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Haiqin Wu, Lulu Ye, Xiaoxi Lu, Shuang Xie, Qian Yang, Qinghua Yu
SCOPE: The intestinal mucosal barrier, including the mucus layer, protects against invasion of enteropathogens, thereby inhibiting infection. In this study, the protective effect of Lactobacillus on intestinal barrier against Salmonella infection was investigated. The underlying mechanism of its effect, specifically on regulation of goblet cells through Notch pathway, was also elucidated. METHODS AND RESULTS: Here, we explored the protective effect of Lactobacillus on alleviating changes in the intestinal barrier caused by Salmonella infection...
September 10, 2018: Molecular Nutrition & Food Research
E Canalis
Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling...
September 7, 2018: Osteoporosis International
Rasoul Baharlou, Nader Tajik, Mahdi Behdani, Mohammad Ali Shokrgozar, Vajiheh Tavana, Fatemeh Kazemi-Lomedasht, Fatemeh Faraji, Mahdi Habibi-Anbouhi
OBJECTIVES: Angiogenesis targeting is an attractive approach for cancer treatment. Delta-like ligand 4 (DLL4) plays a pivotal role in neovascular development and its inhibitors have recently entered clinical trials for solid tumors. The aim of this study was to evaluate the possibilities of using anti-DLL4 antibody fragment as an angiogenesis maturation inhibitor. MATERIALS AND METHODS: In this study, a DLL4-specific Nanobody, named 3Nb3, was selected and assessed by western blotting and internalization assays...
September 5, 2018: Immunopharmacology and Immunotoxicology
Vedran Radojcic, Katelyn Paz, Jooho Chung, Jing Du, Eric T Perkey, Ryan Flynn, Sanja Ivcevic, Michael Zaiken, Ann Friedman, Minhong Yan, Maria A Pletneva, Stefanie Sarantopoulos, Christian W Siebel, Bruce R Blazar, Ivan Maillard
Chronic GVHD (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics...
September 4, 2018: Blood
Aleksandra Kostina, Hanna Bjork, Elena Ignatieva, Olga Irtyuga, Vladimir Uspensky, Daria Semenova, Shohreh Maleki, Alexey Tomilin, Olga Moiseeva, Anders Franco-Cereceda, Mikhail Gordeev, Giuseppe Faggian, Anna Kostareva, Per Eriksson, Anna Malashicheva
Cellular and molecular mechanisms of thoracic aortic aneurysm are still not clear and therapeutic approaches are mostly absent. The role of endothelial cells in aortic wall integrity is emerging from recent studies. Although Notch pathway ensures endothelial development and integrity, and NOTCH1 mutations have been associated with thoracic aortic aneurysms, the role of this pathway in aneurysm remains elusive. The purpose of the present work was to study functions of Notch genes in endothelial cells of patients with sporadic thoracic aortic aneurysm...
August 25, 2018: Atherosclerosis. Supplements
Sanchita Basu, Iulia Barbur, Alexander Calderon, Suhanti Banerjee, Aaron Proweller
Functional interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) in the arterial wall are necessary for controlling vasoreactivity that underlies vascular resistance and tone. Key signaling pathways converge on the phosphorylation of myosin light chain (P-MLC), the molecular signature of force production in SMCs, through coordinating the relative activities of myosin light chain kinase (MLCK) and myosin phosphatase (MP). Notch signaling in the vessel wall serves critical roles in arterial formation and maturation and has been implicated in arterial vasoregulation...
August 31, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Bin Sun, Changxian Dong, Hongzhao Lei, Yubin Gong, Miaomiao Li, Yuanfang Zhang, Hongyu Zhang, Longlong Sun
Infantile hemangioma (IH) is one of the most common benign vascular tumors of infancy. Propranolol has been recently introduced for the treatment of IH. However, the mechanism of protective effect has not been fully understood. In this study, hemangioma-derived endothelial cells (HemECs) were isolated and treated with propranolol. The cell viability was measured by MTT assay, and the cell cycle arrest was detected using flow cytometry. Cell invasion was determined using transwell assay. The expressions of matrix metalloproteinase (MMP)-2, MMP-9, Delta-like 4 (DLL4), Notch1, Akt, p-Akt, and vascular endothelial growth factor (VEGF) were detected using western blot...
October 1, 2018: Chemico-biological Interactions
Ivan Lobov, Natalia Mikhailova
Background: Retina is the highest oxygen-demanding and vascularized tissue in the body. Retinal development and function require proper vascularization and blood vessel function and integrity. Dll4 is most prominently expressed in the endothelium of angiogenic blood vessels and in quiescent arteries and capillaries in all tissues and organs of the mammalian species, and it is the key regulator of blood vessel sprouting. Results: Dll4 is a transmembrane protein that acts as a ligand for Notch receptors 1 and 4...
2018: Journal of Ophthalmology
Lou Zhong, Siyuan Sun, Sumei Yao, Xiao Han, Mingming Gu, Jiahai Shi
Histone deacetylase 5 (HDAC5), as a member of the class IIa family of HDACs, is frequently dysregulated in human malignancies. However, little is known regarding the specific role of HDAC5 in lung cancer. We aimed to evaluate HDAC5 expression in human lung cancer and to determine the effects of HDAC5 on lung cancer cells. First, the expression levels of both HDAC5 protein and mRNA were evaluated in lung cancer tissues and cell lines by western blot analysis and RT‑qPCR, and the results suggested that HDAC5 was significantly upregulated in human lung cancer tissues and cell lines...
October 2018: Oncology Reports
Zhongwei Liu, Yuan Wang, Haitao Zhu, Chuan Qiu, Gongchang Guan, Junkui Wang, Yan Guo
Vascular smooth muscle cells (VSMCs) contractile- synthetic phenotypic conversion takes responsibility in the atherosclerotic plaque formation by abnormal synthesis, secretion and deposition of extracellular matrix (ECM). Matrine exerts therapeutic effects on both cardiovascular diseases and organ fibrosis. In this study, we investigated matrine's inhibitory effect and mechanisms on AGEs- induced VSMC contractile- synthetic phenotypic conversion. Cultured human coronary smooth muscle cells (HCSMCs) were exposed to AGEs...
September 15, 2018: European Journal of Pharmacology
Yang Liu, Ran He, Yaping Xiao, Hongjin Wang, Yi Chen, Weihai Chen, Xiaoyu Xu
Although the critical role of hypoxia inducible factor-1α (HIF-1α) in cerebral neovascularization after stroke has been well characterized, the details regarding the regulation of endothelial progenitor cell (EPC)-dependent neovascularization by HIF-1α are not completely understood. Using lentiviral shRNA to knockdown HIF-1α, we showed that HIF-1α plays a central role in bone marrow-derived EPC (bmEPC) homing and sprouting in the post-acute stage of ischemic Sprague Dawley (SD) rat brains. First, knockdown of HIF-1α decreased the homing of both endogenous and exogenous bmEPCs to the ischemic brain...
July 27, 2018: Brain Pathology
María J García-León, Patricia Fuentes, José Luis de la Pompa, María L Toribio
T-cell development is a complex dynamic process that relies on ordered stromal signals delivered to thymus-seeding progenitors that migrate throughout different thymus microenvironments (TMEs). Particularly, Notch signaling provided by thymic epithelial cells (TECs) is crucial for T-cell fate specification and generation of mature T cells. Four canonical Notch ligands (Dll1, Dll4, Jag1 and Jag2) are expressed in the thymus, but their spatial distribution in functional TMEs is largely unknown, especially in humans, and their impact on Notch1 activation during T-lymphopoiesis remains undefined...
August 13, 2018: Development
Hung-An Ting, Denise de Almeida Nagata, Andrew J Rasky, Carrie-Anne Malinczak, Ivan P Maillard, Matthew A Schaller, Nicholas W Lukacs
Notch ligand Delta-like ligand 4 (DLL4) has been shown to regulate CD4 T-cell differentiation, including regulatory T cells (Treg ). Epigenetic alterations, which include histone modifications, are critical in cell differentiation decisions. Recent genome-wide studies demonstrated that Treg have increased trimethylation on histone H3 at lysine 4 (H3K4me3) around the Treg master transcription factor, Foxp3 loci. Here we report that DLL4 dynamically increased H3K4 methylation around the Foxp3 locus that was dependent upon upregulated SET and MYDN domain containing protein 3 (SMYD3)...
July 23, 2018: Mucosal Immunology
Penglai Wang, Shaoyue Zhu, Changyong Yuan, Lei Wang, Jianguang Xu, Zongxiang Liu
Effects of shear stress on endotheliaxl differentiation of stem cells from human exfoliated deciduous teeth (SHEDs) were investigated. SHEDs were treated with shear stress, then reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to analyse the mRNA expression of arterial markers and western blot analysis was performed to analyse protein expression of angiogenic markers. Additionally, in vitro matrigel angiogenesis assay was performed to evaluate vascular-like structure formation...
October 2018: International Journal of Molecular Medicine
Marchien G Dallinga, Bahar Yetkin-Arik, Richelle P Kayser, Ilse M C Vogels, Patrycja Nowak-Sliwinska, Arjan W Griffioen, Cornelis J F van Noorden, Ingeborg Klaassen, Reinier O Schlingemann
Tip cells, the leading cells of angiogenic sprouts, were identified in cultures of human umbilical vein endothelial cells (HUVECs) by using CD34 as a marker. Here, we show that tip cells are also present in primary human microvascular endothelial cells (hMVECs), a more relevant endothelial cell type for angiogenesis. By means of flow cytometry, immunocytochemistry, and qPCR, it is shown that endothelial cell cultures contain a dynamic population of CD34+ cells with many hallmarks of tip cells, including filopodia-like extensions, elevated mRNA levels of known tip cell genes, and responsiveness to stimulation with VEGF and inhibition by DLL4...
June 27, 2018: Angiogenesis
Josephina A N Meester, Maja Sukalo, Kim C Schröder, Denny Schanze, Gareth Baynam, Guntram Borck, Nuria C Bramswig, Duygu Duman, Brigitte Gilbert-Dussardier, Muriel Holder-Espinasse, Peter Itin, Diana S Johnson, Shelagh Joss, Hannele Koillinen, Fiona McKenzie, Jenny Morton, Heike Nelle, Willie Reardon, Claudia Roll, Mustafa A Salih, Ravi Savarirayan, Ingrid Scurr, Miranda Splitt, Elizabeth Thompson, Hannah Titheradge, Colm P Travers, Lionel Van Maldergem, Margo Whiteford, Dagmar Wieczorek, Geert Vandeweyer, Richard Trembath, Lut Van Laer, Bart L Loeys, Martin Zenker, Laura Southgate, Wim Wuyts
Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort...
September 2018: Human Mutation
Arnab Chattopadhyay, Xinying Yang, Pallavi Mukherjee, Dawoud Sulaiman, Hannah R Fogelman, Victor Grijalva, Steven Dubinett, Tonya C Wasler, Manash K Paul, Ramin Salehi-Rad, Julia J Mack, M Luisa Iruela-Arispe, Mohamad Navab, Alan M Fogelman, Srinivasa T Reddy
Having demonstrated that apolipoprotein A-I (apoA-I) mimetic peptides ameliorate cancer in mouse models, we sought to determine the mechanism for the anti-tumorigenic function of these peptides. CT-26 cells (colon cancer cells that implant and grow into tumors in the lungs) were injected into wild-type BALB/c mice. The day after injection, mice were either continued on chow or switched to chow containing 0.06% of a concentrate of transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F). After four weeks, the number of lung tumors was significantly lower in Tg6F-fed mice...
June 13, 2018: Scientific Reports
Jaya Mary Thomas, Sumi Surendran, Mathew Abraham, Dhakshmi Sasankan, Sridutt Bhaadri, Arumugam Rajavelu, Chandrasekharan C Kartha
OBJECTIVE: Arteriovenous malformations (AVMs) are characterised by tangles of dysplastic blood vessels which shunt blood from arteries to veins with no intervening capillary bed. It is not known at what stage of development and differentiation, AVM vessels became aberrant. To address this, we have analysed the expression of vascular differentiation, vascular maturation and brain capillary specific genes in AVM nidus. METHODOLOGY: We performed immunohistochemistry and western blot analysis of vascular differentiation (HEY2, DLL4, EFNB2, and COUP-TFII), vascular maturation (ENG and KLF2) and brain capillary specific genes (GGTP and GLUT1) on ten surgically excised human brain AVMs and ten normal human brain tissues...
2018: PloS One
Hai-Yan Song, Ying Wang, Hong Lan, Yu-Xiang Zhang
Pancreatic cancer is the fourth leading cause of cancer-associated mortality in developed countries. Pancreatic ductal adenocarcinoma (PDAC) accounts for ~90% of all pancreatic cancer cases. The Notch signaling pathway serves a crucial role in embryonic development, as well as during the tumorigenesis of different types of cancer. However, Notch signaling serves either oncogenic or tumor suppressor roles depending on the tissue type. There are four Notch receptors (Notch1-4) and five ligands [Jagged1, Jagged2, δ-like ligand protein (DLL)1, DLL3 and DLL4]; therefore, it has been suggested that the different Notch receptors serve distinct roles in the same type of tissue...
July 2018: Experimental and Therapeutic Medicine
Monika A Jarzabek, William R Proctor, Jennifer Vogt, Rupal Desai, Patrick Dicker, Gary Cain, Rajiv Raja, Jens Brodbeck, Dale Stevens, Eric P van der Stok, John W M Martens, Cornelis Verhoef, Priti S Hegde, Annette T Byrne, Jacqueline M Tarrant
Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively...
2018: PloS One
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