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inhibitors of notch

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https://www.readbyqxmd.com/read/28817274/notch-inhibitors-from-calotropis-gigantea-that-induce-neuronal-differentiation-of-neural-stem-cells
#1
Tatsuro Yoneyama, Midori A Arai, Ryuta Akamine, Kazune Koryudzu, Anna Tsuchiya, Samir K Sadhu, Firoj Ahmed, Motoyuki Itoh, Ryuichi Okamoto, Masami Ishibashi
Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease occur due to loss of the structure and function of neurons. For the potential treatment of neurodegenerative diseases, accelerators of neuronal differentiation of neural stem cells (NSCs) have been focused on and a cell-based assay system for measuring Notch signaling pathway activity was constructed. Using this assay system, eight compounds isolated from Calotropis gigantea were identified as inhibitors of the Notch signaling pathway...
August 17, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28798480/magnesium-chloride-promotes-osteogenesis-through-notch-signaling-activation-and-expansion-of-mesenchymal-stem-cells
#2
Juan M Díaz-Tocados, Carmen Herencia, Julio M Martínez-Moreno, Addy Montes de Oca, Maria E Rodríguez-Ortiz, Noemi Vergara, Alfonso Blanco, Sonja Steppan, Yolanda Almadén, Mariano Rodríguez, Juan R Muñoz-Castañeda
Mesenchymal stem cells (MSC) are osteoblasts progenitors and a variety of studies suggest that they may play an important role for the health in the field of bone regeneration. Magnesium supplementation is gaining importance as adjuvant treatment to improve osteogenesis, although the mechanisms involving this process are not well understood. The objective of this study was to investigate the effects of magnesium on MSC differentiation. Here we show that in rat bone marrow MSC, magnesium chloride increases MSC proliferation in a dose-dependent manner promoting osteogenic differentiation and mineralization...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28789624/hedgehog-inhibitor-sonidegib-potentiates-177-lu-octreotate-therapy-of-got1-human-small-intestine-neuroendocrine-tumors-in-nude-mice
#3
Johan Spetz, Britta Langen, Nils Rudqvist, Toshima Z Parris, Khalil Helou, Ola Nilsson, Eva Forssell-Aronsson
BACKGROUND: (177)Lu-octreotate can be used to treat somatostatin receptor expressing neuroendocrine tumors. It is highly effective in animal models, but clinical studies have so far only demonstrated low cure rates. Hedgehog inhibitors have shown therapeutic effect as monotherapy in neuroendocrine tumor model systems and might be one option to enhance the efficacy of (177)Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy using (177)Lu-octreotate and the Hedgehog signaling pathway inhibitor sonidegib...
August 8, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28776955/antineoplastic-effects-of-histone-deacetylase-inhibitors-in-neuroendocrine-cancer-cells-are-mediated-through-transcriptional-regulation-of-notch1-by-activator-protein-1
#4
Samuel Jang, Haining Jin, Madhuchhanda Roy, Alice L Ma, Shaoqin Gong, Renata Jaskula-Sztul, Herbert Chen
Notch signaling is minimally active in neuroendocrine (NE) cancer cells. While histone deacetylase inhibitors (HDACi) suppress NE cancer growth by inducing Notch, the molecular mechanism underlying this interplay has not yet been defined. NE cancer cell lines BON, H727, and MZ-CRC-1 were treated with known HDACi Thailadepsin-A (TDP-A) and valproic acid (VPA), and Notch1 mRNA expression was measured with RT-PCR. Truncated genomic fragments of the Notch1 promotor region fused with luciferase reporter were used to identify the potential transcription factor (TF) binding site...
August 4, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28772216/minocycline-attenuates-the-development-of-diabetic-neuropathy-by-inhibiting-spinal-cord-notch-signaling-in-rat
#5
Cheng Yang, Jie Gao, Banglin Wu, Nuo Yan, Hui Li, Yiqing Ren, Yufei Kan, Jiamin Liang, Yang Jiao, Yonghao Yu
We studied the effects of minocycline (an inhibitor of microglial activation) on the expression and activity of Notch-1 receptor, and explored the therapeutic efficacy of minocycline combined with Notch inhibitor DAPT in the treatment of diabetic neuropathic pain (DNP). Diabetic rat model was established by intraperitoneal injection (ip) of Streptozotocin (STZ). Expression and activity of Notch-1 and expression of macrophage/microglia marker Iba-1 were detected by WB. Diabetes induction significantly attenuated sciatic nerve conduction velocity, and dramatically augmented the expression and the activity of Notch-1 in the lumbar enlargement of the spinal cord...
July 31, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28771710/brain-endothelial-cells-induce-astrocytic-expression-of-the-glutamate-transporter-glt-1-by-a-notch-dependent-mechanism
#6
Meredith L Lee, Zila Martinez-Lozada, Elizabeth N Krizman, Michael B Robinson
Neuron-secreted factors induce astrocytic expression of the glutamate transporter, GLT-1 (EAAT2). In addition to their elaborate anatomic relationships with neurons, astrocytes also have processes that extend to and envelop the vasculature. Although previous studies have demonstrated that brain endothelia contribute to astrocyte differentiation and maturation, the effects of brain endothelia on astrocytic expression of GLT-1 have not been examined. In the present study, we tested the hypothesis that endothelia induce expression of GLT-1 by co-culturing astrocytes from mice that utilize non-coding elements of the GLT-1 gene to control expression reporter proteins with the mouse endothelial cell line, bEND...
August 3, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28771672/med12-mutations-and-notch-signalling-in-chronic-lymphocytic-leukaemia
#7
Bian Wu, Mikołaj Słabicki, Leopold Sellner, Sascha Dietrich, Xiyang Liu, Alexander Jethwa, Jennifer Hüllein, Tatjana Walther, Lena Wagner, Zhiqin Huang, Marc Zapatka, Thorsten Zenz
Mutations in the N-terminus of MED12 protein occur at high frequency in uterine leiomyomas and breast fibroepithelial tumours, and are frequently found in chronic lymphocytic leukaemia (CLL). MED12 mutations have been previously linked to aberrant Cyclin C-CDK8 kinase activity, but the exact oncogenic function in CLL is unknown. Here, we characterized MED12 mutations in CLL and identified recurrent mutations in 13 out of 188 CLL patients (6·9%), which clustered in the N-terminus. MED12 mutations were associated with unmutated IGHV (P = 0·024)...
August 2, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28769027/synergistic-effect-of-notch-3-specific-inhibition-and-paclitaxel-in-non-small-cell-lung-cancer-nsclc-cells-via-activation-of-the-intrinsic-apoptosis-pathway
#8
Fenglian He, Ting Du, Qian Jiang, Yanbei Zhang
BACKGROUND Lung cancers are resistant to conventional chemotherapeutic interventions such as paclitaxel. Notch signaling is crucial in the chemoresistance of lung cancer cells. The Notch inhibitor gamma-secretase inhibitor (GSI) inhibits the Notch signaling pathway. MATERIAL AND METHODS Here, we evaluated how Notch-3 inhibition by GSI can enhance the sensitivity of lung cancer cells to paclitaxel. To study how Notch-3-specific inhibition affects non-small cell lung cancer (NSCLC), we compared the cell viability, apoptosis, and colony formation of A549 and H1299 cells treated with Notch-3 siRNA and GSI...
August 3, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28759157/mtor-notch3-signaling-mediates-pulmonary-hypertension-in-hypoxia-exposed-neonatal-rats-independent-of-changes-in-autophagy
#9
Julijana Ivanovska, Sparsh Shah, Mathew J Wong, Crystal Kantores, Amish Jain, Martin Post, Behzad Yeganeh, Robert P Jankov
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) is a pivotal regulator of cell proliferation, survival, and autophagy. Autophagy is increased in adult experimental chronic pulmonary hypertension (PHT), but its contributory role to pulmonary vascular disease remains uncertain and has yet to be explored in the neonatal animal. Notch is a major pro-proliferative pathway activated by mTOR. A direct relationship between autophagy and Notch signaling has not been previously explored. Our aim was to examine changes in mTOR-, Notch-, and autophagy-related pathways and the therapeutic effects of autophagy modulators in experimental chronic neonatal PHT secondary to chronic hypoxia...
July 31, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28738360/targeting-developmental-pathways-the-achilles-heel-of-cancer
#10
Wolfram C M Dempke, Klaus Fenchel, Peter Uciechowski, Timothy Chevassut
Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development...
July 22, 2017: Oncology
https://www.readbyqxmd.com/read/28736522/gliotoxin-targets-nuclear-notch2-in-human-solid-tumor-derived-cell-lines-in-vitro-and-inhibits-melanoma-growth-in-xenograft-mouse-model
#11
Rainer Hubmann, Wolfgang Sieghart, Susanne Schnabl, Mohammad Araghi, Martin Hilgarth, Marlies Reiter, Dita Demirtas, Peter Valent, Christoph Zielinski, Ulrich Jäger, Medhat Shehata
Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28730338/jagged1-promotes-aromatase-inhibitor-resistance-by-modulating-tumor-associated-macrophage-differentiation-in-breast-cancer-patients
#12
Hang Liu, Jingxuan Wang, Minghui Zhang, Qijia Xuan, Zhipeng Wang, Xin Lian, Qingyuan Zhang
PURPOSE: Endocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration. METHODS: The Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival...
July 20, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28707966/targeted-molecular-ablation-of-cancer-stem-cells-for-curing-gastrointestinal-cancers
#13
Yong Seok Kim, Ho Jae Lee, Jong-Min Park, Young-Min Han, Napapan Kangwan, Ji Young Oh, Dong Yoon Lee, Ki Baik Hahm
Abundance of the ATPase-binding cassette (ABC) transporters and deranged self-renewal pathways characterize the presence of cancer stem cells (CSCs) in gastrointestinal cancers (GI cancers), which play crucial roles in tumorigenesis, chemotherapy resistance, tumor recurrence, and cancer metastasis. Therefore, in order to ensure high cure rates, chemoquiescence, CSCs should be ablated. Recent advances in either understanding CSCs or biomarker identification enable scientists to develop techniques for ablating CSCs and clinicians to provide cancer cure, especially in GI cancers characterized by inflammation-driven carcinogenesis...
July 14, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28695451/the-endoscopic-findings-of-the-upper-gastrointestinal-tract-in-patients-with-crohn-s-disease
#14
REVIEW
Yoshiki Nomura, Kentaro Moriichi, Mikihiro Fujiya, Toshikatsu Okumura
Crohn's disease (CD) is a type of chronic inflammatory bowel disease (IBD) associated with ulceration, and the main foci of the inflammation in CD patients are typically the terminal ileum and colon. However, in the upper gastrointestinal tract (GIT), including the esophagus, stomach and duodenum, inflammatory lesions are also detected as well, with a relatively high frequency (30-75%). Recent advances in imaging modalities, including endoscopy, have aided in the diagnosis of CD. Various lesions, including aphtha, erosion, ulcers, bamboo-joint-like appearance and notch-like appearance, are detected in the upper GI of CD patients...
August 2017: Clinical Journal of Gastroenterology
https://www.readbyqxmd.com/read/28688971/tumor-vessel-normalization-by-the-pi3k-inhibitor-hs-173-enhances-drug-delivery
#15
Soo Jung Kim, Kyung Hee Jung, Mi Kwon Son, Jung Hee Park, Hong Hua Yan, Zhenghuan Fang, Yeo Wool Kang, Boreum Han, Joo Han Lim, Soon-Sun Hong
Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization...
July 6, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28684431/convergent-roles-of-atf3-and-csl-in-chromatin-control-of-cancer-associated-fibroblast-activation
#16
Dong Eun Kim, Maria-Giuseppina Procopio, Soumitra Ghosh, Seung-Hee Jo, Sandro Goruppi, Francesco Magliozzi, Pino Bordignon, Victor Neel, Paolo Angelino, G Paolo Dotto
Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes...
August 7, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28672785/comprehensive-expression-profiling-and-functional-network-analysis-of-porphyra-334-one-mycosporine-like-amino-acid-maa-in-human-keratinocyte-exposed-with-uv-radiation
#17
Sung-Suk Suh, Sung Gu Lee, Ui Joung Youn, Se Jong Han, Il-Chan Kim, Sanghee Kim
Mycosporine-like amino acids (MAAs) have been highlighted as pharmacologically active secondary compounds to protect cells from harmful UV-radiation by absorbing its energy. Previous studies have mostly focused on characterizing their physiological properties such as antioxidant activity and osmotic regulation. However, molecular mechanisms underlying their UV-protective capability have not yet been revealed. In the present study, we investigated the expression profiling of porphyra-334-modulated genes or microRNA (miRNAs) in response to UV-exposure and their functional networks, using cDNA and miRNAs microarray...
June 24, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28669599/inactivation-of-stat3-signaling-impairs-hair-cell-differentiation-in%C3%A2-the%C3%A2-developing-mouse-cochlea
#18
Qianqian Chen, Yizhou Quan, Naitao Wang, Chengying Xie, Zhongzhong Ji, Hao He, Renjie Chai, Huawei Li, Shankai Yin, Y Eugene Chin, Xunbin Wei, Wei-Qiang Gao
Although STAT3 signaling is demonstrated to regulate sensory cell differentiation and regeneration in the zebrafish, its exact role is still unclear in mammalian cochleae. Here, we report that STAT3 and its activated form are specifically expressed in hair cells during mouse cochlear development. Importantly, conditional cochlear deletion of Stat3 leads to an inhibition on hair cell differentiation in mice in vivo and in vitro. By cell fate analysis, inactivation of STAT3 signaling shifts the cell division modes from asymmetric to symmetric divisions from supporting cells...
July 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28669409/notch-signaling-pathway-regulates-the-growth-and-the-expression-of-inflammatory-cytokines-in-mouse-basophils
#19
Shuo-Yao Qu, Jia-Ji Lin, Jian Zhang, Li-Qiang Song, Xue-Min Yang, Chang-Gui Wu
Basophils (BAs) are the least common granulocytes of all leukocytes, but they play an important role in orchestrating of chronic allergic inflammation. The Notch signaling pathway is a highly conserved pathway that influences cell lineage decisions and differentiation during various stages of development. However, the relationship between Notch signaling and BA remains to be elucidate. Here, we report that several Notch signaling molecules were found to be expressed in BAs. γ-secretase inhibitor (GSI) treatment increase BAs apoptosis, and suppress BAs proliferation...
May 27, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28661121/dual-mode-imaging-guided-synergistic-chemo-and-magnetohyperthermia-therapy-in-a-versatile-nanoplatform-to-eliminate-cancer-stem-cells
#20
Jinglong Tang, Huige Zhou, Jiaming Liu, Jing Liu, Wanqi Li, Yuqing Wang, Fan Hu, Qing Huo, Jiayang Li, Ying Liu, Chunying Chen
Cancer stem cells (CSCs) have been identified as a new target for therapy in diverse cancers. Traditional therapies usually kill the bulk of cancer cells, but are often unable to effectively eliminate CSCs, which may lead to drug resistance and cancer relapse. Herein, we propose a novel strategy: fabricating multifunctional magnetic Fe3O4@PPr@HA hybrid nanoparticles and loading it with the Notch signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycinet-butylester (DAPT) to eliminate CSCs...
July 19, 2017: ACS Applied Materials & Interfaces
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