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Soraya Sajadimajd, Razieh Yazdanparast
Trastuzumab (Herceptin) monoclonal antibody directed against HER2 receptor has been administered as a treatment for metastatic HER2 positive breast cancer. The problematic issue in treatment of HER2 positive breast cancer cells is commonly the induction of resistance to trastuzumab which might be due to modulation of some vital signaling elements such as Notch1 and Pin1. In this study, we were aimed to investigate whether the cross talk between pin1 and Notch1 has a role in this event. Our results indicated that the expression level of Pin1 in resistant SKBR3 cells increased by about twofold relative to sensitive SKBR3 cells...
October 21, 2016: Apoptosis: An International Journal on Programmed Cell Death
Shasha Li, Hao Hu, Zhiheng He, Deguang Liang, Rui Sun, Ke Lan
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic pathogen that displays latent and lytic life cycles. In KS lesions, infiltrated immune cells, secreted viral and/or cellular cytokines, and hypoxia orchestrate a chronic pro-lytic microenvironment that can promote KSHV reactivation. However, only a small subset of viruses spontaneously undergoes lytic replication in this pro-lytic microenvironment while the majority remains in latency. Here, we show that the expression of the Notch ligand JAG1 is induced by KSHV-encoded replication and transcription activator (RTA) during reactivation...
October 2016: PLoS Pathogens
Liming Yu, Chongxi Fan, Zhi Li, Jian Zhang, Xiaodong Xue, Yinli Xu, Guolong Zhao, Yang Yang, Huishan Wang
Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague-Dawley rats were subjected to MI/R surgery and high glucose (HG, 500 g/L) infusion (4 ml/kg/h) to induce temporary hyperglycemia...
October 18, 2016: Journal of Pineal Research
Yu-Hui Yan, Shao-Heng Li, Zhong Gao, Sa-Feng Zou, Hong-Yan Li, Zhen-Yu Tao, Jie Song, Jing-Xian Yang
AIMS: Recently, the potential for neural stem cells (NSCs) to be used in the treatment of Alzheimer's disease (AD) has been reported; however, the therapeutic effects are modest by virtue of the low neural differentiation rate. In our study, we transfected bone marrow-derived NSCs (BM-NSCs) with Neurotrophin-3 (NT-3), a superactive neurotrophic factor that promotes neuronal survival, differentiation, and migration of neuronal cells, to investigate the effects of NT-3 gene overexpression on the proliferation and differentiation into cholinergic neuron of BM-NSCs in vitro and its possible molecular mechanism...
October 6, 2016: Life Sciences
Dahai Liu, Qiang Zhang, Hong Zhang, Ling Tang, Wei Li, Dongming Zhang, Guoying Wu, Shoudong Ye, Qian Ban, Kan He
The mutation of somitogenesis protein Mesogenin 1 (Msgn1) has been widely used to study the direct link between somitogenesis and the development of an embryo. Several studies have used gene expression profiling of somitogenesis to identify the key genes in the process, but few have focused on the pathways involved and the coexpression patterns of associated pathways. Here we employed time-course microarray datasets of differentiating embryonic stem cells by overexpressing the transcription factor Msgn1 from the public database library of Gene Expression Omnibus (GEO)...
October 6, 2016: Aging
Francisca F Vasconcelos, Alessandro Sessa, Cátia Laranjeira, Alexandre A S F Raposo, Vera Teixeira, Daniel W Hagey, Diogo M Tomaz, Jonas Muhr, Vania Broccoli, Diogo S Castro
The generation of neurons from neural stem cells requires large-scale changes in gene expression that are controlled to a large extent by proneural transcription factors, such as Ascl1. While recent studies have characterized the differentiation genes activated by proneural factors, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 while promoting neuronal differentiation. We combined functional studies of MyT1 during neurogenesis with the characterization of its transcriptional program...
October 4, 2016: Cell Reports
Nick E Phillips, Cerys S Manning, Tom Pettini, Veronica Biga, Elli Marinopoulou, Peter Stanley, James Boyd, James Bagnall, Pawel Paszek, David G Spiller, Michael Rh White, Marc Goodfellow, Tobias Galla, Magnus Rattray, Nancy Papalopulu
Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally...
October 4, 2016: ELife
Bo Huang, Ryan Butler, Yifei Miao, Yubing Dai, Wanfu Wu, Wen Su, Yoshiaki Fujii-Kuriyama, Margaret Warner, Jan-Åke Gustafsson
The aryl hydrocarbon receptor (AhR) is now recognized as an important physiological regulator in the immune and reproductive systems, and in the development of the liver and vascular system. AhR regulates cell cycle, cell proliferation, and differentiation through interacting with other signaling pathways, like estrogen receptor α (ERα), androgen receptor (AR), and Notch signaling. In the present study, we investigated Notch and estrogen signaling in AhR(-/-) mice. We found low fertility with degenerative changes in the testes, germ cell apoptosis, and a reduced number of early spermatids...
September 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yi-Liang Bi, Min Min, Wei Shen, Yan Liu
The present study aims to evaluate whether repression of the Numb/Notch signaling pathway affects the radiosensitivity of human pancreatic cancer cell lines. Different doses of X-rays (0, 2, 3, 4, and 5 Gy) were applied to the PANC-1, SW1990, and MIA PaCa-2 human pancreatic cancer cell lines, and the Numb/Notch pathway inhibitor DAPT was added at different doses (0, 1, 3, and 5 μmol/l). MTT assay, colony formation assay, flow cytometry, scratch assay, and Transwell experiments were performed, and qRT-PCR and Western blot were conducted for the detection of Numb expression...
September 27, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Laura Asnaghi, Arushi Tripathy, Qian Yang, Harpreet Kaur, Allison Hanaford, Wayne Yu, Charles G Eberhart
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3...
September 20, 2016: Oncotarget
Yiwei Wang, Dan Huang, Kai-Yuan Chen, Min Cui, Weihuan Wang, Xiaoran Huang, Amad Awadellah, Qing Li, Ann Friedman, William W Xin, Luca Di Martino, Fabio Cominelli, Alex Miron, Ricky Chan, James Fox, Yan Xu, Xiling Shen, Mathew F Kalady, Sanford Markowitz, Ivan Maillard, John B Lowe, Wei Xin, Lan Zhou
BACKGROUND & AIMS: De novo synthesis of GDP-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or TSTA3). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect ascending and transverse colon. We investigated whether lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. METHODS: FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency...
September 14, 2016: Gastroenterology
Ana Hidalgo-Sastre, Roxanne L Brodylo, Clara Lubeseder-Martellato, Bence Sipos, Katja Steiger, Marcel Lee, Guido von Figura, Barbara Grünwald, Suyang Zhong, Marija Trajkovic-Arsic, Florian Neff, Roland M Schmid, Jens T Siveke
Perturbation of the pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), which is a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a(+/Cre); Hes1(fl/fl))...
September 14, 2016: American Journal of Pathology
Shuman Zhang, Pan Wang, Lili Ren, Chunli Hu, Jing Bi
BACKGROUND: Amyloid-beta (Aβ) plays a key role in Alzheimer's disease (AD) pathogenesis, and soluble Aβ oligomers are more cytotoxic than Aβ fibrils. Recent evidence suggests that Notch signaling is affected by AD and other brain diseases. Melatonin exerts beneficial effects on many aspects of AD and may protect against myocardial ischemia via Notch1 signaling regulation. Therefore, we hypothesized that the Notch1 signaling pathway is involved in the neuroprotective role of melatonin against soluble Aβ1-42...
2016: Alzheimer's Research & Therapy
Hyeok Gu Kang, Da-Hyun Kim, Seok-Jun Kim, Yunhee Cho, Junghyun Jung, Wonhee Jang, Kyung-Hee Chun
Ovarian cancer is the most lethal gynecologic disease because usually, it is lately sensed, easily acquires chemoresistance, and has a high recurrence rate. Recent studies suggest that ovarian cancer stem cells (CSCs) are involved in these malignancies. Here, we demonstrated that galectin-3 maintains ovarian CSCs by activating the Notch1 intracellular domain (NICD1). The number and size of ovarian CSCs decreased in the absence of galectin-3, and overexpression of galectin-3 increased them. Overexpression of galectin-3 increased the resistance for cisplatin and paclitaxel-induced cell death...
September 9, 2016: Oncotarget
Chang Liu, Karina Rodriguez, Humphrey H-C Yao
Testis morphogenesis is a highly orchestrated process involving lineage determination of male germ cells and somatic cell types including supporting (Sertoli cells) and interstitial cells (Leydig cells and others). While the origin and differentiation of germ cells are known, the developmental course specific for each somatic cell lineage has not been clearly defined. Here we construct a comprehensive map of somatic cell lineage progression in the mouse testis. Both supporting and interstitial cell lineages arise from WT1(+) somatic progenitor pool in the gonadal primordium...
September 12, 2016: Development
Zheng Liu, Qiang Fu, Hangcheng Fu, Zewei Wang, Le Xu, Huimin An, Yanfeng Li, Jiejie Xu
We constructed a three-molecule score based on the expression of Notch pathway molecules: Jagged1, intracellular Notch1 (ICN1) and Hes1 (JIH score). To assess prognostic value of the JIH score in non-metastasis clear cell renal cell carcinoma (ccRCC), we identified 467 patients who underwent nephrectomy during 2008-2009 as our study population. Immunohistochemistry was used to evaluate the expression of these three molecules. Cox regression models were applied to construct the JIH score, while Kaplan-Meier methods, multivariate analyses and nomogram were used to explore prognostic value of the JIH score...
September 6, 2016: Oncotarget
L G Kondratyeva, A A Sveshnikova, E V Grankina, I P Chernov, M R Kopantseva, E P Kopantzev, E D Sverdlov
We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFβ1...
July 2016: Doklady. Biochemistry and Biophysics
Pengpeng Bi, Feng Yue, Anju Karki, Beatriz Castro, Sara E Wirbisky, Chao Wang, Abigail Durkes, Bennett D Elzey, Ourania M Andrisani, Christopher A Bidwell, Jennifer L Freeman, Stephen F Konieczny, Shihuan Kuang
Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction...
September 19, 2016: Journal of Experimental Medicine
Zhiyun Yang, Li Wang, Xianbo Wang
Matrine is a Chinese medicine, which is widely utilized for the attenuation of liver injuries and promotion of liver regeneration. It was previously observed that the in vivo administration of matrine promoted oval cell‑mediated liver regeneration in a rat model, suggesting that this compound may affect the differentiation of hepatic progenitor cells. The present study aimed to determine the mechanisms underlying this observation and to investigate the effect of matrine on the differentiation of the WB‑F344 rat hepatic progenitor cell line...
October 2016: Molecular Medicine Reports
Jiunn-Ren Wu, Jwu-Lai Yeh, Shu-Fen Liou, Zen-Kong Dai, Bin-Nan Wu, Jong-Hau Hsu
Patent ductus arteriosus (PDA) can cause morbidity and mortality in neonates. Vascular remodeling, characterized by proliferation and migration of smooth muscle cells (SMCs), is an essential process for postnatal DA closure. Notch signaling is an important mediator of vascular remodelling but its role in DA is unkonwn. We investigated the effects and underlying mechanisms of γ-secretase inhibitor DAPT, a Notch signaling inhibitor on angiotensin II (Ang II)-induced proliferation and migration of DASMCs. Proliferation and migration of DASMCs cultured from neonatal Wistar rats were induced by Ang II, with or without DAPT pre-treatment...
2016: International Journal of Biological Sciences
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