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EphA4

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https://www.readbyqxmd.com/read/28196613/potent-and-selective-epha4-agonists-for-the-treatment-of-als
#1
Bainan Wu, Surya K De, Anna Kulinich, Ahmed F Salem, Jordan Koeppen, Rengang Wang, Elisa Barile, Si Wang, Dongxiang Zhang, Iryna Ethell, Maurizio Pellecchia
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is critical for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The molecules exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the molecules appear to act as agonists for the receptor in certain surrogate cellular assays...
February 8, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28153688/the-identification-of-a-novel-isoform-of-epha4-and-its-expression-in-sod1-g93a-mice
#2
Jing Zhao, Andrew W Boyd, Perry F Bartlett
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons, leading to progressive muscle atrophy and fatal paralysis. Mutations in more than 20 genes, including full-length EphA4 (EphA4-FL), have been implicated in this pathogenesis. The present study aimed to identify novel isoforms of EphA4-FL and to investigate the expression of EphA4-FL and its isoforms in the superoxide dismutase 1 (SOD1) mutant mouse model of ALS. Two novel transcripts were verified in mouse and humans...
January 30, 2017: Neuroscience
https://www.readbyqxmd.com/read/28130310/reestablishment-of-glucose-inhibition-of-glucagon-secretion-in-small-pseudo-islets
#3
Christopher A Reissaus, David W Piston
Misregulated hormone secretion from the islet of Langerhans is central to the pathophysiology of diabetes. While insulin plays a key role in glucose regulation, the importance of glucagon is increasingly acknowledged. However, the mechanisms that regulate glucagon secretion from α-cells are still unclear. We utilized pseudo-islets reconstituted from dispersed islet cells to study α-cells with and without various indirect effects from other islet cells. Dispersed islet cells secrete aberrant levels of glucagon and insulin at basal and elevated glucose levels...
January 27, 2017: Diabetes
https://www.readbyqxmd.com/read/27994470/identification-of-feature-genes-for-smoking-related-lung-adenocarcinoma-based-on-gene-expression-profile-data
#4
Ying Liu, Ran Ni, Hui Zhang, Lijun Miao, Jing Wang, Wenqing Jia, Yuanyuan Wang
This study aimed to identify the genes and pathways associated with smoking-related lung adenocarcinoma. Three lung adenocarcinoma associated datasets (GSE43458, GSE10072, and GSE50081), the subjects of which included smokers and nonsmokers, were downloaded to screen the differentially expressed feature genes between smokers and nonsmokers. Based on the identified feature genes, we constructed the protein-protein interaction (PPI) network and optimized feature genes using closeness centrality (CC) algorithm...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27993984/an-epha4-sipa1l3-wnt-pathway-regulates-eye-development-and-lens-maturation
#5
Melanie Rothe, Noreen Kanwal, Petra Dietmann, Franziska A Seigfried, Annemarie Hempel, Desiree Schütz, Dominik Reim, Rebecca Engels, Alexander Linnemann, Michael J Schmeisser, Juergen Bockmann, Michael Kühl, Tobias M Boeckers, Susanne J Kühl
The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification...
January 15, 2017: Development
https://www.readbyqxmd.com/read/27993871/flt3-internal-tandem-duplication-mutation-cmpl-and-cd34-expressions-predict-low-survival-in-acute-myeloid-leukemia-patients
#6
Eman K Ebrahim, Magda M Assem, Ahmed I Amin, Mahmoud M Kamel, Yomna M El Meligui, Ayman M Metwally
OBJECTIVES: To detect FMS-like tyrosine kinase-3 internal tandem duplicate (FLT3 ITD) mutation, Myeloproliferative leukemia virus oncogene (cMPL) and Ephrin A 4 receptor (EphA4) expressions in Acute myeloid leukemia (AML) and their correlation to patient's clinicopathological characteristics and survival. METHODS: RNA was extracted from blood samples of 58 AML patients (39 adults and 19 children) and 20 age and sex matched controls. FLT3 ITD mutation, cMPL and EphA4 expression was studied using RT-PCR and correlated to the clinical and survival data of the patients...
December 2016: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/27959424/epha4-may-contribute-to-microvessel-remodeling-in-the-hippocampal-ca1-and-ca3-areas-in-a-mouse-model-of-temporal-lobe-epilepsy
#7
Li Feng, Yi Shu, Qian Wu, Tiantian Liu, Hongyu Long, Huan Yang, Yi Li, Bo Xiao
Unclustered and pre-clustered ephrin-A5-Fc have identical anti-epileptic effects in the dentate gyrus of hippocampus in a mouse model of temporal lobe epilepsy (TLE), and act through alleviating ephrin receptor A4 (EphA4)‑mediated neurogenesis and angiogenesis. However, the effects of ephrin‑A5‑Fcs on EphA4 and angiogenesis in Cornu Ammonis (CA)1 and CA3 areas remain unclear. In the present study, male C57BL/6 mice underwent pilocarpine‑induced TLE. The expression of EphA4 and ephrin‑A5 proteins was analyzed by immunohistochemistry, and the mean density and diameter of platelet endothelial cell adhesion molecule‑1‑labeled microvessels in CA1 and CA3 were calculated in the absence or presence of two types of ephrin‑A5‑Fc intrahippocampal infusion...
January 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27935866/hic1-hypermethylated-in-cancer-1-sumoylation-is-dispensable-for-dna-repair-but-is-essential-for-the-apoptotic-dna-damage-response-ddr-to-irreparable-dna-double-strand-breaks-dsbs
#8
Sonia Paget, Marion Dubuissez, Vanessa Dehennaut, Joe Nassour, Brennan T Harmon, Nathalie Spruyt, Ingrid Loison, Corinne Abbadie, Brian R Rood, Dominique Leprince
The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/27847705/a-model-of-glial-scarring-analogous-to-the-environment-of-a-traumatically-injured-spinal-cord-using-kainate
#9
Jong Yoon Yoo, Chang Ho Hwang, Hea Nam Hong
OBJECTIVE: To develop an in vitro model analogous to the environment of traumatic spinal cord injury (SCI), the authors evaluated change of astrogliosis following treatments with kainate and/or scratch, and degree of neurite outgrowth after treatment with a kainate inhibitor. METHODS: Astrocytes were obtained from the rat spinal cord. Then, 99% of the cells were confirmed to be GFAP-positive astrocytes. For chemical injury, the cells were treated with kainate at different concentrations (10, 50 or 100 µM)...
October 2016: Annals of Rehabilitation Medicine
https://www.readbyqxmd.com/read/27826286/transcriptomic-biomarkers-for-tuberculosis-evaluation-of-dock9-epha4-and-npc2-mrna-expression-in-peripheral-blood
#10
Leonardo S de Araujo, Lea A I Vaas, Marcelo Ribeiro-Alves, Robert Geffers, Fernanda C Q Mello, Alexandre S de Almeida, Adriana da S R Moreira, Afrânio L Kritski, José R Lapa E Silva, Milton O Moraes, Frank Pessler, Maria H F Saad
Lately, much effort has been made to find mRNA biomarkers for tuberculosis (TB) disease/infection with microarray-based approaches. In a pilot investigation, through RNA sequencing technology, we observed a prominent modulation of DOCK9, EPHA4, and NPC2 mRNA abundance in the blood of TB patients. To corroborate these findings, independent validations were performed in cohorts from different areas. Gene expression levels in blood were evaluated by quantitative real-time PCR (Brazil, n = 129) or reanalysis of public microarray data (UK: n = 96; South Africa: n = 51; Germany: n = 26; and UK/France: n = 63)...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27804940/-estimation-of-the-diagnostic-potential-of-apod-ptov1-and-epha4-for-prostatic-neoplasms
#11
D O Allina, Yu Yu Andreeva, L E Zavalishina, L V Moskvina, G A Frank
: Prostate cancer is one of the most frequently detected malignancies in men. The gold standard for its diagnosis is morphological examination; at the same time the differential diagnosis of adenocarcinoma, high-grade prostatic intraepithelial neoplasia (HGPIN), and benign conditions that are able to mimic the malignancies is tremendously difficult in a number of cases, this being so, the hyperdiagnosis rate of HGPIN requiring mandatory repeat biopsy is as high as 24%. The currently available differential diagnostic panel of antibodies is imperfect, which necessitates a search for novel markers...
2016: Arkhiv Patologii
https://www.readbyqxmd.com/read/27673329/motor-experience-reprograms-development-of-a-genetically-altered-bilateral-corticospinal-motor-circuit
#12
Najet Serradj, John H Martin
Evidence suggests that motor experience plays a role in shaping development of the corticospinal system and voluntary motor control, which is a key motor function of the system. Here we used a mouse model with conditional forebrain deletion of the gene for EphA4 (Emx1-Cre:EphA4tm2Kldr), which regulates development of the laterality of corticospinal tract (CST). We combined study of Emx1-Cre:EphA4tm2Kldr with unilateral forelimb constraint during development to expand our understanding of experience-dependent CST development from both basic and translational perspectives...
2016: PloS One
https://www.readbyqxmd.com/read/27660688/modifications-of-a-nanomolar-cyclic-peptide-antagonist-for-the-epha4-receptor-to-achieve-high-plasma-stability
#13
Erika J Olson, Bernhard C Lechtenberg, Chunxia Zhao, Elena Rubio de la Torre, Ilaria Lamberto, Stefan J Riedl, Philip E Dawson, Elena B Pasquale
EphA4 is a receptor tyrosine kinase with a critical role in repulsive axon guidance and synaptic function. However, aberrant EphA4 activity can inhibit neural repair after injury and exacerbate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's. We previously identified the cyclic peptide APY-d2 (APYCVYRβASWSC-nh2, containing a disulfide bond) as a potent and selective EphA4 antagonist. However, APY-d2 lacks sufficient plasma stability to be useful for EphA4 inhibition in vivo through peripheral administration...
September 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27632701/the-role-of-epha4-signaling-in-radiation-induced-emt-like-phenotype-in-colorectal-cancer-cells
#14
Priscila Guimarães de Marcondes, José Andrés Morgado-Díaz
Radiotherapy is widely used for advanced rectal tumors. However, refractory metastasis has become the major cause of therapy failure in rectal cancer patients. Understanding the molecular mechanism that controls the aggressive cellular response to this treatment is essential for developing new therapeutic applications and improving radiotherapy response in colorectal cancer patients. Using the progeny of cells that were submitted to irradiation, we have demonstrated that the PI3K/AKT, Wnt/β-catenin signaling pathways as well as ERK1/2 downstream of EPHA4 receptor activation, play an important role in the regulation of events related with the EMT development, which may be associated with the therapeutic failure in rectal cancer after radiotherapy...
September 15, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27584932/rare-genetic-variation-in-unc13a-may-modify-survival-in-amyotrophic-lateral-sclerosis
#15
Benjamin Gaastra, Aleksey Shatunov, Sara Pulit, Ashley R Jones, William Sproviero, Alexandra Gillett, Zhongbo Chen, Janine Kirby, Isabella Fogh, John F Powell, P Nigel Leigh, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, Leonard H van den Berg, Jan H Veldink, Cathryn M Lewis, Ammar Al-Chalabi
Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0...
October 2016: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/27553673/immunohistochemistry-of-aberrant-neuronal-development-induced-by-6-propyl-2-thiouracil-in-rats
#16
Ayako Shiraki, Takeshi Tanaka, Yousuke Watanabe, Fumiyo Saito, Yumi Akahori, Nobuya Imatanaka, Toshinori Yoshida, Makoto Shibutani
6-Propyl-2-thiouracil (PTU)-induced hypothyroidism disrupts neuronal/glial development. This study sought to identify the sensitive immunohistochemical parameters of developmental neurotoxicity (DNT) following PTU-exposure, as well as their responses in a 28-day toxicity study in adults. In the developmental exposure study, pregnant rats were treated with 0, 1, 3, and 10ppm PTU in drinking water from gestational day 6 to postnatal day (PND) 21 and pups were examined on PNDs 21 and 77. In the adult-stage exposure study, 5-week-old male rats were treated with 0, 0...
November 2, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27533087/ephrin-b3-interacts-with-multiple-epha-receptors-and-drives-migration-and-invasion-in-non-small-cell-lung-cancer
#17
Ghazal Efazat, Metka Novak, Vitaliy O Kaminskyy, Luigi De Petris, Lena Kanter, Therese Juntti, Per Bergman, Boris Zhivotovsky, Rolf Lewensohn, Petra Hååg, Kristina Viktorsson
Ephrin receptors (Ephs) are reported to control metastatic signaling of non-small cell lung cancer (NSCLC) and other tumors. Here we show for the first time that blocking expression of the Eph ligand Ephrin B3 inhibits NSCLC cell migration and invasion. We demonstrate that Ephrin B3 directly binds the EphAs EphA2, EphA3, EphA4, and EphA5. EphA2 Ser897 was previously shown to drive migration propensity of tumor cells and our study reveals that EphA2 stays phosphorylated on Ser897 in the Ephrin B3/EphA2 complex in NSCLC cells of different histology...
September 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27518800/regional-regulation-of-purkinje-cell-dendritic-spines-by-integrins-and-eph-ephrins
#18
Tristan G Heintz, Richard Eva, James W Fawcett
Climbing fibres and parallel fibres compete for dendritic space on Purkinje cells in the cerebellum. Normally, climbing fibres populate the proximal dendrites, where they suppress the multiple small spines typical of parallel fibres, leading to their replacement by the few large spines that contact climbing fibres. Previous work has shown that ephrins acting via EphA4 are a signal for this change in spine type and density. We have used an in vitro culture model in which to investigate the ephrin effect on Purkinje cell dendritic spines and the role of integrins in these changes...
2016: PloS One
https://www.readbyqxmd.com/read/27487126/lncrna-rsu1p2-contributes-to-tumorigenesis-by-acting-as-a-cerna-against-let-7a-in-cervical-cancer-cells
#19
Qian Liu, Xu Gao, Shengshun Que, Xi Yang, Hongxia Fan, Min Liu, Xin Li, Hua Tang
Long non-coding RNAs (lncRNAs) can regulate gene expression at different levels and are widely participate in various physiological and pathological processes. Emerging evidences suggests that a number of differentially expressed lncRNAs are involved in tumorigenesis. However, the function and expression regulation of a vast majority of these unique RNAs is little known. Here, we found that the lncRNA Ras suppressor protein 1 pseudogene 2 (RSU1P2) is upregulateded in cervical cancer tissues and has a tumour-promoting role...
July 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27478038/lower-and-reduced-expression-of-epha4-is-associated-with-advanced-tnm-stage-lymph-node-metastasis-and-poor-survival-in-breast-carcinoma
#20
Yuejun Sun, Jianzhong Qian, Min Lu, Hongming Xu
The expression of EphA4 has been well documented in the development of nerve and in certain types of human cancer. Few studies of EphA4, however, have focused on breast carcinoma. In this study, a set of breast carcinomas was subjected to immunohistochemical staining. In normal luminal cells, EphA4 was weakly detected in 11 (14.3 %), moderately detected in 15 (19.5 %) and highly detected in 51 out of 77 (66.2 %) samples, while in breast carcinoma cells, EphA4 was weakly detected in 42 (54.5 %), moderately detected in 19 (24...
September 2016: Pathology International
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