs have been shown to have one of these driver mutations. In addition, mutations in epigenetic regulators and RNA splicing genes were found to co-exist with driver mutations and to play critical roles in the disease progression of MPNs...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Roy Fleischmann, Michael Schiff, Désirée van der Heijde, Cesar Ramos-Remus, Alberto Spindler, Marina Stanislav, Cristiano A F Zerbini, Sirel Gurbuz, Christina Dickson, Stephanie de Bono, Douglas Schlichting, Scott Beattie, Wen-Ling Kuo, Terence Rooney, William Macias, Tsutomu Takeuchi
Objective This Phase 3 study evaluated baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and naive to biologic DMARDs. Methods Patients (N=588) were randomized 4:3:4 (MTX: baricitinib 4 mg once daily: baricitinib 4 mg + MTX) for 52 weeks. The primary endpoint assessment was noninferiority of baricitinib monotherapy to MTX based on American College of Rheumatology 20% (ACR20) response at Week 24...
October 9, 2016: Arthritis & Rheumatology
Wenda Zhang, Ting Ma, Shanshan Li, Yanwei Yang, Jianpeng Guo, Wenying Yu, Lingyi Kong
STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC50 range in 0.33-0.75 μM in various cancer cell lines...
September 22, 2016: European Journal of Medicinal Chemistry
K-H Lim, Y-C Chang, Y-H Chiang, H-C Lin, C-Y Chang, C-S Lin, L Huang, W-T Wang, C Gon-Shen Chen, W-C Chou, Y-Y Kuo
CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b...
October 7, 2016: Blood Cancer Journal
Ana Karina Alves de Medeiros, Reinhart Speeckaert, Eline Desmet, Mireille Van Gele, Sofie De Schepper, Jo Lambert
The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3...
2016: PloS One
Robert E Chapin, Douglas J Ball, Zaher A Radi, Steven W Kumpf, Petra H Koza-Taylor, David M Potter, W Mark Vogel
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity...
October 5, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Xin Xu, Kunkun Han, Jingyu Zhu, Hongwu Mao, Xu Lin, Zubin Zhang, Biyin Cao, Yuanying Zeng, Xinliang Mao
The activated JAK2-STAT3 signaling pathway is a high risk factor for multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, SC09, a potential inhibitor of cholesterol absorption, was identified in a STAT3-targeted drug screen. SC09 suppressed the activation of STAT3 in a time-course and concentration-dependent manner but did not affect its family members STAT1 and STAT5. SC09 inhibited STAT3 transcriptional activity and downregulated the expression of STAT3-regulated genes. Further studies showed that SC09 selectively inhibited JAK2 activation but not other kinases including c-Src, ERK, p38 and mTOR that are all associated with STAT3 activation...
September 26, 2016: Oncotarget
Georgia Dalagiorgou, Christina Piperi, Christos Adamopoulos, Urania Georgopoulou, Antonios N Gargalionis, Anastasia Spyropoulou, Ilianna Zoi, Marjan Nokhbehsaim, Anna Damanaki, James Deschner, Efthimia K Basdra, Athanasios G Papavassiliou
Polycystin-1 (PC1) has been proposed as a chief mechanosensing molecule implicated in skeletogenesis and bone remodeling. Mechanotransduction via PC1 involves proteolytic cleavage of its cytoplasmic tail (CT) and interaction with intracellular pathways and transcription factors to regulate cell function. Here we demonstrate the interaction of PC1-CT with JAK2/STAT3 signaling axis in mechanically stimulated human osteoblastic cells, leading to transcriptional induction of Runx2 gene, a master regulator of osteoblastic differentiation...
October 3, 2016: Cellular and Molecular Life Sciences: CMLS
Michael Leung, Kaitlin Highsmith, Amber Rexwinkle
Myelofibrosis is a BCR-ABL-negative myeloproliferative neoplasm characterized by abnormal hematopoiesis. Alterations to the Janus kinase-signal transducer and activator of transcription pathway result in dysregulation of gene transcription and cell proliferation. Patients with symptomatic myelofibrosis present with a variety of signs and symptoms including, but not limited to myelosuppression, marked splenomegaly, abdominal discomfort, fatigue, and blood transfusion-dependence. Traditional myelosuppressive therapies including hydroxyurea, azacitidine, and cladribine aim to reduce constitutional symptoms and control the burden of disease...
September 26, 2016: Journal of Oncology Pharmacy Practice
Eun-Cheol Kim, Myo-Kyoung Kim, Richard Leesungbok, Suk-Won Lee, Su-Jin Ahn
OBJECTIVE: Although cobalt-chromium (Co-Cr) dental alloys are routinely used in prosthodontics, the biocompatibility of Co-Cr alloys is controversial. The aims of the present study were to investigate the effects of Co-Cr alloys on human gingival fibroblasts (HGF) and osteoblasts in an in vitro model as well as their potential molecular mechanisms, focusing on NF-E2-related factor 2 (Nrf2) pathways. METHODS: Cells were directly seeded on prepared Co-Cr alloy discs (15...
September 23, 2016: Dental Materials: Official Publication of the Academy of Dental Materials
Oraphan Phuangsawai, Paul Beswick, Siriluk Ratanabunyong, Lueacha Tabtimmai, Praphasri Suphakun, Phongphat Obounchoey, Pimonwan Srisook, Natharinee Horata, Irina Chuckowree, Supa Hannongbua, Simon E Ward, Kiattawee Choowongkomon, M Paul Gleeson
A series of 2,4 diamino-pyrimidines have been identified from an analysis of open access high throughput anti-malarial screening data reported by GlaxoSmithKline at the 3D7 and resistant Dd2 strains. SAR expansion has been performed using structural knowledge of the most plausible parasite target. Seventeen new analogs have been synthesized and tested against the resistant K1 strain of Plasmodium falciparum (Pf). The cytotoxicity of the compounds was assessed in Vero and A549 cells and their selectivity towards human kinases including JAK2 and EGFR were undertaken...
August 30, 2016: European Journal of Medicinal Chemistry
Zsófia Simon, Imelda Marton, Zita Borbényi, Árpád Illés
Primary myelofibrosis is one of the Philadelphia negative chronic myeloproliferative neoplasms. It is a rare disease featured by cytopenias and hepatosplenomegaly. Although the etiology of the disease is still unknown, our knowledge about its pathology and prognosis has been improving in the last few years. Furthermore, the JAK2 inhibitor ruxolitinib has become available in Hungary since 2015. Beside its high efficacy in spleen volume and in reduction of myelofibrosis-associated symptoms, this novel therapy also exerts a disease-modifying effect and, therefore, ruxolitinib may improve the life expectancy too...
September 2016: Orvosi Hetilap
Chunlai Liu, Yongwen Li, Yunlong Dong, Hongbing Zhang, Ying Li, Hongyu Liu, Jun Chen
BACKGROUND: The EML4-ALK fusion gene is a newly discovered driver gene of non-small cell lung cancer and exhibits special clinical and pathological features. The JAK-STAT signaling pathway, an important downstream signaling pathway of EML4-ALK, is aberrantly sustained and activated in EML4-ALK-positive lung cancer cells fusion gene, but the underlying reason remains unknown. The suppressor of cytokine signaling (SOCS) is a negative regulatory factor that mainly inhibits the proliferation, differentiation, and induction of apoptotic cells by inhibiting the JAK-STAT signaling pathway...
September 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
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