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Mertk

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https://www.readbyqxmd.com/read/29342502/antiphospholipid-antibodies-inhibit-trophoblast-toll-like-receptor-and-inflammasome-negative-regulators
#1
Melissa J Mulla, Ingrid C Weel, Julie A Potter, Stefan M Gysler, Jane E Salmon, Maria T S Peraçoli, Carla V Rothlin, Lawrence W Chamley, Vikki M Abrahams
OBJECTIVE: Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications associated with poor placentation and placental inflammation. While these antibodies are heterogeneous, some anti-β2 GPI antibodies can activate human first trimester trophoblast TLR4 and NLRP3. The objective of this study was to determine the role of negative regulators of TLR and inflammasome function in aPL-induced trophoblast inflammation. METHODS: Human trophoblast cells were treated with or without anti-β2 GPI aPL or control IgG in the presence or absence of the common TAM receptor ligand, GAS6, or the autophagy inducer, rapamycin...
January 17, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29316776/phagocytic-roles-of-glial-cells-in-healthy-and-diseased-brains
#2
REVIEW
Yeon-Joo Jung, Won-Suk Chung
Glial cells are receiving much attention since they have been recognized as important regulators of many aspects of brain function and disease. Recent evidence has revealed that two different glial cells, astrocytes and microglia, control synapse elimination under normal and pathological conditions via phagocytosis. Astrocytes use the MEGF10 and MERTK phagocytic pathways, and microglia use the classical complement pathway to recognize and eliminate unwanted synapses. Notably, glial phagocytosis also contributes to the clearance of disease-specific protein aggregates, such as β-amyloid, huntingtin, and α-synuclein...
January 10, 2018: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/29310530/unc569-induced-morphological-changes-in-pigment-epithelia-and-photoreceptor-cells-in-the-retina-through-mertk-inhibition-in-mice
#3
Ayako Sayama, Keiko Okado, Koichi Nakamura, Tatsuya Kawaguchi, Takuma Iguchi, Toshihiko Makino, Koichi Yabe, Kiyonori Kai, Kazuhiko Mori
Mer proto-oncogene tyrosine kinase (MerTK), which is expressed in the retinal pigment epithelium (RPE), regulates phagocytosis of shed photoreceptor outer segments (POS). To investigate the effects of drug-induced MerTK inhibition on the retina, UNC569, a specific MerTK inhibitor, was orally administered to male mice at a concentration of 60, 100, or 150 mg/kg for up to 14 days. Furthermore, MerTK inhibition in the retinal tissue sample was examined using a phosphorylation assay following a single dose of UNC569 at 100 mg/kg...
January 1, 2018: Toxicologic Pathology
https://www.readbyqxmd.com/read/29299721/mutations-in-mertk-are-not-associated-with-age-related-macular-degeneration
#4
Hasenin Al-Khersan, Alan Kwong, Michael A Grassi
PURPOSE: To assess whether mutations in Mer tyrosine kinase (MERTK) are associated with age-related macular degeneration (AMD). METHODS: An association study using whole-genome sequencing was performed to determine whether rare variants in MERTK are associated with AMD. The data set included 4787 propensity score-matched case-control samples: 2394 AMD cases and 2393 controls. Whole-genome sequencing was performed and variants in MERTK were identified. Combined annotation-dependent depletion (CADD) scores and allele frequencies were calculated for each variant identified in MERTK...
January 3, 2018: International Ophthalmology
https://www.readbyqxmd.com/read/29285287/mertk-inhibition-by-rxdx-106-in-mertk-activated-gastric-cancer-cell-lines
#5
Jung Eun Kim, Youjin Kim, Gary Li, Seung Tae Kim, Kyung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Tae Sung Sohn, Kyoung-Mee Kim, Won Ki Kang, Jeeyun Lee
RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29277773/effects-of-mertk-inhibitors-unc569-and-unc1062-on-the-growth-of-acute-myeloid-leukaemia-cells
#6
Yuki Koda, Mai Itoh, Shuji Tohda
BACKGROUND: MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells. MATERIALS AND METHODS: Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated...
January 2018: Anticancer Research
https://www.readbyqxmd.com/read/29251628/erythrocyte-efferocytosis-modulates-macrophages-towards-recovery-after-intracerebral-hemorrhage
#7
Che-Feng Chang, Brittany A Goods, Michael H Askenase, Matthew D Hammond, Stephen C Renfroe, Arthur F Steinschneider, Margaret J Landreneau, Youxi Ai, Hannah E Beatty, Luís Henrique Angenendt da Costa, Matthias Mack, Kevin N Sheth, David M Greer, Anita Huttner, Daniel Coman, Fahmeed Hyder, Sourav Ghosh, Carla V Rothlin, J Christopher Love, Lauren H Sansing
Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery...
December 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29247646/incomplete-clearance-of-apoptotic-cells-by-core-1-derived-o-glycan-deficient-resident-peritoneal-macrophages
#8
Hiromasa Wakui, Sayaka Fuseya, Riku Suzuki, Miki Shimbo, Risa Okada, Mitchito Hamada, Akihiro Kuno, Kozue Hagiwara, Takashi Sato, Hisashi Narimatsu, Takashi Kudo, Satoru Takahashi
The core 1 β1,3-galactosyltransferase-specific molecular chaperon (Cosmc) is essential for the synthesis of the core 1 structure of mucin-type O-glycans. To clarify the physiological role of core 1-derived O-glycans in macrophages, we exploited the LysM-Cre transgene to generate a conditional Cosmc mutant allele (conditional Cosmc knockout; cKO) in myeloid cells. cKO mice developed normally with no gross phenotypic abnormalities or abnormal peripheral blood counts. Resident peritoneal macrophages (rpMacs) of cKO mice exhibited impaired engulfment of apoptotic cells but showed normal macrophage differentiation and counts...
December 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29228560/mertk-is-a-novel-therapeutic-target-in-gastric-cancer
#9
Jun Ho Yi, Jiryeon Jang, Jeonghee Cho, In-Gu Do, Mineui Hong, Seung Tae Kim, Kyoung-Mee Kim, Sujin Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Jeeyun Lee
Introduction: The role of MerTK has not been assessed in gastric cancer (GC). The aim of this study was to identify a subgroup of GC patients with MerTK tumor overexpression, and to evaluate MerTK as a potential therapeutic target in this disease. Methods: Protein and mRNA expression of MerTK were evaluated, and other various in vitro analyses including shRNA transfection, cell cycle anslysis, MTS assay and colony forming assay were carried out with GC cell lines and GC patient-derived cells (PDCs)...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29185561/near-infrared-imaging-of-mer-tyrosine-kinase-mertk-using-meri-sir-reveals-tumor-associated-macrophage-uptake-in-metastatic-disease
#10
Miles A Miller, Eunha Kim, Michael F Cuccarese, Alec L Plotkin, Mark Prytyskach, Rainer H Kohler, Mikael J Pittet, Ralph Weissleder
The receptor tyrosine kinase Mer (MERTK) is a promising drug target in cancer, where it can influence the metastasis-promoting signaling of both tumor cells and immune cells alike; however, no small molecule probes currently exist to selectively image Mer. In this work, we design and synthesize a selective near-infrared fluorescent molecular probe of Mer (MERi-SiR). Confocal microscopy of metastases in mice reveals predominant probe accumulation in Mer-expressing tumor-associated macrophages.
November 29, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29180230/glucocorticoids-genes-and-brain-function
#11
REVIEW
Grzegorz R Juszczak, Adrian M Stankiewicz
The identification of key genes in transcriptomic data constitutes a huge challenge. Our review of microarray reports revealed 88 genes whose transcription is consistently regulated by glucocorticoids (GCs), such as cortisol, corticosterone and dexamethasone, in the brain. Replicable transcriptomic data were combined with biochemical and physiological data to create an integrated view of the effects induced by GCs. The most frequently reported genes were Errfi1 and Ddit4. Their up-regulation was associated with the altered transcription of genes regulating growth factor and mTORC1 signaling (Gab1, Tsc22d3, Dusp1, Ndrg2, Ppp5c and Sesn1) and progression of the cell cycle (Ccnd1, Cdkn1a and Cables1)...
November 24, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29177020/epigenetic-regulation-of-axl-and-risk-of-childhood-asthma-symptoms
#12
Lu Gao, Joshua Millstein, Kimberly D Siegmund, Louis Dubeau, Rachel Maguire, Frank D Gilliland, Susan K Murphy, Cathrine Hoyo, Carrie V Breton
Background: AXL is one of the TAM (TYRO3, AXL and MERTK) receptor tyrosine kinases and may affect numerous immune-related health conditions. However, the role for AXL in asthma, including its epigenetic regulation, has not been extensively studied. Methods: We investigated the association between AXL DNA methylation at birth and risk of childhood asthma symptoms at age 6 years. DNA methylation of multiple CpG loci across the regulatory regions of AXL was measured in newborn bloodspots using the Illumina HumanMethylation450 array on a subset of 246 children from the Children's Health Study (CHS)...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/29176978/requirement-of-gamma-carboxyglutamic-acid-modification-and-phosphatidylserine-binding-for-the-activation-of-tyro3-axl-and-mertk-receptors-by-growth-arrest-specific-6
#13
Ke Geng, Sushil Kumar, Stanley G Kimani, Vladyslav Kholodovych, Canan Kasikara, Kensaku Mizuno, Oleta Sandiford, Pranela Rameshwar, Sergei V Kotenko, Raymond B Birge
The Tyro3, Axl, and Mertk (TAM) receptors are homologous type I receptor tyrosine kinases that have critical functions in the clearance of apoptotic cells in multicellular organisms. TAMs are activated by their endogenous ligands, growth arrest-specific 6 (Gas6), and protein S (Pros1), that function as bridging molecules between externalized phosphatidylserine (PS) on apoptotic cells and the TAM ectodomains. However, the molecular mechanisms by which Gas6/Pros1 promote TAM activation remains elusive. Using TAM/IFNγR1 reporter cell lines to monitor functional TAM activity, we found that Gas6 activity was exquisitely dependent on vitamin K-mediated γ-carboxylation, whereby replacing vitamin K with anticoagulant warfarin, or by substituting glutamic acid residues involved in PS binding, completely abrogated Gas6 activity as a TAM ligand...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29118755/apoptotic-cells-induced-signaling-for-immune-homeostasis-in-macrophages-and-dendritic-cells
#14
REVIEW
Uriel Trahtemberg, Dror Mevorach
Inefficient and abnormal clearance of apoptotic cells (efferocytosis) contributes to systemic autoimmune disease in humans and mice, and inefficient chromosomal DNA degradation by DNAse II leads to systemic polyarthritis and a cytokine storm. By contrast, efficient clearance allows immune homeostasis, generally leads to a non-inflammatory state for both macrophages and dendritic cells (DCs), and contributes to maintenance of peripheral tolerance. As many as 3 × 10(8) cells undergo apoptosis every hour in our bodies, and one of the primary "eat me" signals expressed by apoptotic cells is phosphatidylserine (PtdSer)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29116131/context-dependent-compensation-among-phosphatidylserine-recognition-receptors
#15
Kristen K Penberthy, Claudia Rival, Laura S Shankman, Michael H Raymond, Jianye Zhang, Justin S A Perry, Chang Sup Lee, Claudia Z Han, Suna Onengut-Gumuscu, Krzysztof Palczewski, Jeffrey J Lysiak, Kodi S Ravichandran
Phagocytes express multiple phosphatidylserine (PtdSer) receptors that recognize apoptotic cells. It is unknown whether these receptors are interchangeable or if they play unique roles during cell clearance. Loss of the PtdSer receptor Mertk is associated with apoptotic corpse accumulation in the testes and degeneration of photoreceptors in the eye. Both phenotypes are linked to impaired phagocytosis by specialized phagocytes: Sertoli cells and the retinal pigmented epithelium (RPE). Here, we overexpressed the PtdSer receptor BAI1 in mice lacking MerTK (Mertk (-/-) Bai1 (Tg) ) to evaluate PtdSer receptor compensation in vivo...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29109727/dexamethasone-and-monophosphoryl-lipid-a-induce-a-distinctive-profile-on-monocyte-derived-dendritic-cells-through-transcriptional-modulation-of-genes-associated-with-essential-processes-of-the-immune-response
#16
Paulina A García-González, Katina Schinnerling, Alejandro Sepúlveda-Gutiérrez, Jaxaira Maggi, Ahmed M Mehdi, Hendrik J Nel, Bárbara Pesce, Milton L Larrondo, Octavio Aravena, María C Molina, Diego Catalán, Ranjeny Thomas, Ricardo A Verdugo, Juan C Aguillón
There is growing interest in the use of tolerogenic dendritic cells (tolDCs) as a potential target for immunotherapy. However, the molecular bases that drive the differentiation of monocyte-derived DCs (moDCs) toward a tolerogenic state are still poorly understood. Here, we studied the transcriptional profile of moDCs from healthy subjects, modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), referred to as Dex-modulated and MPLA-activated DCs (DM-DCs), as an approach to identify molecular regulators and pathways associated with the induction of tolerogenic properties in tolDCs...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29101300/pharmacoproteomic-characterisation-of-human-colon-and-rectal-cancer
#17
Martin Frejno, Riccardo Zenezini Chiozzi, Mathias Wilhelm, Heiner Koch, Runsheng Zheng, Susan Klaeger, Benjamin Ruprecht, Chen Meng, Karl Kramer, Anna Jarzab, Stephanie Heinzlmeir, Elaine Johnstone, Enric Domingo, David Kerr, Moritz Jesinghaus, Julia Slotta-Huspenina, Wilko Weichert, Stefan Knapp, Stephan M Feller, Bernhard Kuster
Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype...
November 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/29056937/cd14-cells-with-the-phenotype-of-infiltrated-monocytes-consist-of-distinct-populations-characterized-by-anti-inflammatory-as-well-as-pro-inflammatory-activity-in-gouty-arthritis
#18
Ji Hye Jeong, Seokchan Hong, Oh Chan Kwon, Byeongzu Ghang, Inseok Hwang, Yong-Gil Kim, Chang-Keun Lee, Bin Yoo
It has been suggested that inflammasome-mediated IL-1β production in monocytic cells is responsible for the acute inflammatory response in gouty arthritis. However, phenotypical and functional analyses of monocytes during gouty arthritis have yet to be conducted. Therefore, we investigated the characteristics of monocytes/macrophages in the synovial fluid cells of patients with acute gout. The number and frequency of monocytes/macrophages in the synovial fluid mononuclear cells (SFMCs) of patients was examined...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29050198/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#19
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#20
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
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