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notch signaling inhibitors and stimulators

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 13, 2016: Stem Cell Research
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
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
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
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
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
Jiesi Zhou, Saket Jain, Abul K Azad, Xia Xu, Hai Chuan Yu, Zhihua Xu, Roseline Godbout, YangXin Fu
Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of epithelial ovarian cancer (EOC). However, the mechanisms that regulate EMT in EOC are not fully understood. Here, we report that activation of Notch1 induces EMT in EOC cells as evidenced by downregulation of E-cadherin and cytokeratins, upregulation of Slug and Snail, as well as morphological changes. Interestingly, activation of Notch1 increases TGFβ/Smad signaling by upregulating the expression of TGFβ and TGFβ type 1 receptor...
August 2016: Cellular Signalling
Guo-Yong Yu, Gui-Zhou Zheng, Bo Chang, Qin-Xiao Hu, Fei-Xiang Lin, De-Zhong Liu, Chu-Cheng Wu, Shi-Xin Du, Xue-Dong Li
Naringin is a major flavonoid found in grapefruit and is an active compound extracted from the Chinese herbal medicine Rhizoma Drynariae. Naringin is a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of naringin involves the Notch signaling pathway. Rat bone marrow stromal cells (BMSCs) were cultured in osteogenic medium containing-naringin, with or without DAPT (an inhibitor of Notch signaling), the effects on ALP activity, calcium deposits, osteogenic genes (ALP, BSP, and cbfa1), adipogenic maker gene PPARγ2 levels, and Notch expression were examined...
2016: Stem Cells International
Li-Na Qiao, Hong-Bo Xu, Kun Shi, Tong-Fu Zhou, Yi-Min Hua, Han-Min Liu
OBJECTIVE: Notch signal is particularly important to vascular remodeling during the process of embryonic development, vessel repair and tumor growth, but there are few studies about pulmonary vascular remodeling in pulmonary hypertension. This study was to explore the effect of inhibiting Notch signal on pulmonary vascular remodeling induced by angiotensin II. METHODS: Vessel strips taken from healthy Wistar rats were cocultured with extrogenous angiotensin II and the potent smooth muscle cell proliferation stimulators for 7 days...
January 2013: Translational pediatrics
Ji Hwan Min, Chul Hee Lee, Yong Woo Ji, Areum Yeo, Hyemi Noh, Insil Song, Eung Kweon Kim, Hyung Keun Lee
PURPOSE: By using hypoxia-inducible factor-1 alpha conditional knockout (HIF-1α CKO) mice and a dry eye (DE) mouse model, we aimed to determine the role played by delta-like ligand 4 (Dll4)/Notch signaling and HIF-1α in the lymphangiogenesis of lacrimal glands (LGs). METHODS: C57BL/6 mice were housed in a controlled-environment chamber for DE induction. During DE induction, the expression level of Dll4/Notch signaling and lymphangiogenesis in LGs was measured by quantitative RT-PCR, immunoblot, and immunofluorescence staining...
2016: PloS One
Jing Zhao, Yuan Liang, Fan Song, Shouzhu Xu, Lun Nian, Xuanxuan Zhou, Siwang Wang
Lysophosphatidylcholine (LPC) induces inflammation in endothelial cells (ECs) but the mechanism is not fully understood. The Notch signaling pathway is involved in chronic EC inflammation, but its functions in LPC-induced endothelial inflammatory damage and 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside's (TSG) protective effect during LPC-induced inflammatory damage in human umbilical vein endothelial cells (HUVECs) is largely unknown. We report that Notch signaling activation contributed to LPC-induced injury in HUVECs, and that TSG protected HUVECs from LPC-induced injury by antagonizing Notch signaling activation by LPC...
January 2016: IUBMB Life
Yuji Tamagawa, Norihisa Ishimura, Goichi Uno, Masahito Aimi, Naoki Oshima, Takafumi Yuki, Shuichi Sato, Shunji Ishihara, Yoshikazu Kinoshita
Crosstalk between the Notch signaling pathway and Caudal-related homeobox 2 (Cdx2) has important roles in the development of Barrett's esophagus (BE). We investigated the expression and function of the Notch signaling ligand Delta-like 1 (Dll1) during the development of BE. We determined the expression levels of Dll1 and intracellular signaling molecules related to Notch signaling ((Notch1, Hairy/enhancer of split 1 (Hes1), and Atonal homolog 1 (ATOH1)) in human esophageal squamous and Barrett's epithelium samples...
March 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
A A Farooqi, M Ismail
Cancer is a multifaceted disease and research over decades has sequentially broadened our understanding of the mechanisms which underlie its development, progression and resistance against wide ranging molecular therapeutics. Data obtained through in-vitro studies and xenografted mice based investigations clearly suggested that inactivation of tumor suppressor genes, overexpression of oncogenes, imbalance of pro- and anti-apoptotic proteins, loss of apoptosis, dysregulation of spatio-temporally controlled intracellular signaling cascades, epithelial to mesenchymal transition, intra-tumor heterogeneity are significantly involved in regulation of different steps of cancer...
2015: Cellular and Molecular Biology
Jie Yin, Hesheng Hu, Xiaolu Li, Mei Xue, Wenjuan Cheng, Ye Wang, Yongli Xuan, Xinran Li, Na Yang, Yugen Shi, Suhua Yan
Inflammation-dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although being a key immune mediator, the role of Notch has yet to be explored. We investigated whether Notch regulates macrophage responses to inflammation and affects cardiac sympathetic reinnervation in rats undergoing MI. MI was induced by coronary artery ligation...
January 1, 2016: American Journal of Physiology. Cell Physiology
Ekaterina Hatch, David Morrow, Weimin Liu, Paul A Cahill, Eileen M Redmond
BACKGROUND: Ethanol (EtOH) inhibits Notch-mediated vascular smooth muscle cell (SMC) proliferation, an event that is key in vessel remodeling and atherogenesis. The object of this study was to determine whether EtOH inhibits Notch signaling in SMC at the level of γ-secretase, a protease that in concert with α-secretase catalyzes the release of the intracellular domain of the Notch receptor necessary for signaling. METHODS: Human coronary artery SMCs (HCASMCs) were treated with a recombinant soluble Notch ligand, Delta-like ligand 4 (DLL4) (2 μg/ml), or transfected with a constitutively active Notch 1 intracellular domain (N1ICD), in the absence or presence of EtOH...
November 2015: Alcoholism, Clinical and Experimental Research
Guangchun Sun, Lily V Mackey, David H Coy, Cui-Yun Yu, Lichun Sun
Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth...
2015: Journal of Cancer
Yonghong Zhang, Xinming Xie, Yanting Zhu, Lu Liu, Wei Feng, Yilin Pan, Cui Zhai, Rui Ke, Shaojun Li, Yang Song, Yuncun Fan, Fenling Fan, Xiaochuang Wang, Fengjuan Li, Manxiang Li
It has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling...
2015: Experimental Lung Research
Baruch Frenkel, Wendy White, Jan Tuckermann
Osteoporosis is among the most devastating side effects of glucocorticoid (GC) therapy for the management of inflammatory and auto-immune diseases. Evidence from both humans and mice indicate deleterious skeletal effects within weeks of pharmacological GC administration, both related and unrelated to a decrease in bone mineral density (BMD). Osteoclast numbers and bone resorption are also rapidly increased, and together with osteoblast inactivation and decreased bone formation, these changes lead the fastest loss in BMD during the initial disease phase...
2015: Advances in Experimental Medicine and Biology
Lichun Sun, Qingqing Qian, Guangchun Sun, L Vienna Mackey, Joseph A Fuselier, David H Coy, Cui-Yun Yu
BACKGROUND: Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization. MATERIALS AND METHODS: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST)...
2016: Journal of Drug Targeting
Alexandre Patenaude, Stefan Woerher, Patricia Umlandt, Fred Wong, Rawa Ibrahim, Alastair Kyle, Sandy Unger, Megan Fuller, Jeremy Parker, Andrew Minchinton, Connie J Eaves, Aly Karsan
Pericytes are perivascular support cells, the origin of which in tumor tissue is not clear. Recently, we identified a Tie1(+) precursor cell that differentiates into vascular smooth muscle, in a Notch-dependent manner. To understand the involvement of Notch in the ontogeny of tumor pericytes we used a novel flow immunophenotyping strategy to define CD146(+)/CD45(-)/CD31(-/lo) pericytes in the tumor stroma. This strategy combined with ex vivo co-culture experiments identified a novel pericyte progenitor cell population defined as Sca1(hi)/CD146(-)/CD45(-)/CD31(-)...
September 2015: Microvascular Research
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