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https://www.readbyqxmd.com/read/29353059/ask-family-kinases-are-required-for-optimal-nlrp3-inflammasome-priming
#1
David E Place, Parimal Samir, Rajendra Karki, Benoit Briard, Peter Vogel, Thirumala-Devi Kanneganti
Activation of the multimeric inflammasome complex leads to inflammatory responses to biotic and abiotic triggers. The inflammasome sensor, Nod-like receptor family Pyrin domain containing 3 (NLRP3), is activated by a range of stimuli and is tightly regulated to restrict excessive inflammation. Because NLRP3 responds broadly to cellular insults and regulates cell death similar to the stress-activated apoptosis signal-regulating kinases 1 and 2 (ASK1/2), we hypothesized that ASK1/2 may regulate NLRP3 activity...
January 15, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29348845/decreased-expression-of-the-long-non-coding-rna-slc7a11-as1-predicts-poor-prognosis-and-promotes-tumor-growth-in-gastric-cancer
#2
Yajun Luo, Cheng Wang, Peng Yong, Pengcheng Ye, Zilin Liu, Zhiming Fu, Fei Lu, Wanping Xiang, Wang Tan, Jiangwei Xiao
Many lncRNA and mRNA sense-antisense transcripts have been systematically identified in malignant cells. However, the molecular mechanisms of most lncRNA-mRNA pairs in gastric cancer remain largely unknown. We found the gastric cancer-associated lncRNA SLC7A11-AS1 and coding transcript mRNA SLC7A11 in human gastric cancer specimens by microarray. SLC7A11-AS1, antisense to SLC7A11, is significantly down-regulated in gastric cancer and could promote tumor growth in vitro and in vivo. The effects of SLC7A11-AS1 depend on the regulation of SLC7A11 via the ASK1-p38MAPK/JNK signaling pathway...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348070/rational-approach-to-highly-potent-and-selective-apoptosis-signal-regulating-kinase-1-ask1-inhibitors
#3
Frank Lovering, Paul Morgan, Christophe Allais, Ann Aulabaugh, Joanne Brodfuehrer, Jeanne Chang, Jotham Coe, WeiDong Ding, Heather Dowty, Margaret Fleming, Richard Frisbie, Julia Guzova, David Hepworth, Jayasankar Jasti, Steve Kortum, Ravi Kurumbail, Shashi Mohan, Nikolaos Papaioannou, Joseph W Strohbach, Fabien Vincent, Katherine Lee, Christoph W Zapf
Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases...
December 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29346071/identification-of-potential-inhibitors-against-nuclear-dam1-complex-subunit-ask1-of-candida-albicans-using-virtual-screening-and-md-simulations
#4
Himanshu Tripathi, Feroz Khan
Identification of hit compounds against specific target form the starting point for a drug discovery program. A consistent decline of new chemical entities (NCEs) in recent years prompted a challenge to explore newer approaches to discover potential hit compounds that in turn can be converted into leads, and ultimately drug with desired therapeutic efficacy. The vast amount of omics and activity data available in public databases offers an opportunity to identify novel targets and their potential inhibitors...
January 1, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29334873/nobiletin-prevents-cadmium-induced-neuronal-apoptosis-by-inhibiting-reactive-oxygen-species-and-modulating-jnk-erk1-2-and-akt-mtor-networks-in-rats
#5
Youyang Qu, Yu Liu, Li Chen, Yanmei Zhu, Xingjun Xiao, Di Wang, Yulan Zhu
Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b...
January 16, 2018: Neurological Research
https://www.readbyqxmd.com/read/29334839/bax-inhibitor-1-is-required-for-resisting-the-early-brain-injury-induced-by-subarachnoid-hemorrhage-through-regulating-ire1-jnk-pathway
#6
Lei Shi, Zaizong Wang, Xianjin Liu, Mao Li, Shangfei Zhang, Xiaobin Song
Background and Purpose Bax inhibitor-1 (BI-1) has been identified as a suppressor of Bax-mediated cell apoptosis by regulation of endoplasmic reticulum stress-induced cell death. However, the role of BI-1 in Early Brain Injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. In the present study, we aim to explore the neuroprotective functions of BI-1 in EBI after SAH by using models of SAH that induced endovascular perforation in rats. Method The neurological score, brain water content and blood-brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators...
January 16, 2018: Neurological Research
https://www.readbyqxmd.com/read/29330470/%C3%AE-ecdysterone-protects-sh-sy5y-cells-against-%C3%AE-amyloid-induced-apoptosis-via-c-jun-n-terminal-kinase-and-akt-associated-complementary-pathways
#7
Tianjiao Xu, Chengu Niu, Xiaojie Zhang, Miaoxian Dong
Recently, the significantly higher incidence of Alzheimer's disease (AD) in women than in men has been attributed to the loss of neuroprotective estrogen after menopause. Does phytoestrogen have the ability to protect against amyloid-β (Aβ) toxicity? The aim of this study was to evaluate hypothesis that β-ecdysterone (β-Ecd) protects SH-SY5Y cells from Aβ-induced apoptosis by separate signaling pathways involving protein kinase B (Akt) and c-Jun N-terminal kinase (JNK). Here, we demonstrate that phytoestrogen β-Ecd inhibits Aβ-triggered mitochondrial apoptotic pathway, as indicated by Bcl-2/Bax ratio elevation, cytochrome c (cyt c) release reduction, and caspase-9 inactivation...
January 12, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29301832/pharmacological-inhibition-of-nos-activates-ask1-jnk-pathway-augmenting-docetaxel-mediated-apoptosis-in-triple-negative-breast-cancer
#8
Daniel Dávila-González, Dong Soon Choi, Roberto R Rosato, Sergio Granados-Principal, John G Kuhn, Wen-Feng Li, Wei Qian, Wen Chen, Anthony J Kozielski, Helen H Wong, Bhuvanesh Dave, Jenny C Chang
PURPOSE: Chemoresistance in triple negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacological NOS-inhibition on TNBC. EXPERIMENTAL DESIGN: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS-inibitor (L-NMMA) for 24, 48 and 72 hours...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29277546/inhibition-of-apoptosis-signal-regulating-kinase-1-attenuates-myocyte-hypertrophy-and-fibroblast-collagen-synthesis
#9
Wendi Yang, Bing Hui Wang, Ian Wang, Li Huang, Feby Savira, Andrew Kompa, Beat M Jucker, Robert N Willette, Darren Kelly, Henry Krum, Zhiliang Li, Qian Fu
BACKGROUND: Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. METHODS: Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2hours before stimulated with 100nM angiotensin II (AngII), 10μM indoxyl sulphate (IS) or 10ng/ml transforming growth factor β1 (TGFβ1) for 48hours...
December 14, 2017: Heart, Lung & Circulation
https://www.readbyqxmd.com/read/29277458/discovery-of-2-arylquinazoline-derivatives-as-a-new-class-of-ask1-inhibitors
#10
Andrii Monastyrskyi, Simon Bayle, Victor Quereda, Wayne Grant, Michael Cameron, Derek Duckett, William Roush
The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive...
December 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29261301/redox-inactive-peptide-disrupting-trx1-ask1-interaction-for-selective-activation-of-stress-signaling
#11
Dilini N Kekulandara, Shima Nagi, Hyosuk Seo, Christine S Chow, Young-Hoon Ahn
Thioredoxin 1 (Trx1) and glutaredoxin 1 (Grx1) are two ubiquitous redox enzymes that are central for redox homeostasis, but also are implicated in many other processes, including stress sensing, inflammation, and apoptosis. In addition to their enzymatic redox activity, there is increasing evidence showing that Trx1 and Grx1 play regulatory roles via protein-protein interactions with specific proteins, including Ask1. The currently available inhibitors of Trx1 and Grx1 are thiol-reactive electrophiles or disulfides that may suffer from low selectivity due to their thiol reactivity...
December 20, 2017: Biochemistry
https://www.readbyqxmd.com/read/29259759/correction-to-structure-based-design-of-ask1-inhibitors-as-potential-agents-for-heart-failure
#12
Marion Lanier, Jason Pickens, Simone V Bigi, Erica L Bradshaw-Pierce, Alison Chambers, Zacharia S Cheruvallath, Derek Cole, Douglas R Dougan, Jacques Ermolieff, Tony Gibson, Petro Halkowycz, Aki Hirokawa, Anthony Ivetac, Christopher McBride, Joanne Miura, Evan Nunez, Mark Sabat, John Tyhonas, Haixia Wang, Xiaolun Wang, Steve Swann
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].
December 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29248607/involvement-of-mitogen-activated-kinase-kinase-7-intracellular-signalling-pathway-in-sunitinib-induced-cardiotoxicity
#13
Samantha Louise Cooper, Hardip Sandhu, Afthab Hussain, Christopher Mee, Helen Maddock
The tyrosine kinase inhibitor Sunitinib is used to treat cancer and is linked to severe adverse cardiovascular events. Mitogen activated kinase kinase 7 (MKK7) is involved in the development of cardiac injury and is a component of the c-Jun N-terminal kinase (JNK) signal transduction pathway. Apoptosis signal-regulating kinase 1 (ASK1) is the upstream activator of MKK7 and is specifically inhibited by 2,7-dihydro-2,7-dioxo-3H-naphtho[1,2,3-de]quinoline-1-carboxylic acid ethyl ester (NQDI-1). This study investigates the role of ASK1, MKK7 and JNK during Sunitinib-induced cardiotoxicity...
December 14, 2017: Toxicology
https://www.readbyqxmd.com/read/29247356/current-and-future-pharmacological-therapies-for-nafld-nash
#14
REVIEW
Yoshio Sumida, Masashi Yoneda
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation...
December 16, 2017: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29228685/eb1-phosphorylation-mediates-the-functions-of-ask1-in-pancreatic-cancer-development
#15
Siqi Gao, Youguang Luo, Xiaofan Wu, Yuanyuan Li, Yunqiang Zhou, Rui Lyu, Min Liu, Dengwen Li, Jun Zhou
Pancreatic cancer has a poor prognosis due to its rapid rate of metastasis and frequent late-stage diagnosis. An improved understanding of the molecular mechanisms underlying this disease is urgently needed to promote the development of improved diagnostic tools and more effective therapies. Apoptosis signal-regulating kinase 1 (ASK1) has been shown to be overexpressed in pancreatic cancer and to promote the proliferation of pancreatic cancer cells in a kinase activity-dependent manner. However, the molecular mechanisms by which ASK1 promotes cell proliferation remain to be elucidated...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29227477/the-deubiquitinating-enzyme-tnfaip3-mediates-inactivation-of-hepatic-ask1-and-ameliorates-nonalcoholic-steatohepatitis
#16
Peng Zhang, Pi-Xiao Wang, Ling-Ping Zhao, Xin Zhang, Yan-Xiao Ji, Xiao-Jing Zhang, Chun Fang, Yue-Xin Lu, Xia Yang, Mao-Mao Gao, Yan Zhang, Song Tian, Xue-Yong Zhu, Jun Gong, Xin-Liang Ma, Feng Li, Zhihua Wang, Zan Huang, Zhi-Gang She, Hongliang Li
Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes...
December 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29186683/trim48-promotes-ask1-activation-and-cell-death-through-ubiquitination-dependent-degradation-of-the-ask1-negative-regulator-prmt1
#17
Yusuke Hirata, Kazumi Katagiri, Keita Nagaoka, Tohru Morishita, Yuki Kudoh, Tomohisa Hatta, Isao Naguro, Kuniyuki Kano, Tsuyoshi Udagawa, Tohru Natsume, Junken Aoki, Toshifumi Inada, Takuya Noguchi, Hidenori Ichijo, Atsushi Matsuzawa
Apoptosis signal-regulating kinase 1 (ASK1) is an oxidative stress-responsive kinase that is regulated by various interacting molecules and post-translational modifications. However, how these molecules and modifications cooperatively regulate ASK1 activity remains largely unknown. Here, we showed that tripartite motif 48 (TRIM48) orchestrates the regulation of oxidative stress-induced ASK1 activation. A pull-down screen identified a TRIM48-interacting partner, protein arginine methyltransferase 1 (PRMT1), which negatively regulates ASK1 activation by enhancing its interaction with thioredoxin (Trx), another ASK1-negative regulator...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29175071/icarisideii-improves-left-ventricular-remodeling-in-spontaneously-hypertensive-rats-by-inhibiting-the-ask1-jnk-p38-signaling-pathway
#18
Yuting Wu, Zhiqiang Qian, Shu Fu, Yun Yue, Yeli Li, Ruimin Sun, Bo Huang, Danli Yang
Inhibition or removal of excess reactive oxygen species can effectively protect cellular function or reduce cell death because oxidative stress is the main cause of cellular damage in many diseases. The flavonoid compound IcarisideII having a slight inhibitory effect on PDE5, is the main active components of epimedium in vivo and has a wide range of pharmacological effects on oxidation and apoptosis. However, whether IcarisideII has the same protective effect on ventricular remodeling in spontaneously hypertensive rats (SHR) is unknown...
November 21, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29154282/role-of-ask1-p38-cascade-in-a-mouse-model-of-alzheimer-s-disease-and-brain-aging
#19
Yu Hasegawa, Kensuke Toyama, Ken Uekawa, Hidenori Ichijo, Shokei Kim-Mitsuyama
To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38...
November 14, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29147906/regulation-of-signal-transduction-by-dj-1
#20
Stephanie E Oh, M Maral Mouradian
The ability of DJ-1 to modulate signal transduction has significant effects on how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy to adapt to changing environmental stimuli and stresses. Perturbations of DJ-1 levels or function can disrupt the equilibrium of homeostatic signaling networks and set off cascades that play a role in the pathogenesis of conditions such as cancer and Parkinson's disease.DJ-1 plays a major role in various pathways. It mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway...
2017: Advances in Experimental Medicine and Biology
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