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HES1 Inhibitor

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https://www.readbyqxmd.com/read/28526405/hypoxia-inducible-factor-l%C3%AE-mediates-aggrecan-and-collagen-%C3%AE-expression-via-notch1-signaling-in-nucleus-pulposus-cells-during-intervertebral-disc-degeneration
#1
Zhuochao Liu, Changwei Li, Xiangchao Meng, Yunting Bai, Jin Qi, Jun Wang, Qi Zhou, Weibin Zhang, Xingkai Zhang
Although hypoxia-inducible factor-lα (HIF-lα) has been reported to have an important role in the metabolism and synthesis of the extracellular matrix (ECM) of nucleus pulposus cells (NPCs), the underlying mechanism has not been fully clarified. Here, we show for the first time that NOTCH1 expression is decreased in NPs isolated from degenerated human intervertebral discs (IVDs), as well as in the NPs of NP-specific HIF-1α(-/-) mice. Our study reveals that overexpression of HIF-1α leads to increased expression of NOTCH1, the NOTCH1 ligand JAGGED1, and its target gene hairy and enhancer of split-1 (HES1), while also upregulating collagen Π and aggrecan expression in human NPCs...
May 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28522881/notch-signaling-and-maintenance-of-sox2-expression-in-rat-anterior-pituitary-cells
#2
Khongorzul Batchuluun, Morio Azuma, Ken Fujiwara, Takashi Yashiro, Motoshi Kikuchi
After publication of reports describing the presence of stem/progenitor cells among non-hormone-producing cells in the pituitary, the mechanism responsible for proliferation and differentiation generated considerable interest. Several studies have suggested that Notch signaling is involved. In the present study, we examined the histochemical relationship between Notch signaling molecules and the transcription factor SOX2 in rat pituitary. Combined in situ hybridization and immunohistochemistry showed that Notch2 mRNA and SOX2 were co-expressed at embryonic day 14...
April 27, 2017: Acta Histochemica et Cytochemica
https://www.readbyqxmd.com/read/28521301/activation-of-signal-transducer-and-activator-of-transcription-3-stat3-signaling-in-egfr-mutant-non-small-cell-lung-cancer-nsclc
#3
Carles Codony-Servat, Jordi Codony-Servat, Niki Karachaliou, Miguel Angel Molina, Imane Chaib, Jose Luis Ramirez, Maria de Los Llanos Gil, Flavio Solca, Trever G Bivona, Rafael Rosell
Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28482141/notch-pathway-is-active-during-osteogenic-differentiation-of-human-bone-marrow-mesenchymal-stem-cells-induced-by-pulsed-electromagnetic-fields
#4
Leila Bagheri, Agnese Pellati, Paola Rizzo, Giorgio Aquila, Leo Massari, Monica De Mattei, Alessia Ongaro
Pulsed electromagnetic fields (PEMFs) have been used to treat bone diseases, particularly non-union healing. Although it is known that PEMFs promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs), to date PEMF molecular mechanisms remain not clearly elucidated. The Notch signaling is a highly conserved pathway which regulates cell fate decisions and skeletal development. The aim of this study was to investigate if the known PEMF-induced osteogenic effects may involve the modulation of the Notch pathway...
May 8, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28431315/effects-of-pm2-5-exposure-on-the-notch-signaling-pathway-and-immune-imbalance-in-chronic-obstructive-pulmonary-disease
#5
Xing-Yu Gu, Xu Chu, Xiao-Li Zeng, Hai-Rong Bao, Xiao-Ju Liu
Chronic Obstructive Pulmonary Disease (COPD) is associated with T lymphocytes subset (Th1/Th2, Th17/Treg) imbalance. Notch signaling pathway plays a key role in the development of the adaptive immunity. The immune disorder induced by fine particulate matter (PM2.5) is related to COPD. The aim of this study was to investigate the mechanism by which PM2.5 influences the Notch signaling pathway leading to worsening immune disorder and accelerating COPD development. A COPD mouse model was established by cigarette smoke exposure...
April 18, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28428712/notch-signaling-mediated-by-tgf-%C3%AE-smad-pathway-in-concanavalin-a-induced-liver-fibrosis-in-rats
#6
Yi Wang, Ruo-Wu Shen, Bing Han, Zhen Li, Le Xiong, Feng-Yu Zhang, Bei-Bei Cong, Bei Zhang
AIM: To explore the exact interaction between Notch and transforming growth factor (TGF)-β signaling in liver fibrosis. METHODS: We established a rat model of liver fibrosis induced by concanavalin A. Peripheral blood mononuclear cells (PBMCs) were isolated from the modeled rats, and cultured with γ-secretase inhibitor DAPT and TGF-β inhibitor for 24 h. The mRNA levels of Notch and TGF-β signaling were detected by quantitative real-time polymerase chain reaction...
April 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28416482/notch1-signaling-regulates-self-renewal-and-platinum-chemoresistance-of-cancer-stem-like-cells-in-human-non-small-cell-lung-cancer
#7
Yun Zhang, Wei Xu, Huiqin Guo, Yanmei Zhang, Yuexi He, Sau Har Lee, Xin Song, Xiaoyan Li, Yongqing Guo, Yunlong Zhao, Cheng Ding, Fei Ning, Yuanyuan Ma, Qun-Ying Lei, Xiaoyu Hu, Shengnan Li, Wei Guo
Cancer stem-like cells (CSC) are thought to drive tumor initiation, metastasis, relapse and therapeutic resistance, but their specific pathogenic characters in many cancers including non-small cell lung cancer (NSCLC) have yet to be well defined. Here we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166(+)CD49f(hi)CD104(-)Lin(-) LCSC present in all human specimens of NSCLC examined, regardless of their histological subtypes or genetic driver mutations...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28400072/notch-signaling-pathway-promotes-the-development-of-ovine-ovarian-follicular-granulosa-cells
#8
Jiongjie Jing, Xiaolong Jiang, Jianwei Chen, Xiaolei Yao, Miaomiao Zhao, Pengfei Li, Yangyang Pan, Youshe Ren, Wenzhong Liu, Lihua Lyu
The Notch signaling pathway regulates cell proliferation, differentiation and apoptosis involved in development of the organs and tissues such as nervous system, cartilage, lungs, kidneys and prostate as well as the ovarian follicles. This study aimed to investigate the mRNA expression and localization of NOTCH2, as the key factor in Notch signaling pathway. This was determined by PCR, real-time PCR and immunohistochemistry. Additionally, the effects of inhibiting Notch signaling pathway with different concentrations (5μM, 10μM and 20μM) of N-[N-(3, 5-Difuorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of Notch signaling pathway, on ovine granulosa cells was determined in vitro by detecting estradiol production using enzyme linked immunosorbent assay and expressions of the genes related to the cell cycle and apoptosis using real-time polymerase chain reaction (PCR)...
March 28, 2017: Animal Reproduction Science
https://www.readbyqxmd.com/read/28386145/significance-of-stat3-signaling-in-epithelial-cell-differentiation-of-fetal-mouse-lungs
#9
Hiroki Kameyama, Shinji Kudoh, Jun Hatakeyama, Akira Matuo, Takaaki Ito
To study the significance of signal transducer and activator of transcription (Stat) 3 in lung epithelial development of fetal mice, we examined fetal mouse lungs, focusing on the expression of Clara cell secretory protein (CCSP), Forkhead box protein J1 (Foxj1), calcitonin gene-related peptide (CGRP), phosphorylated Stat3 (Tyr705), and hairy/enhancer of split (Hes) 1, and observed cultured fetal lungs upon treatment with IL-6, a Stat3 activator, or cucurbitacin I, a Stat3 inhibitor. Moreover, the interaction of Stat3 signaling and Hes1 was studied using Hes1 gene-deficient mice...
February 28, 2017: Acta Histochemica et Cytochemica
https://www.readbyqxmd.com/read/28286920/blockade-of-notch-signaling-promotes-acetaminophen-induced-liver-injury
#10
Longfeng Jiang, Michael Ke, Shi Yue, Wen Xiao, Youde Yan, Xiaozhao Deng, Qi-Long Ying, Jun Li, Bibo Ke
Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS...
March 13, 2017: Immunologic Research
https://www.readbyqxmd.com/read/28256007/targeting-notch-activated-m1-macrophages-attenuates-joint-tissue-damage-in-a-mouse-model-of-inflammatory-arthritis
#11
Wen Sun, Hengwei Zhang, Hua Wang, Yahui Grace Chiu, Mengmeng Wang, Christopher T Ritchlin, Amy Kiernan, Brendan F Boyce, Lianping Xing
Expression levels of Notch signaling molecules are increased in synovium from patients with rheumatoid arthritis (RA). However, it is not known which cell type(s) in RA synovium have Notch activation or if they play a pathogenetic role in RA. Here, we used Hes1-GFP/TNF-transgenic (TNF-Tg) mice to investigate the role of cells with active Notch signaling (GFP+) in RA. The number of GFP+ cells was significantly increased in synovium in Hes1-GFP/TNF-Tg mice and about 60% of them were F4/80+ macrophages expressing the inflammatory macrophage (M1) marker...
March 3, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28186678/gamma-secretase-inhibitor-ix-gsi-impairs-concomitant-activation-of-notch-and-wnt-beta-catenin-pathways-in-cd44-gastric-cancer-stem-cells
#12
Samarpita Barat, Xi Chen, Khac Cuong Bui, Przemyslaw Bozko, Julian Götze, Matthias Christgen, Till Krech, Nisar P Malek, Ruben R Plentz
Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44(+) CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28157712/the-interference-of-notch1-target-hes1-affects-cell-growth-differentiation-and-invasiveness-of-glioblastoma-stem-cells-through-modulation-of-multiple-oncogenic-targets
#13
Carlo Cenciarelli, Hany E Marei, Manuela Zonfrillo, Patrizia Casalbore, Armando Felsani, Stefano Giannetti, Gianluca Trevisi, Asma Althani, Annunziato Mangiola
The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28122586/mir-182-promotes-cancer-invasion-by-linking-ret-oncogene-activated-nf-%C3%AE%C2%BAb-to-loss-of-the-hes1-notch1-regulatory-circuit
#14
Alf Spitschak, Claudia Meier, Bhavani Kowtharapu, David Engelmann, Brigitte M Pützer
BACKGROUND: Dominant-activating mutations in the RET proto-oncogene, a receptor tyrosine kinase, are responsible for the development of medullary thyroid carcinoma (MTC) and causative for multiple endocrine neoplasia (MEN) type 2A and 2B. These tumors are highly aggressive with a high propensity for early metastasis and chemoresistance. This attribute makes this neoplasia an excellent model for probing mechanisms underlying cancer progression. METHODS: The expression level of miR-182 was measured in MTC tumor specimens and in TT cells by real-time RT-PCR...
January 26, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28112174/2-3-5-4-tetrahydroxystilbene-2-o-%C3%AE-d-glucoside-protects-murine-hearts-against-ischemia-reperfusion-injury-by-activating-notch1-hes1-signaling-and-attenuating-endoplasmic-reticulum-stress
#15
Meng Zhang, Li-Ming Yu, Hang Zhao, Xuan-Xuan Zhou, Qian Yang, Fan Song, Li Yan, Meng-En Zhai, Bu-Ying Li, Bin Zhang, Zhen-Xiao Jin, Wei-Xun Duan, Si-Wang Wang
2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg(-1)·d(-1), ig) for 2 weeks and then were subjected to MI/R surgery...
March 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28086833/delta-like-4-notch-signaling-promotes-apc-min-tumor-initiation-through-angiogenic-and-non-angiogenic-related-mechanisms
#16
Marina Badenes, Alexandre Trindade, Hugo Pissarra, Luís Lopes-da-Costa, António Duarte
BACKGROUND: Delta like 4 (Dll4)/Notch signaling is a key regulator of tumor angiogenesis. Additionally, the role of Dll4 has been studied on tumor stem cells. However, as these cells are implicated in tumor angiogenesis, it is conceivable that the effect of Dll4 on these cells may be a consequence of its angiogenic function. Our aim was to evaluate the expression and dissect the functions of Dll4 in the Apc (Min/+) model of colorectal cancer. METHODS: We evaluated the protein expression pattern of Dll4 and other Notch members in the Apc (Min/+) tumors relatively to the normal gut and compared endothelial-specific with ubiquitous Dll4 knockout mice on an Apc (Min/+) background...
January 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28079885/mirna182-regulates-percentage-of-myeloid-and-erythroid-cells-in-chronic-myeloid-leukemia
#17
Deepak Arya, Sasikala P Sachithanandan, Cecil Ross, Dasaradhi Palakodeti, Shang Li, Sudhir Krishna
The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28058624/zebrafish-phenotypic-screen-identifies-novel-notch-antagonists
#18
Vithya Velaithan, Kazuhide Shaun Okuda, Mei Fong Ng, Norazwana Samat, Sze Wei Leong, Siti Munirah Mohd Faudzi, Faridah Abas, Khozirah Shaari, Sok Ching Cheong, Pei Jean Tan, Vyomesh Patel
Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors...
January 5, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28028172/histone-deacetylase-1-is-essential-for-rod-photoreceptor-differentiation-by-regulating-acetylation-at-histone-h3-lysine-9-and-histone-h4-lysine-12-in-the-mouse-retina
#19
Renata C Ferreira, Evgenya Y Popova, Jessica James, Marcelo R S Briones, Samuel S Zhang, Colin J Barnstable
Histone acetylation has a regulatory role in gene expression and is necessary for proper tissue development. To investigate the specific roles of histone deacetylases (HDACs) in rod differentiation in neonatal mouse retinas, we used a pharmacological approach that showed that inhibition of class I but not class IIa HDACs caused the same phenotypic changes seen with broad spectrum HDAC inhibitors, most notably a block in the differentiation of rod photoreceptors. Inhibition of HDAC1 resulted in increase of acetylation of lysine 9 of histone 3 (H3K9) and lysine 12 of histone 4 (H4K12) but not lysine 27 of histone 3 (H3K27) and led to maintained expression of progenitor-specific genes such as Vsx2 and Hes1 with concomitant block of expression of rod-specific genes...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27981247/aspartate-%C3%AE-hydroxylase-asph-a-potential-therapeutic-target-in-human-malignant-gliomas
#20
Lisa-Marie Sturla, Ming Tong, Nick Hebda, Jinsong Gao, John-Michael Thomas, Mark Olsen, Suzanne M de la Monte
BACKGROUND: Despite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBM's highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF-1α), NOTCH, and aspartate-β-hydroxylase (ASPH). METHODS: Human astrocytoma biopsy specimens (n = 37), WHO Grades II-IV, were analyzed for levels and distributions of ASPH and HIF-1α immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1α mRNA expression by quantigene multiplex analysis...
December 2016: Heliyon
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