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https://www.readbyqxmd.com/read/28923396/smac-mimetics-and-type-ii-interferon-synergistically-induce-necroptosis-in-various-cancer-cell-lines
#1
Michael John Cekay, Stefanie Roesler, Tanja Frank, Anne-Kathrin Knuth, Ines Eckhardt, Simone Fulda
Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered as a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. The synergistic is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i...
September 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28894570/nadph-oxidase-inhibitor-diphenyleneiodonium-prevents-necroptosis-in-hk-2-cells
#2
Wei Dong, Zhilian Li, Yuanhan Chen, Li Zhang, Zhiming Ye, Huaban Liang, Ruizhao Li, Lixia Xu, Bin Zhang, Shuangxin Liu, Weidong Wang, Chunling Li, Jialun Luo, Wei Shi, Xinling Liang
The aim of the present study was to investigate the protective effect of the NADPH oxidase inhibitor, diphenyleneiodonium (DPI) against necroptosis in renal tubular epithelial cells. A necroptosis model of HK-2 cells was established using tumor necrosis factor-α, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone and antimycin A (collectively termed TZA), as in our previous research. The necroptosis inhibitor, necrostatin-1 (Nec-1) or the NADPH oxidase inhibitor, DPI were administered to the necroptosis model...
September 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28892415/susceptibility-of-m-tuberculosis-infected-host-cells-to-phospho-mlkl-driven-necroptosis-is-dependent-on-cell-type-and-presence-of-tnf%C3%AE
#3
Rachel E Butler, Nitya Krishnan, Waldo Garcia-Jimenez, Robert Francis, Abbe Martyn, Tom Mendum, Shaza Felemban, Nicolas Locker, Javier Salguero-Bodes, Brian Robertson, Graham R Stewart
An important feature of Mycobacterium tuberculosis pathogenesis is the ability to control cell death in infected host cells, including inhibition of apoptosis and stimulation of necrosis. Recently an alternative form of programmed cell death, necroptosis, has been described where necrotic cell death is induced by apoptotic stimuli under conditions where apoptotic execution is inhibited. We show for the first time that M. tuberculosis and TNFα synergise to induce necroptosis in murine fibroblasts via RIPK1-dependent mechanisms and characterized by phosphorylation of Ser345 of the MLKL necroptosis death effector...
September 11, 2017: Virulence
https://www.readbyqxmd.com/read/28884134/intracellular-ph-regulates-trail-induced-apoptosis-and-necroptosis-in-endothelial-cells
#4
Zhu-Xu Zhang, Ingrid Gan, Alexander Pavlosky, Xuyan Huang, Benjamin Fuhrmann, Anthony M Jevnikar
During ischemia or inflammation of organs, intracellular pH can decrease if acid production exceeds buffering capacity. Thus, the microenvironment can expose parenchymal cells to a reduced extracellular pH which can alter pH-dependent intracellular functions. We have previously shown that while silencing caspase-8 in an in vivo ischemia reperfusion injury (IRI) model results in improved organ function and survival, removal of caspase-8 function in a donor organ can paradoxically result in enhanced receptor-interacting protein kinase 1/3- (RIPK1/3-) regulated necroptosis and accelerated graft loss following transplantation...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28878015/thioredoxin-1-actively-maintains-the-pseudokinase-mlkl-in-a-reduced-state-to-suppress-disulfide-bond-dependent-mlkl-polymer-formation-and-necroptosis
#5
Eduardo Reynoso, Hua Liu, Lin Li, Anthony L Yuan, She Chen, Zhigao Wang
Necroptosis is an immunogenic cell death program that is associated with a host of human diseases, including inflammation, infections and cancer. Receptor-interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like protein (MLKL) are required for necroptosis activation. Specifically, RIPK3-dependent MLKL phosphorylation promotes the assembly of disulfide bond-dependent MLKL polymers that drive the execution of necroptosis. However, how MLKL disulfide bond formation is regulated is not clear...
September 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28863321/the-role-of-necroptosis-in-status-epilepticus-induced-brain-injury-in-juvenile-rats
#6
Qianyun Cai, Jing Gan, Rong Luo, Yi Qu, Shiping Li, Chaomin Wan, Dezhi Mu
PURPOSE: To study the role of necroptosis in status epilepticus (SE)-induced injury in the developing brain and the possible associations of necroptosis with epileptogenesis and cognitive dysfunction. METHODS: The lithium-pilocarpine epilepsy model was reproduced in male rats at postnatal day 25. Propidium iodide (PI) staining was used to detect cell death after SE. Transmission electron microscopy (TEM) was performed to observe morphological changes in injured neurons...
August 29, 2017: Epilepsy & Behavior: E&B
https://www.readbyqxmd.com/read/28860618/interferon-gamma-regulates-inflammatory-cell-death-by-targeting-necroptosis-in-experimental-autoimmune-arthritis
#7
Seung Hoon Lee, Ji Ye Kwon, Se-Young Kim, KyoungAh Jung, Mi-La Cho
Interferon γ (IFN-γ) induces an inflammatory response and apoptotic cell death. Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with increased levels of inflammatory mediators, including tumour necrosis factor α (TNF-α) and T helper (Th) 17 cells, and downregulation of apoptosis of inflammatory cells. We hypothesized that IFN-γ would reduce inflammatory cell death in vitro and that loss of IFN-γ would aggravate inflammation in vivo. IFN-γ downregulated necroptosis and the expression of cellular FLICE-like inhibitory protein (cFLIPL) and mixed lineage kinase domain-like (MLKL)...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28854080/biological-events-and-molecular-signaling-following-mlkl-activation-during-necroptosis
#8
Yi-Nan Gong, Cliff Guy, Jeremy Chase Crawford, Douglas R Green
Necroptosis is a form of programmed necrotic cell death mediated by the kinase RIPK3 and its substrate MLKL. MLKL, which displays plasma membrane (PM) pore-forming activity upon phosphorylation, functions as the executioner during necroptosis. Thus, it was previously assumed that MLKL phosphorylation is the endpoint of the necroptotic signaling pathway. Here, we summarize several events that characterize the dying necroptotic cells after MLKL phosphorylation, including Ca(2+) influx, phosphatidylserine (PS) externalization, PM repair by ESCRT-III activation, and the final compromise of PM integrity...
August 30, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28845215/ppar-%C3%AE-activation-prevents-septic-cardiac-dysfunction-via-inhibition-of-apoptosis-and-necroptosis
#9
Shiyan Peng, Junmei Xu, Wei Ruan, Suobei Li, Feng Xiao
Sepsis-induced cardiac dysfunction remains one of the major causes of death in intensive care units. Overwhelmed inflammatory response and unrestrained cell death play critical roles in sepsis-induced cardiac dysfunction. Peroxisome proliferator-activated receptor- (PPAR-) γ has been proven to be cardioprotective in sepsis. However, the mechanism of PPAR-γ-mediated cardioprotection and its relationship with inflammation and cell death are unclear. We hypothesized that activation of PPAR-γ by reducing cardiac inflammation, myocardial apoptosis, and necroptosis may prevent myocardial dysfunction in sepsis...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28844856/rip3-and-pmlkl-promote-necroptosis-induced-inflammation-and-alter-membrane-permeability-in-intestinal-epithelial-cells
#10
Anna Negroni, Eleonora Colantoni, Maria Pierdomenico, Francesca Palone, Manuela Costanzo, Salvatore Oliva, Antonio Tiberti, Salvatore Cucchiara, Laura Stronati
BACKGROUND: Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). AIMS: The aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation. METHODS: In vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn's disease; 20 with ulcerative colitis) and from 20 controls...
August 10, 2017: Digestive and Liver Disease
https://www.readbyqxmd.com/read/28827318/mlkl-forms-disulfide-bond-dependent-amyloid-like-polymers-to-induce-necroptosis
#11
Shuzhen Liu, Hua Liu, Andrea Johnston, Sarah Hanna-Addams, Eduardo Reynoso, Yougui Xiang, Zhigao Wang
Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α-induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy...
August 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28807105/ripk1-ripk3-mlkl-dependent-necrosis-promotes-the-aging-of-mouse-male-reproductive-system
#12
Dianrong Li, Lingjun Meng, Tao Xu, Yaning Su, Xiao Liu, Zhiyuan Zhang, Xiaodong Wang
A pair of kinases, RIPK1 and RIPK3, as well as the RIPK3 substrate MLKL cause a form of programmed necrotic cell death in mammals termed necroptosis. We report here that male reproductive organs of both Ripk3- and Mlkl-knockout mice retain 'youthful' morphology and function into advanced age, while those of age-matched wild-type mice deteriorate. The RIPK3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild-type mice...
August 15, 2017: ELife
https://www.readbyqxmd.com/read/28767435/the-degradation-of-mixed-lineage-kinase-domain-like-protein-promotes-neuroprotection-after-ischemic-brain-injury
#13
Yanlong Zhou, Beiqun Zhou, Hui Tu, Yan Tang, Chen Xu, Yanbo Chen, Zhong Zhao, Zhigang Miao
Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28764929/inhibition-of-aurora-kinase-a-induces-necroptosis-in-pancreatic-carcinoma
#14
Yangchun Xie, Shan Zhu, Meizuo Zhong, Minghua Yang, Xiaofan Sun, Jinbao Liu, Guido Kroemer, Michael Lotze, Herbert J Zeh, Rui Kang, Daolin Tang
BACKGROUND & AIMS: Induction of non-apoptotic cell death could be an approach to eliminate apoptosis-resistant tumors. We investigated necroptosis-based therapies in mouse models of pancreatic ductal adenocarcinoma cancer (PDAC). METHODS: We screened 273 commercially available kinase inhibitors for cytotoxicity against a human PDAC cell line (PANC1). We evaluated the ability of the aurora kinase inhibitor CCT137690 to stimulate necroptosis in PDAC cell lines (PANC1, PANC2...
July 29, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28763140/necroptosis-in-the-periodontal-homeostasis-signals-emanating-from-dying-cells
#15
REVIEW
J Li, X Ke, F Yan, L Lei, H Li
Periodontal tissues are constantly exposed to microbial stimuli. The equilibrium between microbes and host defense system helps maintain the homeostasis in the periodontal microenvironment. Growth of pathogenic bacteria in dental biofilms may induce proinflammatory cytokine production to recruit sentinel cells, mainly neutrophils and monocytes into the gingival sulcus or the periodontal pocket. Moreover, dysbiosis with overgrowth of anaerobic pathogens, such as Porphyromonas gingivalis and Tannerella forsythia, may induce death of both immune cells and host resident cells...
August 1, 2017: Oral Diseases
https://www.readbyqxmd.com/read/28758999/necroptosis-activation-in-alzheimer-s-disease
#16
Antonella Caccamo, Caterina Branca, Ignazio S Piras, Eric Ferreira, Matthew J Huentelman, Winnie S Liang, Ben Readhead, Joel T Dudley, Elizabeth E Spangenberg, Kim N Green, Ramona Belfiore, Wendy Winslow, Salvatore Oddo
Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD...
September 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28744127/necrostatin-1-attenuates-early-brain-injury-after-subarachnoid-hemorrhage-in-rats-by-inhibiting-necroptosis
#17
Fuxiang Chen, Xingfen Su, Zhangya Lin, Yuanxiang Lin, Lianghong Yu, Jiawei Cai, Dezhi Kang, Liwen Hu
Necroptosis is programmed cell death that has been recently proposed and reported to be involved in several neurologic diseases. However, the role of necroptosis in early brain injury after subarachnoid hemorrhage (SAH) is still unknown. The purpose of this study was to investigate whether necroptosis was involved in SAH-induced early brain injury, and to assess the possible neuroprotective effect of necrostatin-1 using an endovascular perforation rat model of SAH. Our results showed that the expression levels of necroptosis-related proteins including RIP1, RIP3 and MLKL in the basal cortex all increased at 3 hours after SAH (P<0...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28730475/characterization-of-ligand-binding-to-pseudokinases-using-a-thermal-shift-assay
#18
Isabelle S Lucet, James M Murphy
The protocol herein describes a robust and proven method for the measurement of pseudokinase-ligand interaction using a fluorescence-based thermal shift assay (TSA). Pseudokinases are kinase-like proteins that have recently emerged as crucial regulatory modules of signal transduction pathways and may well represent a novel class of drug targets. However, unlike kinases, the regulatory activity of pseudokinases is mainly conferred through protein-protein interactions. Understanding the mechanisms that underlie pseudokinase conformational changes through ligand binding and how such conformational changes can tune signaling pathways is a necessary step to unravel their biological functions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28724891/hypoxia-inducible-factor-1-alpha-is-involved-in-rip-induced-necroptosis-caused-by-in-vitro-and-in-vivo-ischemic-brain-injury
#19
Xiao-Sa Yang, Tai-Long Yi, Sai Zhang, Zhong-Wei Xu, Ze-Qi Yu, Hong-Tao Sun, Cheng Yang, Yue Tu, Shi-Xiang Cheng
Necroptosis, a novel type of programmed cell death, is involved in stroke-induced ischemic brain injury. Although studies have sought to explore the mechanisms of necroptosis, its signaling pathway has not yet to be completely elucidated. Thus, we used oxygen-glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) models mimicking ischemic stroke (IS) conditions to investigate mechanisms of necroptosis. We found that OGD and MCAO induced cell death, local brain ischemia and neurological deficit, while zVAD-fmk (zVAD, an apoptotic inhibitor), GSK'872 (a receptor interacting protein kinase-3 (RIP3) inhibitor), and combined treatment alleviated cell death and ischemic brain injury...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723681/inhibition-of-necroptosis-attenuates-kidney-inflammation-and-interstitial-fibrosis-induced-by-unilateral-ureteral-obstruction
#20
Xia Xiao, Chunyang Du, Zhe Yan, Yonghong Shi, Huijun Duan, Yunzhuo Ren
BACKGROUND: Inflammation plays a crucial role in renal interstitial fibrosis, the pathway of chronic kidney diseases. Necroptosis is a novel form of regulated cell death, which plays a potential role in inflammation and renal diseases. The small molecule necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis. This study was aimed at determining the role of necroptosis, RIP1/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway, in renal inflammation and interstitial fibrosis related to primitive tubulointerstitial injury...
2017: American Journal of Nephrology
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