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https://www.readbyqxmd.com/read/28817464/biologics-for-idiopathic-inflammatory-myopathies
#1
Siamak Moghadam-Kia, Rohit Aggarwal, Chester V Oddis
PURPOSE OF REVIEW: As treatment of refractory cases of idiopathic inflammatory myopathies (IIMs) has been challenging, there is growing interest in assessing novel biologics that target various pathways implicated in the pathogenesis of IIM. RECENT FINDINGS: In the largest clinical trial in adult and juvenile IIM assessing the effectiveness of rituximab, the primary outcome was not met but 83% of this refractory group of IIM patients met a predefined definition of improvement and rituximab demonstrated a significant glucocorticoid-sparing effect...
August 16, 2017: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/28810635/curcumin-protects-against-acute-renal-injury-by-suppressing-jak2-stat3-pathway-in-severe-acute-pancreatitis-in-rats
#2
Shuaijun Zhu, Chi Zhang, Qinyong Weng, Bing Ye
The aim of the present study was to investigate the effect of curcumin on acute renal injury in a rat model of severe acute pancreatitis (SAP). A SAP model with acute kidney injury was established in rats by retrograde injection of 5% sodium taurocholate into the pancreatic duct. The serum amylase, creatinine (Cr) and blood urea nitrogen (BUN) levels in rats were measured. Hematoxylin and eosin staining was used to assess pancreatic and renal histological changes. Serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured using ELISA kits...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28801915/manganese-and-1-methyl-4-phenylpyridinium-mpp-induced-neurotoxicity-indicate-differences-in-morphological-electrophysiological-and-genome-wide-alterations-implications-for-idiopathic-parkinson-s-disease
#3
Rajeswara Babu Mythri, Narayana Reddy Raghunath, Santosh Chandrakant Narwade, Mirazkar DasharathaRao Pandareesh, Kollarkandi Rajesh Sabitha, Mohamad Aiyaz, Bipin Chand, Manas Sule, Krittika Ghosh, Senthil Kumar, Bhagyalakshmi Shankarappa, Soundarya Soundararajan, Phalguni Anand Alladi, Meera Purushottam, Narayanappa Gayathri, Deepti Dileep Deobagkar, Thenkanidiyoor Rao Laxmi, Srinivas Bharath Muchukunte Mukunda
Idiopathic Parkinson's disease (iPD) and manganese-induced atypical Parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the PD toxin 1-methyl-4-phenylpyridinium ion (MPP(+) ) and manganese (Mn) followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and Mn mouse models...
August 12, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28798799/central-administration-of-1-deoxynojirimycin-attenuates-hypothalamic-endoplasmic-reticulum-stress-and-regulates-food-intake-and-body-weight-in-mice-with-high-fat-diet-induced-obesity
#4
Jongwan Kim, Eun-Young Yun, Fu-Shi Quan, Seung-Won Park, Tae-Won Goo
The α-glucosidase inhibitor, 1-deoxynojirimycin (DNJ), is widely used for its antiobesity and antidiabetic effects. Researchers have demonstrated that DNJ regulates body weight by increasing adiponectin levels, which affects energy intake and prevents diet-induced obesity. However, the mechanism by which centrally administered DNJ exerts anorexigenic effects has not been studied until now. We investigated the effect of DNJ in the hypothalamus of mice with high-fat diet-induced obesity. Results showed that intracerebroventricular (ICV) administration of DNJ reduced hypothalamic ER stress, which activated the leptin-induced Janus-activated kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathway to cause appetite suppression...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28791654/pharmacotherapy-of-myelofibrosis
#5
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/28791417/diverse-gene-expression-patterns-in-response-to-anticancer-drugs-between-human-and-mouse-cell-lines-revealed-by-a-comparative-transcriptomic-analysis
#6
Yong Guo, Zhuoran Liang, Xiaoliang Hou, Zhi Zhang
The aim of the present study was to perform comparative genomics using gene expression profile datasets of mice and humans who had been treated with anticancer drugs, to determine the similarities and differences in the antitumor mechanisms in the two mammals. This involved data mining of antitumor gene expression regulation, and screening of genetic loci from experimental mouse models of antitumor targets, to provide a theoretical basis of drug design. Subsequently, 9 overlapping genes with opposite expression patterns were identified across mouse and human cell lines that were treated with a specific cyclin‑dependent kinase 4/6 inhibitor, PD0332991...
August 4, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28790974/selective-inhibition-of-janus-kinase-3-has-no-impact-on-infarct-size-or-neurobehavioral-outcomes-in-permanent-ischemic-stroke-in-mice
#7
Kelly M DeMars, Sean C Pacheco, Changjun Yang, David M Siwarski, Eduardo Candelario-Jalil
Janus kinase 3 (JAK3) is associated with the common gamma chain of several interleukin (IL) receptors essential to inflammatory signaling. To study the potential role of JAK3 in stroke-induced neuroinflammation, we subjected mice to permanent middle cerebral artery occlusion and investigated the effects of JAK3 inhibition with decernotinib (VX-509) on infarct size, behavior, and levels of several inflammatory mediators. Results from our double immunofluorescence staining showed JAK3 expression on neurons, endothelial cells, and microglia/macrophages in the ischemic mouse brain (n = 3)...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28790099/gsk2586184-a-jak1-selective-inhibitor-in-two-patients-with-ulcerative-colitis
#8
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
#9
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/28780423/cinnamic-acid-derivatives-inhibit-hepatitis-c-virus-replication-via-the-induction-of-oxidative-stress
#10
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/28771727/salvianolic-acids-enhance-cerebral-angiogenesis-and-neurological-recovery-by-activating-jak2-stat3-signaling-pathway-after-ischemic-stroke-in-mice
#11
Yaoru Li, Xiangjian Zhang, Lili Cui, Rong Chen, Ye Zhang, Cong Zhang, Xingyuan Zhu, Tingting He, Zuyuan Shen, Lipeng Dong, Jingru Zhao, Ya Wen, Xiufen Zheng, Pan Li
Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In the present study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms...
August 3, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28771710/brain-endothelial-cells-induce-astrocytic-expression-of-the-glutamate-transporter-glt-1-by-a-notch-dependent-mechanism
#12
Meredith L Lee, Zila Martinez-Lozada, Elizabeth N Krizman, Michael B Robinson
Neuron-secreted factors induce astrocytic expression of the glutamate transporter, GLT-1 (EAAT2). In addition to their elaborate anatomic relationships with neurons, astrocytes also have processes that extend to and envelop the vasculature. Although previous studies have demonstrated that brain endothelia contribute to astrocyte differentiation and maturation, the effects of brain endothelia on astrocytic expression of GLT-1 have not been examined. In the present study, we tested the hypothesis that endothelia induce expression of GLT-1 by co-culturing astrocytes from mice that utilize non-coding elements of the GLT-1 gene to control expression reporter proteins with the mouse endothelial cell line, bEND...
August 3, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28770966/inhibition-of-mir-221-influences-bladder-cancer-cell-proliferation-and-apoptosis
#13
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/28770377/1-6-o-o-diacetylbritannilactone-inhibits-eotaxin-1-and-alox15-expression-through-inactivation-of-stat6-in-a549-cells
#14
Xi Chen, Ning Ji, Nan Qin, Sheng-An Tang, Ran Wang, Yuling Qiu, Hongquan Duan, Dexin Kong, Meihua Jin
1,6-O,O-Diacetylbritannilactone (OODBL), a plant sesquiterpene lactone, was previously reported to show multiple pharmacological effects such as anti-cancer and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effect of OODBL on interleukin (IL)-4-induced signal transducer and activator of transcription 6 (STAT6) signaling pathway in human lung A549 cells. We found that OODBL dramatically inhibited IL-4-induced messenger RNA (mRNA) expression of eotaxin-1 and arachidonate 15-lipoxygenase-1 (ALOX15) in a dose-dependent manner...
August 2, 2017: Inflammation
https://www.readbyqxmd.com/read/28765941/b7-h3-is-related-to-tumor-progression-in-ovarian-cancer
#15
Jingjing Zhang, Lu Liu, Sai Han, Yi Li, Qiuhong Qian, Qianqian Zhang, Hui Zhang, Ziyan Yang, Youzhong Zhang
B7-H3, a co-stimulatory molecule, has been found expressed in ovarian cancer, but its role and mechanism is not clear. In this study, we further verified the expression of B7-H3 in ovarian carcinoma and normal epithelial ovarian tissues. Three ovarian cancer cell lines, A2780, SKOV3 and HO8910 were selected to explore the effects of B7-H3 on proliferation, apoptosis, migration and invasion. We found that B7-H3 was mainly located in the cytoplasm of ovarian cancer cells as determined by immunofluorescence staining...
July 31, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28765891/non-coding-rna-886-promotes-renal-cell-carcinoma-growth-and-metastasis-through-the-janus-kinase-2-signal-transducer-and-activator-of-transcription-3-signaling-pathway
#16
Jun Lei, Ju-Hua Xiao, Shou-Hua Zhang, Zhi-Qiang Liu, Kai Huang, Zhi-Peng Luo, Xin-Lan Xiao, Zheng-Dong Hong
Non-coding RNA 886 (nc886) has been suggested to serve tumor-suppressing roles in several cancer cells. However, the expression pattern of nc886 and its function in renal cell carcinoma (RCC) has not been reported until now. The present study aimed to examine the expression of nc886 in human RCC tissues and to investigate the role of nc886 in RCC cell proliferation, apoptosis and invasion in vitro. Furthermore, whether nc886 exerts its function on RCC via Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling was investigated...
July 27, 2017: Molecular Medicine Reports
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
#17
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/28762476/use-of-early-clinical-trial-data-to-support-thorough-qt-study-waiver-for-upadacitinib-and-utility-of-food-effect-to-demonstrate-ecg-assay-sensitivity
#18
Mohamed-Eslam F Mohamed, Jiewei Zeng, Ping Jiang, Balakrishna Hosmane, Ahmed A Othman
Exposure-response analyses of QT data from early-stage clinical studies represent a valuable tool to assess the QT prolongation potential for drugs in development in lieu of stand-alone thorough QT (TQT) studies. However, demonstrating adequate ECG assay sensitivity can be challenging in the absence of a positive pharmacological control. Upadacitinib is a Janus Kinase 1 inhibitor currently being evaluated in Phase 3 rheumatoid arthritis trials. Exposure-response analyses to evaluate the QT prolongation potential for upadacitinib from Phase 1 trials and the utility of the effect of food on QTcF to demonstrate ECG assay sensitivity are presented...
August 1, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28760302/developmental-therapeutics-in-myeloproliferative-neoplasms
#19
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/28754958/a-study-on-the-risk-of-fungal-infection-with-tofacitinib-cp-690550-a-novel-oral-agent-for-rheumatoid-arthritis
#20
Yong Chen, Fang-Yuan Gong, Zhen-Jun Li, Zheng Gong, Zhe Zhou, Shu-Yan Ma, Xiao-Ming Gao
Tofacitinib (CP-690550), an oral Janus kinase inhibitor, has shown significant efficacy in the treatment of rheumatoid arthritis through blocking the signaling pathways of pro-inflammatory cytokines. However, recent evidence suggests that long-term tofacitinib treatment is associated with increased risk of infection (e.g. tuberculosis) in patients. In the present study, we illustrate that tofacitinib administration significantly reduced the survival rate of mice given lethal or sub-lethal dose challenge with Candida albicans...
July 28, 2017: Scientific Reports
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