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https://www.readbyqxmd.com/read/28820066/mutational-impact-on-the-interaction-between-human-il27-and-gp130-in-silico-approach-for-defending-hiv-infection
#1
Arundhati Banerjee, Rakhi Dasgupta, Sujay Ray
INTRODUCTION: With advances in proteomics, it is essential to investigate the molecular-level participation of IL27 and gp130 to hinder HIV infection. Their interaction causes cell-cycle arrest in HIV+ cells by activating the receptor-associated JAK signaling and causing apoptosis of cancerous cells. METHODOLOGY: The best human wild-type WT_IL27 model was prepared after varied molecular modeling techniques. The vital tyrosine residues in WT_IL27 were identified, mutated and IL27 was re-modeled...
August 17, 2017: Current HIV Research
https://www.readbyqxmd.com/read/28799436/immunotherapy-based-approaches-in-myelofibrosis
#2
Lucia Masarova, Srdan Verstovsek, Hagop Kantarjian, Naval Daver
Aberrant regulation of the immune system with up-regulation of pro-inflammatory cytokines contributes to disease pathophysiology in myelofibrosis (MF). Therapeutic options for MF associated anemia, thrombocytopenia, and bone marrow fibrosis remain limited. Areas covered: This review focuses on immune based therapies in MF, including immunomodulatory imide drugs (IMiDs), interferons, monoclonal antibodies and targeted agents (SL-401), and checkpoint inhibitors. Published literature was reviewed using available databases (PubMed, Cochrane, Scopus) and web pages (clinicaltrials...
August 11, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28791654/pharmacotherapy-of-myelofibrosis
#3
REVIEW
Douglas Tremblay, Bridget Marcellino, John Mascarenhas
Myelofibrosis (MF) is a myeloproliferative neoplasm that is pathologically characterized by bone marrow myeloproliferation, reticulin and collagen fibrosis, and extramedullary hematopoiesis. Constitutive activation of the Janus associated kinase (JAK)-signal transducers and activators of transcription signaling pathway with resultant elevation in pro-inflammatory cytokine levels is the pathogenic hallmark of MF. JAK inhibitors, namely ruxolitinib, have been successful in alleviating symptoms and reducing splenomegaly, but therapy-related myelosuppression has led to the further development of highly selective JAK2 inhibitors...
August 8, 2017: Drugs
https://www.readbyqxmd.com/read/28790099/gsk2586184-a-jak1-selective-inhibitor-in-two-patients-with-ulcerative-colitis
#4
Leonie C S De Vries, Valerie J Ludbrook, Kirsty J Hicks, Geert R D'Haens
Tofacitinib, a non-selective Janus kinase (JAK) inhibitor, is effective in inducing clinical and endoscopic remission in patients with active ulcerative colitis (UC). Tofacitinib inhibits cytokine signalling through blockade of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Adverse events including neutropenia and anaemia resulting from JAK2 inhibition have been observed in actively treated patients. By selectively targeting JAK1, such adverse events could be expected to be avoided. This open label study was designed to enrol 15 patients with UC, however the trial was discontinued after two inclusions due to safety concerns with the agent in a parallel trial for systemic lupus erythematosus...
August 7, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28789911/discovery-of-tricyclic-dipyrrolopyridine-derivatives-as-novel-jak-inhibitors
#5
Hiroaki Yamagishi, Takayuki Inoue, Yutaka Nakajima, Jun Maeda, Hiroaki Tominaga, Hiroyuki Usuda, Takeshi Hondo, Ayako Moritomo, Fumihiro Nakamori, Misato Ito, Koji Nakamura, Hiroki Morio, Yasuyuki Higashi, Masamichi Inami, Shohei Shirakami
Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability...
July 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28782829/the-participation-of-fibroblast-growth-factor-23-fgf23-in-the-progression-of-osteoporosis-via-jak-stat-pathway
#6
Lijun Xu, Lixia Zhang, Huijuan Zhang, Zaigang Yang, Lei Qi, Yurong Wang, Shuxin Ren
Osteoporosis (OP) is a major skeletal disorder for the old man. The fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by osteoblasts and osteocytes. However, the regulatory mechanisms of FGF23 in the progression of osteoporosis remain poorly understood. This study aims to explore the downstream regulating pathway of FGF23 in postmenopausal osteoporosis. The rat model of osteoporosis was established through ovariectomy (OVX). The investigation demonstrated that the serum levels of FGF23 and the phosphorylation levels of JAK2, STAT1 and STAT3 were up-regulated in the OVX + NVP-BGJ398 group while were down-regulated in the OVX + Anti-FGF23 group than that in the OVX group...
August 7, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28780423/cinnamic-acid-derivatives-inhibit-hepatitis-c-virus-replication-via-the-induction-of-oxidative-stress
#7
Ryota Amano, Atsuya Yamashita, Hirotake Kasai, Tomoka Hori, Sayoko Miyasato, Setsu Saito, Hiromasa Yokoe, Kazunori Takahashi, Tomohisa Tanaka, Teruhime Otoguro, Shinya Maekawa, Nobuyuki Enomoto, Masayoshi Tsubuki, Kohji Moriishi
Several cinnamic acid derivatives have been reported to exhibit antiviral activity. In this study, we prepared 17 synthetic cinnamic acid derivatives and screened them to identify an effective antiviral compound against hepatitis C virus (HCV). Compound 6, one of two hit compounds, suppressed the viral replications of genotypes 1b, 2a, 3a, and 4a with EC50 values of 1.5-8.1 μM and SI values of 16.2-94.2. The effect of compound 6 on the phosphorylation of Tyr(705) in signal transducer and activator of transcription 3 (STAT3) was investigated because a cinnamic acid derivative AG490 was reported to suppress HCV replication and the activity of Janus kinase (JAK) 2...
August 2, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28776046/jak-inhibitors-modulate-production-of-replication-competent-zika-virus-in-human-hofbauer-trophoblasts-and-neuroblastoma-cells
#8
Christina Gavegnano, Leda C Bassit, Bryan D Cox, Hui-Mien Hsiao, Erica L Johnson, Mehul Suthar, Rana Chakraborty, Raymond F Schinazi
Zika Virus (ZIKV) is a flavivirus that has been implicated in causing brain deformations, birth defects, and microcephaly in fetuses, and associated with Guillain-Barre syndrome. Mechanisms responsible for transmission of ZIKV across the placenta to the fetus are incompletely understood. Herein, we define key events modulating infection in clinically relevant cells, including primary placental macrophages (human Hofbauer cells; HC), trophoblasts, and neuroblastoma cells. Consistent with previous findings, HC and trophoblasts are permissive to ZIKV infection...
2017: Pathogens & Immunity
https://www.readbyqxmd.com/read/28770966/inhibition-of-mir-221-influences-bladder-cancer-cell-proliferation-and-apoptosis
#9
H Liu, J-K Chang, J-Q Hou, Z-H Zhao, L-D Zhang
OBJECTIVE: Janus kinase (JAK) - signal transducer and activator of transcription (STAT) signaling pathway participate in cell proliferation and apoptosis. Suppressors of cytokine signaling 3 (SOCS3) are negative regulators of JAK-STAT3. SOCS3 was found significantly declined, while microRNA-221 (miR-221) obviously up-regulated in bladder cancer tissue. Bioinformatics analysis revealed the complementary binding site between miR-221 and 3'-UTR of SOCS3. This study investigated the role of miR-221 in regulating SOCS3/JAK-STAT3 signaling pathway and bladder cancer cell proliferation and apoptosis...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28765121/novel-therapies-for-immune-mediated-inflammatory-diseases-what-can-we-learn-from-their-use-in-rheumatoid-arthritis-spondyloarthritis-systemic-lupus-erythematosus-psoriasis-crohn-s-disease-and-ulcerative-colitis
#10
REVIEW
Kenneth F Baker, John D Isaacs
The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide...
August 1, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28762112/targeted-next-generation-sequencing-identifies-clinically-relevant-mutations-in-patients-with-chronic-neutrophilic-leukemia-at-diagnosis-and-blast-crisis
#11
S E Langabeer, K Haslam, J Kelly, J Quinn, R Morrell, E Conneally
PURPOSE: Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification. MATERIALS AND METHODS: A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients...
July 31, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28760302/developmental-therapeutics-in-myeloproliferative-neoplasms
#12
REVIEW
Prithviraj Bose, Srdan Verstovsek
The unprecedented success of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib in myelofibrosis (MF) provided much-needed impetus for clinical drug development for the Philadelphia chromosome-negative myeloproliferative neoplasms. The survival benefit conferred by this agent, along with its marked efficacy with regard to spleen volume and symptom reduction, have made ruxolitinib the cornerstone of drug therapy in MF. However, there remain significant unmet needs in the treatment of patients with MF, and many novel classes of agents continue to be investigated in efforts to build on the progress made with ruxolitinib...
July 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28756223/bebt-908-a-novel-potent-pi3k-hdac-inhibitor-against-diffuse-large-b-cell-lymphoma
#13
Jin Li, Changgeng Qian, Qianqian Zhou, Jiwei Li, Kunlun Li, Pingyong Yi
The PI3K pathway and epigenetic regulation have been shown to play a pivotal role in the development and progression of diffuse large B-cell lymphoma (DLBCL). In the clinic, existing PI3K and HDAC inhibitors show limited efficacy as single agents toward DLBCL. However, in preclinical studies, the synergistic effects of PI3K inhibitors and HDAC inhibitors on DLBCL have sparked the enthusiasm of researchers to target both PI3K and HDAC. We hypothesized that a novel dual PI3K/HDAC inhibitor, BEBT-908, would display improved pharmacologic effects on DLBCL...
July 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28753520/interleukin-10-inhibits-neuroinflammation-mediated-apoptosis-of-ventral-mesencephalic-neurons-via-jak-stat3-pathway
#14
Yan Zhu, Zhan Liu, Yu-Ping Peng, Yi-Hua Qiu
Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease. Interleukin (IL)-10 is one of the most important and best anti-inflammatory cytokines. The objective of this report is to investigate whether IL-10 has any role in protecting ventral mesencephalic (VM) neurons in in vitro model of neuroinflammation. In this study, primary neuron-enriched culture was prepared from the VM tissues of E14 embryos of rats. The cells were pretreated with IL-10 (15 or 50ng/mL) for 1h followed by lipopolysaccharide (LPS, 50ng/mL) application...
September 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28752178/inhibitory-effect-of-jak-inhibitor-on-mechanical-stress-induced-protease-expression-by-human-articular-chondrocytes
#15
Takahiro Machida, Keiichiro Nishida, Yoshihisa Nasu, Ryuichi Nakahara, Masatsugu Ozawa, Ryozo Harada, Masahiro Horita, Ayumu Takeshita, Daisuke Kaneda, Aki Yoshida, Toshifumi Ozaki
OBJECTIVE: To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes. MATERIALS AND METHODS: Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation...
July 27, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28751937/myricitrin-modulates-nadph-oxidase-dependent-ros-production-to-inhibit-endotoxin-mediated-inflammation-by-blocking-the-jak-stat1-and-nox2-p47-phox-pathways
#16
Shimei Qi, Zunyong Feng, Qiang Li, Zhilin Qi, Yao Zhang
Myricitrin, a naturally occurring polyphenol hydroxy flavonoid, has been reported to possess anti-inflammatory properties. However, the precise molecular mechanism of myricitrin's effects on LPS-induced inflammation is unclear. In the present study, myricitrin significantly alleviated acute lung injury in mice. Myricitrin also markedly suppressed the production of NO, TNF-α, IL-6, and MCP-1 in RAW264.7 macrophage cells. The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of iNOS...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28748356/pd-l1-induced-by-ifn-%C3%AE-from-tumor-associated-macrophages-via-the-jak-stat3-and-pi3k-akt-signaling-pathways-promoted-progression-of-lung-cancer
#17
Xiaohui Zhang, Yuanyuan Zeng, Qiuxia Qu, Jianjie Zhu, Zeyi Liu, Weiwei Ning, Hui Zeng, Nan Zhang, Wenwen Du, Cheng Chen, Jian-An Huang
BACKGROUND: Interferon-γ (IFN-γ) is conventionally regarded as an inflammatory cytokine that has a pivotal role in anti-infection and tumor immune surveillance. It has been used clinically to treat a variety of malignancies. However, increased evidence has suggested IFN-γ can act to induce tumor progression. The role of IFN-γ in regulating antitumor immunity appears to be complex and paradoxical. The mechanism underlying the dual aspects of IFN-γ function in antitumor immunity is not clear...
July 26, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28745314/a-muscle-specific-protein-myoferlin-modulates-il-6-stat3-signaling-by-chaperoning-activated-stat3-to-nucleus
#18
A Yadav, B Kumar, J C Lang, T N Teknos, P Kumar
Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently, myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate vascular endothelial growth factor (VEGFR)-2 and epidermal growth factor receptor (EGFR) signaling by enhancing their stability and recycling. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling...
July 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28744013/the-t-cell-leukemia-associated-ribosomal-rpl10-r98s-mutation-enhances-jak-stat-signaling
#19
T Girardi, S Vereecke, S O Sulima, Y Khan, L Fancello, J W Briggs, C Schwab, J O de Beeck, J Verbeeck, J Royaert, E Geerdens, C Vicente, S Bornschein, C J Harrison, J P Meijerink, J Cools, J D Dinman, K R Kampen, K De Keersmaecker
Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10-R98S) found in T-ALL. The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10-R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10-R98S mice and T-ALL xenograft samples...
July 24, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28739255/wp1066-a-small-molecule-inhibitor-of-the-jak-stat3-pathway-inhibits-ceramide-glucosyltransferase-activity
#20
Hirotaka Tsurumaki, Hikaru Katano, Kousuke Sato, Ryou Imai, Satomi Niino, Yoshio Hirabayashi, Shinichi Ichikawa
WP1066 is a well-known inhibitor of the JAK/STAT3 signaling pathway. By a screen of known small molecule inhibitors of various enzymes and protein factors, we identified WP1066 as a ceramide glucosyltransferase inhibitor. Ceramide glucosyltransferase catalyzes the first glycosylation step during glycosphingolipid synthesis. We found that WP1066 inhibited the activity of ceramide glucosyltransferase with an IC50 of 7.2 μM, and that its action was independent of JAK/STAT3 pathway blockade. Moreover, the modes of inhibition of ceramide glucosyltransferase were uncompetitive with respect to both C6-NBD-cermide and UDP-glucose...
July 21, 2017: Biochemical and Biophysical Research Communications
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