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Julia J Mack, M Luisa Iruela-Arispe
PURPOSE OF REVIEW: The formation of a hierarchical vascular network is a complex process that requires precise temporal and spatial integration of several signaling pathways. Amongst those, Notch has emerged as a key regulator of multiple steps that expand from endothelial sprouting to arterial specification and remains relevant in the adult. This review aims to summarize major concepts and rising hypotheses on the role of Notch signaling in the endothelium. RECENT FINDINGS: A wealth of new information has helped to clarify how Notch signaling cooperates with other pathways to orchestrate vascular morphogenesis, branching, and function...
March 14, 2018: Current Opinion in Hematology
Jingxiao Wang, Mingjie Dong, Zhong Xu, Xinhua Song, Shanshan Zhang, Yu Qiao, Li Che, John Gordan, Kaiwen Hu, Yan Liu, Diego F Calvisi, Xin Chen
Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes...
March 16, 2018: Oncogene
Jungeun Yu, Stefano Zanotti, Lauren Schilling, Chris Schoenherr, Aris Economides, Archana Sanjay, Ernesto Canalis
Mice harboring Notch2 mutations replicating Hajdu Cheney syndrome (Notch2tm1.1ECan ) have osteopenia and exhibit an increase in splenic marginal zone B cells with a decrease in follicular B cells. Whether the altered B-cell allocation is responsible for the osteopenia of Notch2tm1.1ECan mutants is unknown. To determine the effect of NOTCH2 activation in B cells on splenic B-cell allocation and skeletal phenotype, a conditional by inversion (COIN) Hajdu Cheney syndrome allele of Notch2 (Notch2[ΔPEST]COIN ) was used...
March 12, 2018: American Journal of Pathology
Evan Tan, Harry H Asada, Ruowen Ge
NOTCH signalling is an evolutionarily conserved juxtacrine signalling pathway that is essential in development. Jagged1 (JAG1) and Delta-like ligand 4 (DLL4) are transmembrane NOTCH ligands that regulate angiogenesis by controlling endothelial cell (EC) differentiation, vascular development and maturation. In addition, DLL4 could bypass its canonical cell-cell contact-dependent signalling to influence NOTCH signalling and angiogenesis at a distance when it is packaged into extracellular vesicles (EVs). However, it is not clear whether JAG1 could also be packaged into EVs to influence NOTCH signalling and angiogenesis...
March 14, 2018: Angiogenesis
Justyna Niderla-Bielińska, Krzysztof Bartkowiak, Bogdan Ciszek, Eric Czajkowski, Ewa Jankowska-Steifer, Alicja Krejner, Anna Ratajska
Pentoxifylline (PTX), a non-specific inhibitor of cAMP phosphodiesterases, is commonly used for treatment of peripheral vascular disorders although its direct action on endothelial cells is not well described. The aim of this study was to determine the influence of PTX on tubule formation and mRNA expression for angiogenesis-related proteins in endothelial cell line C166 and mouse proepicardial explants cultured on collagen. C166 cells and explants were stimulated with proangiogenic cocktail containing bFGF/VEGF-A120 /VEGF-A164 and with proangiogenic cocktail enriched with PTX...
March 10, 2018: European Journal of Pharmacology
Markus Wirth, Daniel Jira, Armin Ott, Guido Piontek, Anja Pickhard
The clinical impact of the expression of NOTCH1 signaling components in squamous cell carcinoma of the pharynx and larynx has only been evaluated in subgroups. The aim of this study was therefore to evaluate NOTCH1 expression in head and neck squamous cell cancer (HNSCC) patient tissue and cell lines. We analyzed tissue from 195 HNSCCs and tissue from 30 normal patients for mRNA expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 using quantitative real-time PCR. Association of expression results and clinical orpathological factors was examined with multivariate Cox regression...
March 13, 2018: International Journal of Molecular Sciences
Haitham Mirghani, Ludovic Lacroix, Caroline Rossoni, Roger Sun, Anne Aupérin, Odile Casiraghi, Aude Villepelet, Roger Lacave, Gladwys Faucher, Virginie Marty, Charles Ferté, Jean Charles Soria, Caroline Even
BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) patients are characterised by a better prognosis than their HPV-negative counterparts. However, this significant survival advantage is not homogeneous and among HPV-positive patients those with a smoking history have a significantly increased risk of oncologic failure. The reason why tobacco consumption impacts negatively the prognosis is still elusive. Tobacco might induce additional genetic alterations leading to a more aggressive phenotype...
March 10, 2018: European Journal of Cancer
Jianjie Zheng, Jing Li, Bo Kou, Qiuyue Yi, Tao Shi
The aim of the present study was to determine the cardioprotective mechanisms by which micro (mi)RNA-30e protects the heart from myocardial ischemia/reperfusion injury (MI/R) and to explore the signaling pathways that may confer protection for the heart and be potential therapeutic targets. It was demonstrated that miRNA‑30e expression was decreased in patients with MI/R. In H9C2 cells, silencing (si)miRNA‑30e significantly inhibited cellular apoptosis, the expression of apoptosis regulator BAX (Bax) and caspase‑3 activity...
March 7, 2018: International Journal of Molecular Medicine
Di Zhao, Na-Sui Wang, Fu Chen, Zheng-Bing Li, Xi-Tao Li, Xu-Xin Zhu
BACKGROUND: miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated. METHODS: In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured...
March 12, 2018: Experimental and Clinical Endocrinology & Diabetes
Xiao-Xiao Ma, Jin Liu, Chun-Man Wang, Jiang-Ping Zhou, Zhen-Zhou He, Han Lin
AIMS: This study was to determine whether curcumin had any effect on the proliferation of neural stem cell (NSC), analyze the expression of glucocorticoid receptor (GR), signal transducer and activator of transcription 3 (STAT3), and Notch1 at transcription and protein level, and discuss the related mechanisms. METHODS AND RESULTS: NSCs were harvested from E15 SD rat brain and cultured. All experiments were performed at the second passage. Cell cytotoxicity, cell viability, and proliferation assays were used to figure out the optimal concentration of curcumin, which can be used for the protein and mRNA studies...
March 12, 2018: CNS Neuroscience & Therapeutics
Chien-Heng Shen, Shui-Yi Tung, Min-Jen Tseng, Yu-Wei Leu
Notch signaling is a candidate pathway that transmits environmental information into the cell and interferes with the epigenome of gastric cancer. This study aimed to explore if the Notch pathway was abnormally regulated during gastric tumorigenesis. To achieve the goal, Delta-like ligands (DLL1) gene expression, Notch upstream signal, promoter methylation and its correlation with DLL1 expression were examined by methylation-specific PCR and real time (RT)-PCR in cultured gastric cancer cell lines or gastric cancer patient samples...
March 12, 2018: Chinese Journal of Physiology
Ralitza Staneva, Jorge Barbazan, Anthony Simon, Danijela Matic Vignjevic, Denis Krndija
Cell migration is a process that ensures correct cell localization and function in development and homeostasis. In disease such as cancer, cells acquire an upregulated migratory capacity that leads to their dissemination throughout the body. Live imaging of cell migration allows for better understanding of cell behaviors in development, adult tissue homeostasis and disease. We have optimized live imaging procedures to track cell migration in adult murine tissue explants derived from: (1) healthy gut; (2) primary intestinal carcinoma; and (3) the liver, a common metastatic site...
2018: Methods in Molecular Biology
Lei Ma, Haibo Xue, Ruiqun Qi, Yanqin Wang, Libing Yuan
BACKGROUND: Th17 cells and its effective cytokine IL-17A play an important role in the pathogenesis of abnormal immune responses in psoriasis. Notch1 signaling has been implicated in Th17 cell differentiation and function. In this study, our aim was to evaluate the possible inhibitory effect of Notch1 signaling inhibitor, γ-secretase inhibitor DAPT, on psoriatic Th17 cell differentiation and function in a mouse model of psoriasis-like skin inflammation. METHODS: Mouse psoriasis-like skin inflammation model was established by topical 5% imiquimod (IMQ) application, and experimental mice were divided into control group, IMQ-treated group and IM + DAPT-treated group...
March 10, 2018: Journal of Translational Medicine
José E Velázquez Vega, Daniel J Brat
Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH-mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations...
March 8, 2018: Advances in Anatomic Pathology
Santiago Nahuel Villegas, Rita Gombos, Lucia García-López, Irene Gutiérrez-Pérez, Jesús García-Castillo, Diana Marcela Vallejo, Vanina Gabriela Da Ros, Esther Ballesta-Illán, József Mihály, Maria Dominguez
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis...
March 6, 2018: Cell Reports
Si Xiong, Ronghua Wang, Qian Chen, Jing Luo, Jinlin Wang, Zhenxiong Zhao, Yawen Li, Yun Wang, Xiju Wang, Bin Cheng
In this study, we investigated the role of cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC) progression. We showed that CAFs secrete high levels of IL-6, which promoted stem cell-like properties in HCC cells by activating Notch signaling through STAT3 Tyr705 phosphorylation. These effects were abolished by Notch1 shRNA knockdown in HCC cells or treatment with an IL-6 neutralizing antibody or the p-STAT3 (Tyr705) inhibitor cryptotanshinone. Xenografted liver tumors were larger in nude mice injected with HCC cells and CAFs than in those receiving HCC cells alone...
2018: American Journal of Cancer Research
Lichun Sun, Quanyong He, Cheguo Tsai, Jun Lei, Jing Chen, Lily Vienna Makcey, David H Coy
Small cell lung cancer (SCLC) is a malignant human cancer and patients have very limited benefit from traditional anticancer treatments, with a poor five-year survival rate being 10% less. In present study, we observed that Notch signalling activation induced SCLC cell growth suppression via overexpressing Notch active fragments (ICN1, ICN2, ICN3 and ICN4), implying its tumor suppressive role. The histone deacetylase (HDAC) inhibitors also displayed their suppressive effects. Valproic acid (VPA) as a HDAC inhibitor was found to suppress SCLC cell growth and cell cycle arrest at phase G1, and observed to decrease HDAC4 and increase acetylation of histone H4 (AcH4) while activating Notch signalling with an increase of Notch1, Notch target gene HES1 and p21...
2018: American Journal of Translational Research
Stefano Baldoni, Beatrice Del Papa, Erica Dorillo, Patrizia Aureli, Filomena De Falco, Chiara Rompietti, Daniele Sorcini, Emanuela Varasano, Debora Cecchini, Tiziana Zei, Ambra Di Tommaso, Emanuela Rosati, Gabriela Alexe, Giovanni Roti, Kimberly Stegmaier, Mauro Di Ianni, Franca Falzetti, Paolo Sportoletti
Dysregulated NOTCH1 signaling, either by gene mutations or microenvironment interactions, has been increasingly linked to chronic lymphocytic leukemia (CLL). Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression-based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of NOTCH1 mutation and other prognostic markers...
March 6, 2018: International Journal of Cancer. Journal International du Cancer
Yulong Cai, Xiaotong Tang, Xi Chen, Xin Li, Ying Wang, Xiaohang Bao, Lian Wang, Dayu Sun, Jinghui Zhao, Yan Xing, Margaret Warner, Haiwei Xu, Jan-Åke Gustafsson, Xiaotang Fan
The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Deyin Xing, Gang Zheng, John Kenneth Schoolmeester, Zaibo Li, Aparna Pallavajjala, Lisa Haley, Michael G Conner, Russell Vang, Chien-Fu Hung, Tzyy-Choou Wu, Brigitte M Ronnett
Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel...
March 2, 2018: American Journal of Surgical Pathology
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