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https://www.readbyqxmd.com/read/28910144/ask1-inhibition-halts-disease-progression-in-preclinical-models-of-pulmonary-arterial-hypertension
#1
Grant R Budas, Mario Boehm, Baktybek Kojonazarov, Gayathri Viswanathan, Xia Tian, Swathi Veeroju, Tatyana Novoyatleva, Friedrich Grimminger, Ford Hinojosa-Kirschenbaum, Hossein A Ghofrani, Norbert Weissmann, Werner Seeger, John T Liles, Ralph T Schermuly
RATIONALE Progression of pulmonary arterial hypertension (PAH) is associated with pathologic remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of mitogenactivated protein kinases (MAPKs) which stimulate apoptosis, inflammation and fibrosis. OBJECTIVES We investigated whether pharmacological inhibition of the redoxsensitive apical MAPK Apoptosis Signal-Regulating Kinase 1 (ASK1) can halt the progression of pulmonary vascular and RV remodeling...
September 14, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28892558/the-ask1-inhibitor-selonsertib-in-patients-with-nonalcoholic-steatohepatitis-a-randomized-phase-2-trial
#2
Rohit Loomba, Eric Lawitz, Parvez S Mantry, Saumya Jayakumar, Stephen H Caldwell, Hays Arnold, Anna Mae Diehl, C Stephen Djedjos, Ling Han, Robert P Myers, G Mani Subramanian, John G McHutchison, Zachary D Goodman, Nezam H Afdhal, Michael R Charlton
Inhibition of apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis (NASH). We evaluated the safety and efficacy of selonsertib, a selective inhibitor of ASK1, alone or in combination with simtuzumab, in patients with NASH and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab, or simtuzumab alone...
September 11, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28891792/pgam5-promotes-lasting-foxo-activation-after-developmental-mitochondrial-stress-and-extends-lifespan-in-drosophila
#3
Martin Borch Jensen, Yanyan Qi, Rebeccah Riley, Liya Rabkina, Heinrich Jasper
The mitochondrial unfolded protein response (UPR(mt)) has been associated with long lifespan across metazoans. In C. elegans, mild developmental mitochondrial stress activates UPR(mt) reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5 (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK)...
September 11, 2017: ELife
https://www.readbyqxmd.com/read/28888991/lrrk2-functions-as-a-scaffolding-kinase-of-ask1-mediated-neuronal-cell-death
#4
Ji-Hye Yoon, Jung-Soon Mo, Mi-Yeon Kim, Eun-Jung Ann, Ji-Seon Ahn, Eun-Hye Jo, Hye-Jin Lee, Young Chul Lee, Wongi Seol, Sergiy M Yarmoluk, Thomas Gasser, Philipp J Kahle, Guang-Hui Liu, Juan Carlos Izpisua Belmonte, Hee-Sae Park
Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a key causative factor in Parkinson's disease (PD). Identification of novel substrates and the molecular mechanisms underlying the effects of LRRK2 are essential for understanding the pathogenesis of PD. In this study, we showed that LRRK2 played an important role in neuronal cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (ASK1). LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site...
September 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28887319/cold-stress-induced-ferroptosis-involves-the-ask1-p38-pathway
#5
Kazuki Hattori, Hiroyuki Ishikawa, Chihiro Sakauchi, Saki Takayanagi, Isao Naguro, Hidenori Ichijo
A wide variety of cell death mechanisms, such as ferroptosis, have been proposed in mammalian cells, and the classification of cell death attracts global attention because each type of cell death has the potential to play causative roles in specific diseases. However, the precise molecular mechanisms leading to cell death are poorly understood, particularly in ferroptosis. Here, we show that continuous severe cold stress induces ferroptosis and the ASK1-p38 MAPK pathway in multiple cell lines. The activation of the ASK1-p38 pathway is mediated by critical determinants of ferroptosis: MEK activity, iron ions, and lipid peroxide...
September 8, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28882588/ask1-in-neurodegeneration
#6
REVIEW
Xiaoli Guo, Kazuhiko Namekata, Atsuko Kimura, Chikako Harada, Takayuki Harada
Neurodegenerative diseases (NDDs) such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are characterized by the progressive loss of neurons, causing irreversible damage to patients. Longer lifespans may be leading to an increase in the number of people affected by NDDs worldwide. Among the pathways strongly impacting the pathogenesis of NDDs, oxidative stress, a condition that occurs because of an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs...
September 1, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28864268/baicalein-induces-cell-death-in-murine-t-cell-lymphoma-via-inhibition-of-thioredoxin-system
#7
Raghavendra S Patwardhan, Debojyoti Pal, Rahul Checker, Deepak Sharma, Santosh K Sandur
We have earlier demonstrated the radioprotective potential of baicalein using murine splenic lymphocytes. Here, we have studied the effect of baicalein on murine T cell lymphoma EL4 cells and investigated the underlying mechanism of action. We observed that baicalein induced a dose dependent cell death in EL4 cells in vitro and significantly reduced the frequency of cancer stem cells. Previously, we have reported that murine and human T cell lymphoma cells have increased oxidative stress tolerance capacity due to active thioredoxin system...
August 31, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28855861/regulation-of-microglia-and-macrophage-polarization-via-apoptosis-signal-regulating-kinase-1-silencing-after-ischemic-hypoxic-injury
#8
So Yeong Cheon, Eun Jung Kim, Jeong Min Kim, Eun Hee Kam, Byung Woong Ko, Bon-Nyeo Koo
Inflammation is implicated in ischemic stroke and is involved in abnormal homeostasis. Activation of the immune system leads to breakdown of the blood-brain barrier and, thereby, infiltration of immune cells into the brain. Upon cerebral ischemia, infiltrated macrophages and microglia (resident CNS immune cell) are activated, change their phenotype to M1 or M2 based on the microenvironment, migrate toward damaged tissue, and are involved in repair or damage. Those of M1 phenotype release pro-inflammatory mediators, which are associated with tissue damage, while those of M2 phenotype release anti-inflammatory mediators, which are related to tissue recovery...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28822073/isorhynchophylline-attenuates-mpp-induced-apoptosis-through-endoplasmic-reticulum-stress-and-mitochondria-dependent-pathways-in-pc12-cells-involvement-of-antioxidant-activity
#9
Xiao-Ming Li, Xiao-Jie Zhang, Miao-Xian Dong
Endoplasmic reticulum stress (ERS) and mitochondrial dysfunctions are thought to be involved in the dopaminergic neuronal death in Parkinson's disease (PD). In this study, we found that isorhynchophylline (IRN) significantly attenuated 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death and oxidative stress in PC12 cells. IRN markedly reduced MPP(+)-induced-ERS responses, indicative of inositol-requiring enzyme 1 (IRE1) phosphorylation and caspase-12 activation. Furthermore, IRN inhibits MPP(+)-triggered apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal Kinase (JNK) signaling-mediated mitochondria-dependent apoptosis pathway...
August 18, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28798154/a-novel-synthetic-analogue-of-%C3%AF-3-17-18-epoxy-eicosatetraenoic-acid-activates-tnf-receptor-1-ask1-jnk-signaling-to-promote-apoptosis-in-human-breast-cancer-cells
#10
Herryawan Ryadi Eziwar Dyari, Tristan Rawling, Yongjuan Chen, William Sudarmana, Kirsi Bourget, Julie M Dwyer, Sarah E Allison, Michael Murray
A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1)...
August 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28767631/neuroprotective-effects-of-c-terminal-domain-of-tetanus-toxin-on-rat-brain-against-motorneuron-damages-after-experimental-spinal-cord-injury
#11
Murat Celal Sozbilen, Murat Oztürk, Gizem Kaftan, Taner Dagci, Halit Ozyalcin, Güliz Armagan
STUDY DESIGN: Experimental animal study investigating the efficacy of C-terminal domain of tetanus toxin application as neuroprotective effects on rat brain in a model of spinal cord injury. OBJECTIVE: The aim of the present study was to investigate the possible role of C-terminal domain of tetanus toxin (Hc-TeTx) on cell death mechanisms including apoptosis and autophagy following SCI. SUMMARY OF BACKGROUND DATA: Traumatic spinal cord injury (SCI) can lead to post-traumatic inflammation, oxidative stress, motor neuron apoptosis, necrosis and autophagy of tissue...
August 1, 2017: Spine
https://www.readbyqxmd.com/read/28753204/ask1-facilitates-tumor-metastasis-through-phosphorylation-of-an-adp-receptor-p2y12-in-platelets
#12
Miki Kamiyama, Toshiaki Shirai, Shogo Tamura, Katsue Suzuki-Inoue, Shogo Ehata, Kei Takahashi, Kohei Miyazono, Yoshihiro Hayakawa, Takehiro Sato, Kohsuke Takeda, Isao Naguro, Hidenori Ichijo
Tumor metastasis is the major cause of deaths in cancer patients and is modulated by intertwined stress-responsive signaling cascades. Here we demonstrate that deletion of stress-responsive apoptosis signal-regulating kinase 1 (Ask1) in platelets results in unstable hemostasis and drastic attenuation of tumor lung metastasis, both of which are attributable to platelet dysfunction. Platelet-specific deletion of Ask1 in mice leads to defects in ADP-dependent platelet aggregation, unstable hemostasis and subsequent attenuation of tumor metastasis...
July 28, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28739531/oxidative-and-er-stress-dependent-ask1-activation-in-steatotic-hepatocytes-and-kupffer-cells-sensitizes-mice-fatty-liver-to-ischemia-reperfusion-injury
#13
Chiara Imarisio, Elisa Alchera, Chandrashekar Bangalore Revanna, Guido Valente, Antonia Follenzi, Elena Trisolini, Renzo Boldorini, Rita Carini
Steatosis intensifies hepatic ischemia/reperfusion (I/R) injury increasing hepatocyte damage and hepatic inflammation. This study evaluates if this process is associated to a differential response of steatotic hepatocytes (HP) and Kupffer cells (KC) to I/R injury and investigates the molecular mechanisms involved. Control or steatotic (treated with 50 μmol palmitic acid, PA) mouse HP or KC were exposed to hypoxia/reoxygenation (H/R). C57BL/6 mice fed 9 week with control or High Fat diet underwent to partial hepatic IR...
July 21, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28732559/socs-1-is-involved-in-tnf-%C3%AE-induced-mitochondrial-dysfunction-and-apoptosis-in-renal-tubular-epithelial-cells
#14
Chunyang Du, Fang Yao, Yunzhuo Ren, Yunxia Du, Jinying Wei, Haijiang Wu, Huijun Duan, Yonghong Shi
Tumor necrosis factor-α (TNF-α) is suggested to induce mitochondrial dysfunction and apoptosis of renal tubular epithelial cells that possibly exacerbates renal function in chronic kidney disease (CKD). Here we investigated whether suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of cytokine signaling, was involved in TNF-α-induced human renal tubular epithelial cells (HKCs) oxidative stress and apoptosis. TNF-α promoted the protein and mRNA expression of SOCS-1 in a time and dose dependent manner, along with increased cell apoptosis and activation of apoptosis signal regulating kinase-1(ASK1) in HKCs...
June 30, 2017: Tissue & Cell
https://www.readbyqxmd.com/read/28702328/ask1-map3k5-is-transcriptionally-upregulated-by-e2f1-in-adipose-tissue-in-obesity-molecularly-defining-a-human-dys-metabolic-obese-phenotype
#15
Yulia Haim, Matthias Blüher, Daniel Konrad, Nir Goldstein, Nora Klöting, Ilana Harman-Boehm, Boris Kirshtein, Doron Ginsberg, Tanya Tarnovscki, Yftach Gepner, Iris Shai, Assaf Rudich
OBJECTIVE: Obesity variably disrupts human health, but molecular-based patients' health-risk stratification is limited. Adipose tissue (AT) stresses may link obesity with metabolic dysfunction, but how they signal in humans remains poorly-characterized. We hypothesized that a transcriptional AT stress-signaling cascade involving E2F1 and ASK1 (MAP3K5) molecularly defines high-risk obese subtype. METHODS: ASK1 expression in human AT biopsies was determined by real-time PCR analysis, and chromatin immunoprecipitation (ChIP) adopted to AT explants was used to evaluate the binding of E2F1 to the ASK1 promoter...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28669716/the-regulatory-and-signaling-mechanisms-of-the-ask-family
#16
REVIEW
Takuto Nishida, Kazuki Hattori, Kengo Watanabe
Apoptosis signal-regulating kinase 1 (ASK1) was identified as a MAP3K that activates the JNK and p38 pathways, and subsequent studies have reported ASK2 and ASK3 as members of the ASK family. The ASK family is activated by various intrinsic and extrinsic stresses, including oxidative stress, ER stress and osmotic stress. Numerous lines of evidence have revealed that members of the ASK family are critical for signal transduction systems to control a wide range of stress responses such as cell death, differentiation and cytokine induction...
May 22, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28661486/the-role-of-map2-kinases-and-p38-kinase-in-acute-murine-liver-injury-models
#17
Jun Zhang, Robert W M Min, Khanh Le, Sheng Zhou, Mariam Aghajan, Tin A Than, Sanda Win, Neil Kaplowitz
c-Jun N-terminal kinase (JNK) mediates hepatotoxicity through interaction of its phospho-activated form with a mitochondrial outer membrane protein, Sh3bp5 or Sab, leading to dephosphorylation of intermembrane Src and consequent impaired mitochondrial respiration and enhanced ROS release. ROS production from mitochondria activates MAP3 kinases, such as MLK3 and ASK1, which continue to activate a pathway to sustain JNK activation, and amplifies the toxic effect of acetaminophen (APAP) and TNF/galactosamine (TNF/GalN)...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28656265/bioinformatic-analysis-reveals-potential-properties-of-human-claudin-6-regulation-and-functions
#18
Dongjing Lin, Yaxiong Guo, Yanru Li, Yang Ruan, Mingzi Zhang, Xiangshu Jin, Minlan Yang, Yan Lu, Peiye Song, Shuai Zhao, Bing Dong, Yinping Xie, Qihua Dang, Chengshi Quan
Claudin-6 (CLDN6) is an integral component of the tight junction proteins in polarized epithelial and endothelial cells and plays a crucial role in maintaining cell integrity. Deregulation of CLDN6 expression and distribution in tumor tissues have been widely documented and correlated with cancer progression and metastasis. However, a complete mechanistic understanding of CLDN6 regulation and function remains to be studied. Herein, we show new potential properties of CLDN6 regulation and functions from bioinformatics analysis...
June 27, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28651161/connexin-43-mediates-changes-in-protein-phosphorylation-in-hk-2-cells-during-chronic-cadmium-exposure
#19
Zehe Ge, Haipeng Diao, Maohui Yu, Xiaoli Ji, Qingping Liu, Xiuli Chang, Qing Wu
Connexin 43 (Cx43) is believed to play a role in the mechanisms of toxicity of many chemical species, include cadmium (Cd). In this study, human renal proximal tubule (HK-2) cells were exposed to Cd (1μM, 10 days). Of the 584 protein residues detected using a Phospho Explorer antibody microarray (PEX100), more than half changed their levels of phosphorylation after chronic Cd exposure. Cx43 siRNA attenuated Cd-induced apoptosis and inhibited proliferation, while also attenuating changes in the levels of phosphorylation of many protein residues...
July 2017: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/28647884/fluoxetine-induces-apoptosis-through-endoplasmic-reticulum-stress-via-mitogen-activated-protein-kinase-activation-and-histone-hyperacetylation-in-sk-n-be-2-m17-human-neuroblastoma-cells
#20
Ji Hyun Choi, Yeon Ju Jeong, Ah-Ran Yu, Kyung-Sik Yoon, Wonchae Choe, Joohun Ha, Sung Soo Kim, Eui-Ju Yeo, Insug Kang
Fluoxetine (FLX) is an antidepressant drug that belongs to the class of selective serotonin reuptake inhibitors. FLX is known to induce apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of FLX were investigated in SK-N-BE(2)-M17 human neuroblastoma cells. FLX induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP)...
June 24, 2017: Apoptosis: An International Journal on Programmed Cell Death
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