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https://www.readbyqxmd.com/read/28445730/ripk3-mediates-necroptosis-during-embryonic-development-and-postnatal-inflammation-in-fadd-deficient-mice
#1
Qun Zhao, XianJun Yu, HaiWei Zhang, YongBo Liu, XiXi Zhang, XiaoXia Wu, Qun Xie, Ming Li, Hao Ying, Haibing Zhang
RIPK3 mediates cell death and regulates inflammatory responses. Although genetic studies have suggested that RIPK3-MLKL-mediated necroptosis leads to embryonic lethality in Fadd or Caspase-8-deficient mice, the exact mechanisms are not fully understood. Here, we generated Ripk3 mutant mice by altering the RIPK3 kinase domain (Ripk3(Δ/Δ) mice), thus abolishing its kinase activity. Ripk3(Δ/Δ) cells were resistant to necroptosis stimulation in vitro, and Ripk3(Δ/Δ) mice were protected from necroptotic diseases...
April 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28423682/rip3-deficiency-ameliorates-inflammatory-response-in-mice-infected-with-influenza-h7n9-virus-infection
#2
Yu-Lin Xu, Hai-Lin Tang, Hao-Ran Peng, Ping Zhao, Zhong-Tian Qi, Wen Wang
Influenza H7N9 virus infection causes an acute, highly contagious respiratory illness that triggers cell death of infected cells and airway epithelial destruction. RIP3 is a key regulator of cell death responses to a growing number of viral and microbial agents. This study aimed to investigate the role of RIP3 in inflammation of influenza H7N9 virus infection. Here, RIP3 knock out (RIP3-/-) mice and littermate wild type mice were infected intranasally with influenza H7N9 virus (A/Fujian/S03/2015) to determine the contribution of RIP3 to the inflammatory response of influenza H7N9 virus infection...
March 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414098/cytosolic-calcium-mediates-rip1-rip3-complex-dependent-necroptosis-through-jnk-activation-and-mitochondrial-ros-production-in-human-colon-cancer-cells
#3
Wen Sun, Xiaxia Wu, Hongwei Gao, Jie Yu, Wenwen Zhao, Jin-Jian Lu, Jinhua Wang, Guanhua Du, Xiuping Chen
Necroptosis is a form of programmed necrosis mediated by signaling complexes with receptor-interacting protein 1 (RIP1) and RIP3 kinases as the main mediators. However, the underlying execution pathways of this phenomenon have yet to be elucidated in detail. In this study, a RIP1/RIP3 complex was formed in 2-methoxy-6-acetyl-7-methyljuglone (MAM)-treated HCT116 and HT29 colon cancer cells. With this formation, mitochondrial reactive oxygen species (ROS) levels increased, mitochondrial depolarization occurred, and ATP concentrations decreased...
April 14, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28412393/adhesion-induced-eosinophil-cytolysis-requires-the-ripk3-mlkl-signaling-pathway-which-is-counter-regulated-by-autophagy
#4
Susanne Radonjic-Hoesli, Xiaoliang Wang, Elisabeth de Graauw, Christina Stoeckle, Beata Styp-Rekowska, Ruslan Hlushchuk, Dagmar Simon, Peter J Spaeth, Shida Yousefi, Hans-Uwe Simon
BACKGROUND: Eosinophils are a subset of granulocytes which can be involved in the pathogenesis of different diseases, including allergy. Their effector functions are closely linked to their cytotoxic granule proteins. The release takes place by several different mechanisms, one of which is cytolysis, which is associated with the release of intact granules, so-called clusters of free eosinophil granules. The mechanism underlying this activation-induced form of cell death in eosinophils has remained unclear...
April 12, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28388412/escrt-iii-acts-downstream-of-mlkl-to-regulate-necroptotic-cell-death-and-its-consequences
#5
Yi-Nan Gong, Cliff Guy, Hannes Olauson, Jan Ulrich Becker, Mao Yang, Patrick Fitzgerald, Andreas Linkermann, Douglas R Green
The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca(2+)) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles" with exposed PS that are released from the surface of the otherwise intact cell...
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28388403/escrting-necroptosis
#6
Hongyan Guo, William J Kaiser
Necroptosis is a highly inflammatory form of programmed cell death that results from MLKL-mediated disruption of the cell membrane. In this issue of Cell, Gong et al. challenge the notion that MLKL activation is a point of no return by identifying mechanisms to counterbalance necroptosis, sustain plasma membrane integrity, and prolong cell viability.
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28387756/pore-forming-toxin-mediated-ion-dysregulation-leads-to-death-receptor-independent-necroptosis-of-lung-epithelial-cells-during-bacterial-pneumonia
#7
Norberto González-Juarbe, Kelley Margaret Bradley, Anukul Taranath Shenoy, Ryan Paul Gilley, Luis Felipe Reyes, Cecilia Anahí Hinojosa, Marcos Ignacio Restrepo, Peter Herman Dube, Molly Ann Bergman, Carlos Javier Orihuela
We report that pore-forming toxins (PFTs) induce respiratory epithelial cell necroptosis independently of death receptor signaling during bacterial pneumonia. Instead, necroptosis was activated as a result of ion dysregulation arising from membrane permeabilization. PFT-induced necroptosis required RIP1, RIP3 and MLKL, and could be induced in the absence or inhibition of TNFR1, TNFR2 and TLR4 signaling. We detected activated MLKL in the lungs from mice and nonhuman primates experiencing Serratia marcescens and Streptococcus pneumoniae pneumonia, respectively...
April 7, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28387136/the-protective-effect-of-aucubin-from-eucommia-ulmoides-against-status-epilepticus-by-inducing-autophagy-and-inhibiting-necroptosis
#8
Jin Wang, Ying Li, Wei-Hua Huang, Xiang-Chang Zeng, Xiao-Hui Li, Jian Li, Jun Zhou, Jian Xiao, Bo Xiao, Dong-Sheng Ouyang, Kai Hu
Eucommia ulmoides Oliv. is a famous traditional Chinese medicine which exhibits anti-oxidative stress ability and neuro-protective effects. Aucubin is the predominant component of Eucommia ulmoides Oliv. Our present study is intended to investigate aucubin's potential protective effects on neurons against epilepsy in the hippocampus by establishing the lithium-pilocarpine induced status epilepticus (SE) rat model in vivo. Aucubin (at a low dose and a high dose of 5[Formula: see text]mg/kg and 10[Formula: see text]mg/kg, respectively) was administered through gavage for two weeks before lithium-pilocarpine injection...
April 7, 2017: American Journal of Chinese Medicine
https://www.readbyqxmd.com/read/28380356/necroptosis-execution-is-mediated-by-plasma-membrane-nanopores-independent-of-calcium
#9
Uris Ros, Aida Peña-Blanco, Kay Hänggi, Ulrich Kunzendorf, Stefan Krautwald, W Wei-Lynn Wong, Ana J García-Sáez
Necroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux...
April 4, 2017: Cell Reports
https://www.readbyqxmd.com/read/28366204/ripk3-restricts-viral-pathogenesis-via-cell-death-independent-neuroinflammation
#10
Brian P Daniels, Annelise G Snyder, Tayla M Olsen, Susana Orozco, Thomas H Oguin, Stephen W G Tait, Jennifer Martinez, Michael Gale, Yueh-Ming Loo, Andrew Oberst
Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3(-/-) mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected...
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28358377/mitochondrial-complex-i-inhibition-triggers-a-mitophagy-dependent-ros-increase-leading-to-necroptosis-and-ferroptosis-in-melanoma-cells
#11
Farhan Basit, Lisanne Mpe van Oppen, Laura Schöckel, Hasse M Bossenbroek, Sjenet E van Emst-de Vries, Johannes Cw Hermeling, Sander Grefte, Charlotte Kopitz, Melanie Heroult, Peter Hgm Willems, Werner Jh Koopman
Inhibition of complex I (CI) of the mitochondrial respiratory chain by BAY 87-2243 ('BAY') triggers death of BRAF(V600E) melanoma cell lines and inhibits in vivo tumor growth. Here we studied the mechanism by which this inhibition induces melanoma cell death. BAY treatment depolarized the mitochondrial membrane potential (Δψ), increased cellular ROS levels, stimulated lipid peroxidation and reduced glutathione levels. These effects were paralleled by increased opening of the mitochondrial permeability transition pore (mPTP) and stimulation of autophagosome formation and mitophagy...
March 30, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28330474/hypercholesterolemia-downregulates-autophagy-in-the-rat-heart
#12
Zoltán Giricz, Gábor Koncsos, Tomáš Rajtík, Zoltán V Varga, Tamás Baranyai, Csaba Csonka, Adrián Szobi, Adriana Adameová, Roberta A Gottlieb, Péter Ferdinandy
BACKGROUND: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart...
March 23, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/28315674/dichotomy-between-receptor-interacting-protein-1-and-receptor-interacting-protein-3-mediated-necroptosis-in-experimental-pancreatitis
#13
Jianghong Wu, Tunike Mulatibieke, Jianbo Ni, Xiao Han, Bin Li, Yue Zeng, Rong Wan, Xingpeng Wang, Guoyong Hu
Pancreatic acinar cell necrosis and inflammatory responses are two key pathologic processes in acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), and the molecular mechanisms in pancreatitis-associated necroptosis...
March 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28297660/progesterone-prevents-high-grade-serous-ovarian-cancer-by-inducing-necroptosis-of-p53-defective-fallopian-tube-epithelial-cells
#14
Na-Yiyuan Wu, Hsuan-Shun Huang, Tung Hui Chao, Hsien Ming Chou, Chao Fang, Chong-Zhen Qin, Chueh-Yu Lin, Tang-Yuan Chu, Hong Hao Zhou
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28293227/mlkl-mediated-necroptosis-accelerates-jev-induced-neuroinflammation-in-mice
#15
Peiyu Bian, Xuyang Zheng, Li Wei, Chuantao Ye, Hong Fan, Yanhui Cai, Ying Zhang, Fanglin Zhang, Zhansheng Jia, Yingfeng Lei
Japanese encephalitis virus (JEV) is the most prevalent cause of viral encephalitis in Asia and the western Pacific. Neuronal death caused by JEV infection and inflammation induced cytotoxicity leads to progression and deterioration of Japanese encephalitis (JE). Mixed-lineage kinase domain-like protein (MLKL) mediated necroptosis is a newly discovered pathway of programmed cell death and participates in many inflammatory diseases. In this study, we demonstrated for the first time that necroptosis was involved in the neuronal loss during JE via immune-electron microscopy and immunochemistry...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28292903/mouse-cytomegalovirus-m36-and-m45-death-suppressors-cooperate-to-prevent-inflammation-resulting-from-antiviral-programmed-cell-death-pathways
#16
Lisa P Daley-Bauer, Linda Roback, Lynsey N Crosby, A Louise McCormick, Yanjun Feng, William J Kaiser, Edward S Mocarski
The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant ΔM36/M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3-dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis...
March 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28292463/key-players-of-the-necroptosis-pathway-ripk1-and-sirt2-are-altered-in-placenta-from-preeclampsia-and-fetal-growth-restriction
#17
Natalie J Hannan, Sally Beard, Natalie K Binder, Kenji Onda, Tu'uhevaha J Kaitu'u-Lino, Qi Chen, Laura Tuohey, Manarangi De Silva, Stephen Tong
INTRODUCTION: Preeclampsia (PE) and fetal growth restriction (FGR) are among the leading causes of perinatal morbidity and mortality. Placental insufficiency is central to these conditions. The mechanisms underlying placental insufficiency are poorly understood. Apoptosis has long been considered the only form of regulated cell death, recent research has identified an alternate process of programmed cell death known as necroptosis [1]. Necroptosis is distinct from apoptosis, relying on the deacetylase sirtuin-2 [2], receptor interacting kinases RIPK1 and 3, and the pseudokinase MLKL [3]...
March 2017: Placenta
https://www.readbyqxmd.com/read/28289909/ripk1-ripk3-mlkl-mediated-necroptosis-contributes-to-compression-induced-rat-nucleus-pulposus-cells-death
#18
Songfeng Chen, Xiao Lv, Binwu Hu, Zengwu Shao, Baichuan Wang, Kaige Ma, Hui Lin, Min Cui
The aim of this study was to systematically investigate the role of necroptosis in compression-induced rat nucleus pulposus (NP) cells death, as well as explore the underlying mechanisms involved. Rat NP cells underwent various periods of exposure to 1.0 MPa pressure. Cell viability and cell death were quantified by using cell counting kit-8 (CCK-8), and Calcein-AM/propidium iodine (PI) staining respectively. Necroptosis-associated target molecules receptor-interacing protein kinase 1 (RIPK1), phosphorylated RIPK1 (pRIPK1), receptor-interacing protein kinase 3 (RIPK3), phosphorylated RIPK3 (pRIPK3) and mixed lineage kinase domain-like (MLKL) were analyzed by Western-blot and RT-PCR...
March 13, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28279333/dai-another-way-necroptotic-control-of-viral-infection
#19
Jason W Upton, William J Kaiser
Interrogation of murine cytomegalovirus (MCMV)-encoded cell-death suppressors revealed that necroptosis functions as a trap door to eliminate virally infected cells. This crucial host defense pathway is orchestrated by the sensing of infection by DAI/ZBP-1, engagement of the kinase RIPK3, and subsequent membrane permeablization by the pseudokinase MLKL.
March 8, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28267172/discovery-of-a-new-class-of-highly-potent-necroptosis-inhibitors-targeting-the-mixed-lineage-kinase-domain-like-protein
#20
Bo Yan, Lei Liu, Shaoqiang Huang, Yan Ren, Huayi Wang, Zhenglin Yao, Lin Li, She Chen, Xiaodong Wang, Zhiyuan Zhang
We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target...
March 7, 2017: Chemical Communications: Chem Comm
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