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https://www.readbyqxmd.com/read/28767435/the-degradation-of-mixed-lineage-kinase-domain-like-protein-promotes-neuroprotection-after-ischemic-brain-injury
#1
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
#2
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
#3
REVIEW
Jiao Li, XiaoJing Ke, Fuhua Yan, Lang Lei, Houxuan 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,dybiosis with over-growth 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
#4
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...
July 24, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28744127/necrostatin-1-attenuates-early-brain-injury-after-subarachnoid-hemorrhage-in-rats-by-inhibiting-necroptosis
#5
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
#6
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
#7
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
#8
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...
July 20, 2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/28723543/necroptosis-last-message-in-a-bubble
#9
Peter Vandenabeele, Franck Riquet, Benjamin Cappe
RIPK3 kinase-mediated phosphorylation of MLKL pseudokinase is the execution event of necroptosis. Two independent reports-in Immunity (Yoon et al., 2017) and Cell (Gong et al., 2017)-reveal that MLKL affects homeostatic membrane trafficking and necroptosis-enhanced bubble formation involving interaction with the ESCRT machinery.
July 18, 2017: Immunity
https://www.readbyqxmd.com/read/28716527/identification-of-a-synergistic-combination-of-smac-mimetic-and-bortezomib-to-trigger-cell-death-in-b-cell-non-hodgkin-lymphoma-cells
#10
Irfan Ahmed Bhatti, Behnaz Ahangarian Abhari, Simone Fulda
Recently, copy number gains and increased expression levels of cIAP1 and cIAP2 have been reported in B-cell non-Hodgkin lymphomas (NHL). Therefore, we investigated the therapeutic potential of the Smac mimetic BV6 that antagonizes cIAP1/2 and XIAP. Here, we discover that subtoxic concentrations of BV6 prime B-cell NHL cells to proteasome inhibitor Bortezomib-induced cell death. Synergistic induction of cell death by BV6 and Bortezomib is confirmed by calculation of combination index in different cell lines, emphasizing the broader relevance of this combination...
July 14, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28687713/tlr9-is-upregulated-in-human-and-murine-nash-pivotal-role-for-inflammatory-recruitment-and-cell-survival
#11
Auvro R Mridha, Fahrettin Haczeyni, Matthew M Yeh, W Geoffrey Haigh, George N Ioannou, Vanessa Barn, Hussam Ajamieh, Leon Adams, Jeffrey M Hamdorf, Narci C Teoh, Geoffrey C Farrell
Background & Aims: TLR9 deletion protects against steatohepatitis due to choline-amino acid depletion and high-fat diet. We measured TLR9 in human NASH livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of NAFLD. Methods: We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wildtype (Wt) , appetite-dysregulated Alms1 mutant (foz/foz),Tlr9(-/-), and Tlr9(-/-).foz/foz C57BL6/J mice and bone marrow (BM) chimeras were fed 0.2% cholesterol, high-fat, high sucrose (atherogenic[Ath]) diet or chow, and NAFLD activity score (NAS)/NASH pathology, macrophage/neutrophil infiltration, cytokines/chemokines and cell death markers measured in livers...
July 7, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28676433/the-neurotoxicant-pcb-95-by-increasing-the-neuronal-transcriptional-repressor-rest-down-regulates-caspase-8-and-increases-ripk1-ripk3-and-mlkl-expression-determining-necroptotic-neuronal-death
#12
Natascia Guida, Giusy Laudati, Angelo Serani, Luigi Mascolo, Pasquale Molinaro, Paolo Montuori, Gianfranco Di Renzo, Lorella M T Canzoniero, Luigi Formisano
Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases RE1-silencing transcription factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation...
July 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28673991/correction-to-supporting-information-for-conos-et-al-active-mlkl-triggers-the-nlrp3-inflammasome-in-a-cell-intrinsic-manner
#13
(no author information available yet)
No abstract text is available yet for this article.
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28666573/mlkl-the-protein-that-mediates-necroptosis-also-regulates-endosomal-trafficking-and-extracellular-vesicle-generation
#14
Seongmin Yoon, Andrew Kovalenko, Konstantin Bogdanov, David Wallach
Activation of the pseudokinase mixed lineage kinase domain-like (MLKL) upon its phosphorylation by the protein kinase RIPK3 triggers necroptosis, a form of programmed cell death in which rupture of cellular membranes yields release of intracellular components. We report that MLKL also associated with endosomes and controlled the transport of endocytosed proteins, thereby enhancing degradation of receptors and ligands, modulating their induced signaling and facilitating the generation of extracellular vesicles...
July 18, 2017: Immunity
https://www.readbyqxmd.com/read/28663335/mitochondrial-quality-control-in-alveolar-epithelial-cells-damaged-by-s-aureus-pneumonia-in-mice
#15
Hagir B Suliman, Bryan D Kraft, Raquel R Bartz, Lingye Chen, Karen E Welty-Wolf, Claude A Piantadosi
(242 words) Mitochondrial damage is often overlooked in acute lung injury (ALI), but most of the lung's physiological processes, such as airway tone, muco-ciliary clearance, Va/Q matching, and immune surveillance require aerobic energy provision. Because the cell's processes of mitochondrial quality control (QC) regulate the elimination and replacement of damaged mitochondria to support cell survival, we evaluated mitochondrial biogenesis and mitophagy in the alveolar region of mice in a validated S. aureus pneumonia model...
June 29, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28661484/sorafenib-tosylate-inhibits-directly-necrosome-complex-formation-and-protects-in-mouse-models-of-inflammation-and-tissue-injury
#16
Sofie Martens, Manhyung Jeong, Wulf Tonnus, Friederike Feldmann, Sam Hofmans, Vera Goossens, Nozomi Takahashi, Jan Hinrich Bräsen, Eun-Woo Lee, Pieter Van der Veken, Jurgen Joossens, Koen Augustyns, Simone Fulda, Andreas Linkermann, Jaewhan Song, Peter Vandenabeele
Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28661482/necroptosis-in-neurodegenerative-diseases-a-potential-therapeutic-target
#17
REVIEW
Shuo Zhang, Mi-Bo Tang, Hai-Yang Luo, Chang-He Shi, Yu-Ming Xu
Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL)...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28650960/phosphatidylserine-externalization-necroptotic-bodies-release-and-phagocytosis-during-necroptosis
#18
Sefi Zargarian, Inbar Shlomovitz, Ziv Erlich, Aria Hourizadeh, Yifat Ofir-Birin, Ben A Croker, Neta Regev-Rudzki, Liat Edry-Botzer, Motti Gerlic
Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the "find me" and "eat me" signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such "eat me" signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28649853/cationic-liposome-co-encapsulation-of-smac-mimetic-and-zvad-using-a-novel-lipid-bilayer-fusion-loaded-with-mlkl-pdna-for-tumor-inhibition-in-vivo
#19
Dan Sun, Linshu Zhao, Junzhong Lin, Yun Zhao, Yu Zheng
The increase in multidrug resistance among colon cancer cells presents a challenge for the development of effective therapies. Small-molecule analogs of second mitochondria-derived activator of caspase (SMAC) mimetic in association with mixed lineage kinase domain-like protein (MLKL)-pDNA and z-VAD-fmk have shown ideal antitumor effects in colon cancer cells in vitro via induction of RIP3-dependent necroptosis. To achieve synergistic antitumor effects in vivo, liposomes loaded with SMAC mimetic, MLKL-pDNA and z-VAD-fmk have been developed using novel lipid fusion methods to co-localize the molecules of interest within the tumor cells...
June 26, 2017: Journal of Drug Targeting
https://www.readbyqxmd.com/read/28593135/evaluation-of-cell-death-pathways-initiated-by-antitumor-drugs-melatonin-and-valproic-acid-in-bladder-cancer-cells
#20
Siwei Liu, Bilin Liang, Huiting Jia, Yuhan Jiao, Zhongqiu Pang, Yongye Huang
Effective drug combinations have the potential to strengthen therapeutic efficacy and combat drug resistance. Both melatonin and valproic acid (VPA) exhibit antitumor activities in various cancer cells. The aim of this study was to evaluate the cell death pathways initiated by anticancer combinatorial effects of melatonin and VPA in bladder cancer cells. The results demonstrated that the combination of melatonin and VPA leads to significant synergistic growth inhibition of UC3 bladder cancer cells. Gene expression studies revealed that cotreatment with melatonin and VPA triggered the up-regulation of certain genes related to apoptosis (TNFRSF10A and TNFRSF10B), autophagy (BECN, ATG3 and ATG5) and necrosis (MLKL, PARP-1 and RIPK1)...
June 2017: FEBS Open Bio
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