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inhibitors of notch

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https://www.readbyqxmd.com/read/29149593/notch2-hajdu-cheney-mutations-escape-scf-fbw7-dependent-proteolysis-to-promote-osteoporosis
#1
Hidefumi Fukushima, Kouhei Shimizu, Asami Watahiki, Seira Hoshikawa, Tomoki Kosho, Daiju Oba, Seiji Sakano, Makiko Arakaki, Aya Yamada, Katsuyuki Nagashima, Koji Okabe, Satoshi Fukumoto, Eijiro Jimi, Anna Bigas, Keiichi I Nakayama, Keiko Nakayama, Yoko Aoki, Wenyi Wei, Hiroyuki Inuzuka
Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#2
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29127399/radial-extracorporeal-shock-wave-therapy-enhances-the-proliferation-and-differentiation-of-neural-stem-cells-by-notch-pi3k-akt-and-wnt-%C3%AE-catenin-signaling
#3
Jing Zhang, Nan Kang, Xiaotong Yu, Yuewen Ma, Xining Pang
Neural stem cell (NSC) proliferation and differentiation play a pivotal role in the repair of brain function in central nervous system (CNS) diseases. Radial extracorporeal shock wave therapy (rESWT) is a non-invasive and innovative treatment for many conditions, yet little is known about the effects of this treatment on NSCs. Mouse NSCs (NE-4C) were exposed to rESWT with 1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 bar (500 impulses, and 2 Hz) in vitro. Cell viability test results indicated that rESWT, at a dose of 2...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29126263/notch-signaling-regulates-differentiation-and-steroidogenesis-in-female-mouse-ovarian-granulosa-cells
#4
Rexxi D Prasasya, Kelly E Mayo
The Notch pathway is a highly conserved juxtacrine signaling mechanism that is important for many cellular processes during development, including differentiation and proliferation. While Notch is important during ovarian follicle formation and early development, its functions during the gonadotropin-dependent stages of follicle development are largely unexplored. We observed positive regulation of Notch activity and expression of Notch ligands and receptors following activation of the LH-receptor in prepubertal mouse ovary...
November 8, 2017: Endocrinology
https://www.readbyqxmd.com/read/29123981/coculture-of-endothelial-progenitor-cells-and-mesenchymal-stem-cells-enhanced-their-proliferation-and-angiogenesis-through-pdgf-and-notch-signaling
#5
Tangzhao Liang, Lei Zhu, Wenling Gao, Ming Gong, Jianhua Ren, Hui Yao, Kun Wang, Dehai Shi
The beneficial effects of combined use of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) on tissue repair and regeneration after injury have been demonstrated, but the underlying mechanism remains incompletely understood. This study aimed to investigate the effects of direct contact coculture of human bone marrow-derived EPCs (hEPCs)/human bone marrow-derived MSCs (hMSCs) on their proliferation and angiogenic capacities and the underlying mechanism. hEPCs and hMSCs were cocultured in a 2D mixed monolayer or a 3D transwell membrane cell-to-cell coculture system...
November 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/29111218/the-notch-pathway-inhibitor-sahm1-abrogates-the-hallmarks-of-allergic-asthma
#6
Alex KleinJan, Irma Tindemans, Jeffrey E Montgomery, Melanie Lukkes, Marjolein J W de Bruijn, Menno van Nimwegen, Ingrid Bergen, Raymond E Moellering, Henk C Hoogsteden, Louis Boon, Derk Amsen, R W Hendriks
BACKGROUND: The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by the cell-permeable, hydrocarbon-stapled synthetic peptide SAHM1 was results in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, efficacy of SAHM1 in allergic asthma models has remained unexplored. OBJECTIVE: We aimed to investigate therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model...
October 27, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29109859/candidate-synthetic-lethality-partners-to-parp-inhibitors-in-the-treatment-of-ovarian-clear-cell-cancer
#7
Naoki Kawahara, Kenji Ogawa, Mika Nagayasu, Mai Kimura, Yoshikazu Sasaki, Hiroshi Kobayashi
Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies...
November 2017: Biomedical Reports
https://www.readbyqxmd.com/read/29104587/notch-and-its-oncogenic-activity-in-human-malignancies
#8
REVIEW
Marlena Brzozowa-Zasada, Adam Piecuch, Marek Michalski, Oliwia Segiet, Józef Kurek, Marzena Harabin-Słowińska, Romuald Wojnicz
Background: Increasing evidence has demonstrated that Notch signaling is deregulated in human hematological malignancies and solid tumors. This signaling has a protumorigenic effect but may also act as a tumor suppressor. How induction of a single pathway gives rise to the opposite effects in different cell types is still unknown. Methods: This review article includes available data from peer-reviewed publications associated with the role of Notch signaling during cancer pathogenesis...
2017: European Surgery: ACA: Acta Chirurgica Austriaca
https://www.readbyqxmd.com/read/29101337/trichostatin-a-ameliorates-renal-tubulointerstitial-fibrosis-through-modulation-of-the-jnk-dependent-notch-2-signaling-pathway
#9
Chun-Wu Tung, Yung-Chien Hsu, Chang-Jhih Cai, Ya-Hsueh Shih, Ching-Jen Wang, Pey-Jium Chang, Chun-Liang Lin
Renal fibrosis is the final common pathological feature in a variety of chronic kidney disease. Trichostatin A (TSA), a histone deacetylase inhibitor, reportedly attenuates renal fibrosis in various kidney disease models. However, the detailed molecular action of TSA in ameliorating renal fibrotic injury is not yet fully understood. In a cultured renal fibroblastic cell model, we showed that TGF-β1 triggers upregulation of α-SMA and fibronectin, two hallmarks of myofibroblastic activation. During the course of TGF-β1 treatment, activation of Smad2/3, p38, ERK, JNK and Notch-2 was also detected...
November 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29100034/down-regulation-of-notch-signaling-pathway-reverses-the-th1-th2-imbalance-in-tuberculosis-patients
#10
Qifeng Li, Hui Zhang, Liang Yu, Chao Wu, Xinhui Luo, He Sun, Jianbing Ding
Th1/Th2 imbalance to Th2 is of significance in the peripheral immune responses in Tuberculosis (TB) development. However, the mechanisms for Th1/Th2 imbalance are still not well determined. Notch signaling pathway is involved in the peripheral T cell activation and effector cell differentiation. However, whether it affects Th1/Th2 imbalance in TB patients is still not known. Here, we used γ-secretase inhibitor (DAPT) to treat the peripheral blood mononuclear cells (PBMCs) from healthy people or individuals with latent or active TB infection in vitro, respectively...
October 28, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29096354/notch-signaling-pathway-dampens-tumor-infiltrating-cd8-t-cells-activity-in-patients-with-colorectal-carcinoma
#11
Weifeng Yu, Yanjun Wang, Peng Guo
CD8(+) T cells play critical role in controlling the metastasis and prognosis of cancer. Controversy remains as to the contribution of Notch signaling pathway in modulation of CD8(+) T cells activity and development of tumorigenesis. Thus, the aim of the current study was to investigate the immunoregulatory role of Notch signaling pathway to peripheral and tumor-infiltrating CD8(+) T cells in patients with colorectal carcinoma. A total of 46 patients with colorectal carcinoma and 20 health individuals were enrolled, and CD8(+) T cells were purified from both peripheral bloods and carcinoma specimens...
October 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29092089/notch-wnt-cross-signalling-regulates-stemness-of-dental-pulp-stem-cells-through-expression-of-neural-crest-and-core-pluripotency-factors
#12
V Uribe-Etxebarria, J Luzuriaga, P García-Gallastegui, A Agliano, F Unda, G Ibarretxe
Dental pulp stem cells (DPSCs) from adult teeth express neural crest (NC) markers together with core transcriptional factors associated with stem cell pluripotency, such as Oct4a, Sox2, c-Myc, Rex1, Stella/Dppa3, Ssea1/Fut4, Lin28 and Nanog. The possibility to boost the natural stemness features of DPSCs by mild methods, that do not involve gene and/or chromatin modification or gene transfection, is highly desirable for cell therapy. Canonical Wnt and Notch are two highly conserved developmental signalling pathways that are involved in NC emergence and stem cell self-renewal...
November 1, 2017: European Cells & Materials
https://www.readbyqxmd.com/read/29078041/perspectives-on-the-discovery-of-notch2-specific-inhibitors
#13
Peter Dobranowski, Fuqiang Ban, Alberto Contreras-Sanz, Artem Cherkasov, Peter C Black
The Notch pathway is a cell-cell communication system where membrane-bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ-secretase inhibitors as Notch-inhibiting agents are already promising in clinical trials, they are highly non-specific with adverse side effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways...
October 27, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29076782/activation-of-the-notch-1-signaling-pathway-may-be-involved-in-intracerebral-hemorrhage-induced-reactive-astrogliosis-in-rats
#14
Jian-Hua Zhong, Hua-Jun Zhou, Tao Tang, Han-Jin Cui, A-Li Yang, Qi-Mei Zhang, Jing-Hua Zhou, Qiang Zhang, Xun Gong, Zhao-Hui Zhang, Zhi-Gang Mei
OBJECTIVE Reactive astrogliosis, a key feature that is characterized by glial proliferation, has been observed in rat brains after intracerebral hemorrhage (ICH). However, the mechanisms that control reactive astrogliosis formation remain unknown. Notch-1 signaling plays a critical role in modulating reactive astrogliosis. The purpose of this paper was to establish whether Notch-1 signaling is involved in reactive astrogliosis after ICH. METHODS ICH was induced in adult male Sprague-Dawley rats via stereotactic injection of autologous blood into the right globus pallidus...
October 27, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/29061784/bmi1-inhibitors-down-regulate-notch-signaling-and-suppress-proliferation-of-acute-leukemia-cells
#15
Mika Ohtaka, Mai Itoh, Shuji Tohda
BACKGROUND/AIM: B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is up-regulated in several cancers; therefore, we investigated the effects of BMI1 inhibitors on leukemia cells. MATERIALS AND METHODS: Four acute myeloid leukemia and two T-lymphoblastic leukemia cell lines were treated with BMI1 inhibitors artemisinin, PRT4165, and PTC-209 and analyzed for cell proliferation and gene expression by microarray and immunoblotting. RESULTS: PTC-209 and PRT4165 suppressed the growth of all cell lines through apoptosis...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/29057904/the-ank-repeats-of-notch-4-int3-activate-nf-%C3%AE%C2%BAb-canonical-pathway-in-the-absence-of-rbpj-and-causes-mammary-tumorigenesis
#16
Ahmed Raafat, Sharon Bargo, David McCurdy, Robert Callahan
Transgenic mice expressing the Notch-4 intracellular domain (designated Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch-4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, WAP-Int3/Rbpj knockout mice have normal mammary gland development but still developed mammary tumors with a slightly longer latency than the WAP-Int3 mice...
October 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29050323/histone-deacetylase-inhibitor-thailandepsin-a-activates-notch-signaling-and-suppresses-neuroendocrine-cancer-cell-growth-in-vivo
#17
Samuel Jang, Andrew Janssen, Zviadi Aburjania, Matthew B Robers, April Harrison, Ajitha Dammalapati, Yi-Qiang Cheng, Herbert Chen, Renata Jaskula-Sztul
Novel therapies for neuroendocrine (NE) cancers are desperately needed as they frequently present as metastatic disease and cause debilitating symptoms by secreting excessive hormones. Induction of Notch isoforms has a tumor suppressive effect in NE cancer cell lines, and we have observed that histone deacetylase inhibitors (HDACi) potently activate Notch. In this study, we describe the potential for Burkholderia thailandensis-derived class I HDACi thailandepsin A (TDP-A) as a Notch activator and therapeutic agent against NE cancer...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#18
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29048643/novel-transduction-of-nutrient-stress-to-notch-pathway-by-rasgrp3-promotes-malignant-aggressiveness-in-human-esophageal-squamous-cell-carcinoma
#19
Ge Hu, Yuepeng Zhou, Yu Zhu, Ling Zhou, Rui Ling, Dan Wu, Lei Mi, Xuefeng Wang, Dongfang Dai, Chaoming Mao, Deyu Chen
In the process of enlarging of tumors, the dissolving tissue structures and remodeling endothelial cells for restoring gas exchange and nutritional support, further facilitate tumor cell invasion and metastasis. Activation of Ras plays a critical role in the development of esophageal squamous cell carcinoma (ESCC), but the underlying mechanisms remain poorly understood. We therefore investigated whether Ras guanyl-releasing protein 3 (RasGRP3), a Ras activator, could promote metastasis by inducing vascular regeneration and further epithelial-mesenchymal transition under nutrient stress (NS)...
September 25, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29047105/%C3%AE-secretase-inhibitor-reduces-immunosuppressive-cells-and-enhances-tumour-immunity-in-head-and-neck-squamous-cell-carcinoma
#20
Liang Mao, Zhi-Li Zhao, Guang-Tao Yu, Lei Wu, Wei-Wei Deng, Yi-Cun Li, Jian-Feng Liu, Lin-Lin Bu, Bing Liu, Ashok B Kulkarni, Wen-Feng Zhang, Lu Zhang, Zhi-Jun Sun
Immune evasion is a hallmark feature of cancer, and it plays an important role in tumour initiation and progression. In addition, tumour immune evasion severely hampers the desired antitumour effect in multiple cancers. In this study, we aimed to investigate the role of the Notch pathway in immune evasion in the head and neck squamous cell carcinoma (HNSCC) microenvironment. We first demonstrated that Notch1 signalling was activated in a Tgfbr1/Pten-knockout HNSCC mouse model. Notch signalling inhibition using a γ-secretase inhibitor (GSI-IX, DAPT) decreased tumour burden in the mouse model after prophylactic treatment...
October 19, 2017: International Journal of Cancer. Journal International du Cancer
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