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notch signaling inhibitors and stimulators

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https://www.readbyqxmd.com/read/28637014/a-combination-of-valproic-acid-sodium-salt-chir99021-e-616452-tranylcypromine-and-3-deazaneplanocin-a-causes-stem-cell-like-characteristics-in-cancer-cells
#1
Shuang Sha, Yuanfen Zhai, Chengzhao Lin, Heyong Wang, Qing Chang, Shuang Song, Mingqiang Ren, Gentao Liu
Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28624262/dibenzazepine-loaded-nanoparticles-induce-local-browning-of-white-adipose-tissue-to-counteract-obesity
#2
Chunhui Jiang, Mario Alberto Cano-Vega, Feng Yue, Liangju Kuang, Naagarajan Narayanan, Gozde Uzunalli, Madeline P Merkel, Shihuan Kuang, Meng Deng
Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ)...
June 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28600474/use-of-angiotensin-system-inhibitors-is-associated-with-immune-activation-and-longer-survival-in-non-metastatic-pancreatic-ductal-adenocarcinoma
#3
Hao Liu, Kamila Naxerova, Matthias Pinter, Joao Incio, Hang Lee, Kohei Shigeta, William W Ho, Jonathan A Crain, Alex Jacobson, Theodoros Michelakos, Daniella Dias-Santos, Andrea Zanconato, Theodore S Hong, Jeffrey W Clark, Janet E Murphy, David P Ryan, Vikram Deshpande, Keith D Lillemoe, Carlos Fernandez-Del Castillo, Michael Downes, Ronald M Evans, James Michaelson, Cristina R Ferrone, Yves Boucher, Rakesh K Jain
Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.<br /><br />Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions...
June 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28599454/differential-expression-of-the-notch1-receptor-and-its-ligands-dll1-dll3-and-dll4-in-distinct-human-pituitary-adenoma-subtypes
#4
Jianfu Zhang, Hua Gao, Yazhuo Zhang
Pituitary adenoma (PA) is a common type of benign tumor of the pituitary gland that is characterized by specific signs and symptoms, primarily associated with hypersecretion of pituitary glycoprotein hormones (thyroid-stimulating, growth and adrenocorticotrophic hormones, and prolactin). Surgery is the first-line treatment, although postoperative residual tissues/cells and subsequent recurrence remain notable complications. Gene therapy is an effective approach for treatment, as previous studies have demonstrated that the Notch signaling pathway participates in the pathogenesis of PA...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28515436/nimbolide-upregulates-reck-by-targeting-mir-21-and-hif-1%C3%AE-in-cell-lines-and-in-a-hamster-oral-carcinogenesis-model
#5
Jaganathan Kowshik, Rajakishore Mishra, Josephraj Sophia, Satabdi Rautray, Kumaraswamy Anbarasu, G Deepak Reddy, Madhulika Dixit, Sundarasamy Mahalingam, Siddavaram Nagini
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates angiogenesis and Notch signalling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model, a paradigm for oral oncogenesis and chemointervention. We also report the chemotherapeutic effect of nimbolide, a limonoid from the neem tree (Azadirachta indica) based on the upregulation of RECK as well as modulation of the expression of key molecules involved in invasion and angiogenesis...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28486700/dysregulation-of-the-adam17-notch-signalling-pathways-in-endometriosis-from-oxidative-stress-to-fibrosis
#6
Iñaki González-Foruria, Pietro Santulli, Sandrine Chouzenoux, Francisco Carmona, Charles Chapron, Frédéric Batteux
STUDY QUESTION: Is oxidative stress associated with the A disintegrin and metalloproteases (ADAM) metallopeptidase domain 17 (ADAM17)/Notch signalling pathway and fibrosis in the development of endometriosis? SUMMARY ANSWER: Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signalling pathway and a consequent increase in fibrosis in patients with endometriosis. WHAT IS KNOWN ALREADY: It is nowadays accepted that oxidative stress plays an important role in the onset and progression of endometriosis...
May 9, 2017: Molecular Human Reproduction
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
#7
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/28415816/targeting-the-pim-protein-kinases-for-the-treatment-of-a-t-cell-acute-lymphoblastic-leukemia-subset
#8
Sathish K R Padi, Libia A Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H Song, Jon C Aster, Xue-Zhong Yu, Shikhar Mehrotra, Andrew S Kraft
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28371279/ephb4-forward-signalling-mediates-angiogenesis-caused-by-ccm3-pdcd10-ablation
#9
Chao You, Kai Zhao, Philipp Dammann, Kathy Keyvani, Ilonka Kreitschmann-Andermahr, Ulrich Sure, Yuan Zhu
CCM3, also named as PDCD10, is a ubiquitous protein expressed in nearly all tissues and in various types of cells. It is essential for vascular development and post-natal vessel maturation. Loss-of-function mutation of CCM3 predisposes for the familial form of cerebral cavernous malformation (CCM). We have previously shown that knock-down of CCM3 stimulated endothelial angiogenesis via impairing DLL4-Notch signalling; moreover, loss of endothelial CCM3 stimulated tumour angiogenesis and promoted tumour growth...
April 1, 2017: Journal of Cellular and Molecular Medicine
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...
June 2017: Immunologic Research
https://www.readbyqxmd.com/read/28139517/role-of-jagged1-hey1-signal-in-angiotensin-ii-induced-impairment-of-myocardial-angiogenesis
#11
Ai-Li Guan, Tao He, Yi-Bing Shao, Yi-Fan Chi, Hong-Yan Dai, Yan Wang, Li Xu, Xuan Yang, Hua-Min Ding, Shang-Lang Cai
BACKGROUND: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy...
February 5, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28007595/the-notch-ligand-delta-like-3-promotes-tumor-growth-and-inhibits-notch-signaling-in-lung-cancer-cells-in-mice
#12
San-Ming Deng, Xian-Chun Yan, Liang Liang, Li Wang, Yuan Liu, Juan-Li Duan, Zi-Yan Yang, Tian-Fang Chang, Bai Ruan, Qi-Jun Zheng, Hua Han
Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-α. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27925454/rap1a-promotes-ovarian-cancer-metastasis-via-activation-of-erk-p38-and-notch-signaling
#13
Lili Lu, Jingshu Wang, Yougen Wu, Ping Wan, Gong Yang
As one of the Ras-associated proteins, Rap1A has been linked to cancer initiation and development. However, the precise function of Rap1A in ovarian cancer is still not understood. Here, we show that Rap1A promotes ovarian cancer tumorigenesis and metastasis via stimulating cell proliferation, migration and invasion both in vivo and in vitro. Mechanistic study showed that Rap1A activates extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and Notch pathways, leading to the enhanced expression of several epithelial-mesenchymal transition (EMT) markers such as slug, zeb1, vimentin, fibronectin, and MMP9...
December 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27904680/enhancement-of-early-cardiac-differentiation-of-dedifferentiated-fat-cells-by-dimethyloxalylglycine-via-notch-signaling-pathway
#14
Fuhai Li, Zongzhuang Li, Zhi Jiang, Ye Tian, Zhi Wang, Wei Yi, Chenyun Zhang
Background: Hypoxia has been reported to possess the ability to induce mature lipid-filled adipocytes to differentiate into fibroblast-like multipotent dedifferentiated fat (DFAT) cells and stem cells such as iPSCs (interstitial pluripotent stem cells) and ESCs (embryonic stem cells) and then to differentiate into cardiomyocytes. However, the effect of hypoxia on cardiac differentiation of DFAT cells and its underlying molecular mechanism remains to be investigated. Objective: To investigate the role of hypoxia in early cardiac differentiation of DFAT cells and the underlying molecular mechanism...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27643563/notch-hyper-activation-drives-trans-differentiation-of-hesc-derived-endothelium
#15
David Reichman, Limor Man, Laura Park, Raphael Lis, Jeannine Gerhardt, Zev Rosenwaks, Daylon James
During development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue-specific EC sub-types (Rafii et al., 2013) and identify pathways that govern growth and trans-differentiation potential of hESC-derived ECs (James et al., 2010). Here, we elucidate a novel Notch-dependent mechanism that induces endothelial to mesenchymal transition (EndMT) in confluent monolayer cultures of hESC-derived ECs...
September 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27590851/leptin-induced-transphosphorylation-of-vascular-endothelial-growth-factor-receptor-increases-notch-and-stimulates-endothelial-cell-angiogenic-transformation
#16
Viola Lanier, Corey Gillespie, Merle Leffers, Danielle Daley-Brown, Joy Milner, Crystal Lipsey, Nia Webb, Leonard M Anderson, Gale Newman, Johannes Waltenberger, Ruben Rene Gonzalez-Perez
Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2)...
October 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27490118/hif-2%C3%AE-expression-regulates-sprout-formation-into-3d-fibrin-matrices-in-prolonged-hypoxia-in-human-microvascular-endothelial-cells
#17
Tessa D Nauta, Monique C A Duyndam, Ester M Weijers, Victor M W van Hinsbergh, Pieter Koolwijk
BACKGROUND: During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1α and HIF-2α) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. OBJECTIVES: We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling...
2016: PloS One
https://www.readbyqxmd.com/read/27448787/molecularly-targeted-agents-and-immunotherapy-for-the-treatment-of-head-and-neck-squamous-cell-cancer-hnscc
#18
SaÏd C Azoury, Richard C Gilmore, Vivek Shukla
Squamous cell carcinoma is one of the most frequent tumors of the head and neck and often presents at an advanced-stage. Traditionally, treatment for head and neck squamous cell carcinoma (HNSCC) has included surgery, radiation, and chemotherapy depending on both the site and stage of disease. Although the treatment approach for local disease is often standardized, the management of recurrent and advanced disease is evolving. A better understanding of the molecular mechanisms of HNSCC has led to numerous promising investigations and the push for the development of novel therapies...
June 2016: Discovery Medicine
https://www.readbyqxmd.com/read/27206767/lfa-1-icam-1-ligation-in-human-t-cells-promotes-th1-polarization-through-a-gsk3%C3%AE-signaling-dependent-notch-pathway
#19
Navin K Verma, M H U Turabe Fazil, Seow Theng Ong, Madhavi Latha S Chalasani, Jian Hui Low, Amuthavalli Kottaiswamy, Praseetha P, Atish Kizhakeyil, Sunil Kumar, Aditya K Panda, Michael Freeley, Sinead M Smith, Bernhard O Boehm, Dermot Kelleher
In this study, we report that the integrin LFA-1 cross-linking with its ligand ICAM-1 in human PBMCs or CD4(+) T cells promotes Th1 polarization by upregulating IFN-γ secretion and T-bet expression. LFA-1 stimulation in PBMCs, CD4(+) T cells, or the T cell line HuT78 activates the Notch pathway by nuclear translocation of cleaved Notch1 intracellular domain (NICD) and upregulation of target molecules Hey1 and Hes1. Blocking LFA-1 by a neutralizing Ab or specific inhibition of Notch1 by a γ-secretase inhibitor substantially inhibits LFA-1/ICAM-1-mediated activation of Notch signaling...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27171263/mechanical-stimulation-orchestrates-the-osteogenic-differentiation-of-human-bone-marrow-stromal-cells-by-regulating-hdac1
#20
J Wang, C D Wang, N Zhang, W X Tong, Y F Zhang, S Z Shan, X L Zhang, Q F Li
Mechanical stimulation and histone deacetylases (HDACs) have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding what regulates HDAC expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. In this study, we investigated whether mechanical loading regulates HDAC expression directly and examined the role of HDACs in mechanical loading-triggered osteogenic differentiation and bone formation...
2016: Cell Death & Disease
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