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Chantal Dysli, Muriel Dysli, Martin S Zinkernagel, Volker Enzmann
Fluorescence lifetime imaging ophthalmoscopy (FLIO) was used to investigate retinal autofluorescence lifetimes in mouse models of pharmacologically induced retinal degeneration over time. Sodium iodate (NaIO3, 35 mg/kg intravenously) was used to induce retinal pigment epithelium (RPE) degeneration with subsequent loss of photoreceptors (PR) whereas N-methyl-N-nitrosourea (MNU, 45 mg/kg intraperitoneally) was employed for degeneration of the photoreceptor cell layer alone. All mice were measured at day 3, 7, 14, and 28 after the respective injection of NaIO3, MNU or NaCl (control)...
October 21, 2016: Experimental Eye Research
Kenichi Masumura, Naomi Toyoda-Hokaiwado, Akiko Ukai, Yoichi Gondo, Masamitsu Honma, Takehiko Nohmi
Germline mutations are an important component of genetic toxicology; however, mutagenicity tests of germline cells are limited. Recent advances in sequencing technology can be used to detect mutations by direct sequencing of genomic DNA (gDNA). We previously reported induced de novo mutations detected using whole-exome sequencing in the offspring of N-ethyl-N-nitrosourea (ENU)-treated mice in a single-dose experiment (85mg/kg, i.p., weekly on two occasions). In this study, two lower doses (10 and 30mg/kg) were added, and dose-response of inherited germline mutations was analyzed...
November 1, 2016: Mutation Research
Nor Hayati Othman, Sarfraz Ahmed, Siti Amrah Sulaiman
No abstract text is available yet for this article.
February 2016: Pathology
Marian Raschke, Bernd-W Igl, Julia Kenny, Joanne Collins, Stephen D Dertinger, Carson Labash, Javed A Bhalli, Cameron C M Tebbe, Kylie M McNeil, Andreas Sutter
The rodent Pig-a assay is an in vivo method for the detection of gene mutation, where lack of glycosylphosphatidylinositol-anchored proteins on the surface of circulating red blood cells (RBCs) serves as a reporter for Pig-a gene mutation. In the case of rats, the frequency of mutant phenotype RBCs is measured via fluorescent anti-CD59 antibodies and flow cytometry. The Pig-a assay meets the growing expectations for novel approaches in animal experimentation not only focusing on the scientific value of the assay but also on animal welfare aspects (3Rs principles), for example, amenable to integration into pivotal rodent 28-day general toxicology studies...
October 22, 2016: Environmental and Molecular Mutagenesis
Shigeo Ohba, Yuichi Hirose
Glioblastomas are the most aggressive of all gliomas and have the worst prognosis, with 5-year survival rates of less than 10%. Temozolomide (TMZ) is a DNA-methylating agent. Now that TMZ is available, the standard treatment is to resect as much of the tumor as possible without inducing unacceptable neurologic deficits, followed by treatment with radiation and TMZ. TMZ has also been used for maintenance therapy. Recently, bevacizumab, which is a monoclonal antibody to vascular endothelial growth factor, has been used for the initial treatment of glioblastomas and for the treatment of recurrent glioblastomas...
October 14, 2016: Current Medicinal Chemistry
Jeffrey K Wickliffe, Stephen D Dertinger, Dorothea K Torous, Svetlana L Avlasevich, Bridget R Simon-Friedt, Mark J Wilson
Obesity increases the risk of a number of chronic diseases in humans including several cancers. Biological mechanisms responsible for such increased risks are not well understood at present. Increases in systemic inflammation and oxidative stress, endogenous production of mutagenic metabolites, altered signaling in proliferative pathways, and increased sensitivity to exogenous mutagens and carcinogens are some of the potential contributing factors. We hypothesize that obesity creates an endogenously mutagenic environment in addition to increasing the sensitivity to environmental mutagens...
October 14, 2016: Environmental and Molecular Mutagenesis
Kaye Showler, Mayumi Nishimura, Kazuhiro Daino, Tatsuhiko Imaoka, Yukiko Nishimura, Takamitsu Morioka, Benjamin J Blyth, Toshiaki Kokubo, Masaru Takabatake, Maki Fukuda, Hitomi Moriyama, Shizuko Kakinuma, Masahiro Fukushi, Yoshiya Shimada
The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells...
October 13, 2016: Journal of Radiation Research
Ju Yup Lee, Nayoung Kim, Yoon Jeong Choi, Ryoung Hee Nam, Yoon Jin Choi, Seonmin Lee, Daeun Choi, Hye Seung Lee, Jin-Wook Kim, Dong Ho Lee
BACKGROUND: The aim of this study was to investigate the effect of N-methyl-N-nitrosourea (MNU) treatment followed by chronic Helicobacter pylori SS1 and H. felis colonization on the stomachs of C57BL/6 mice. The role of MNU and Helicobacter species in gastric carcinogenesis was also elucidated. METHODS: A total of 69 C57BL/6 mice at 4 weeks of age were divided into 6 groups according to MNU treatment and H. pylori SS1 or H. felis infection. The mice were sacrificed at 21 and 50 weeks...
September 2016: Journal of Cancer Prevention
Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation...
October 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
L C Wu, C Liu, M R Jiang, Y M Jiang, Q H Wang, Z Y Lu, S J Wang, W L Yang, Y X Shao
Development of the eyelid requires coordination of the cellular processes involved in proliferation, cell size alteration, migration, and cell death. C57BL/6J-corneal opacity (B6-Co) mice are mutant mice generated by the administration of N-ethyl-N-nitrosourea (100 mg/kg). They exhibit the eyelids open at birth phenotype, abnormal round cell shape from tightened F-actin bundles in leading edge keratinocytes at E16.5, and gradual corneal opacity with neovessels. The tip of the leading edge in B6-Co mice did not move forward, and demonstrated a sharp peak shape without obvious directionality...
August 26, 2016: Genetics and Molecular Research: GMR
Reeshan Ul Quraish, Norihiro Sudou, Kaori Nomura-Komoike, Fumi Sato, Hiroki Fujieda
PURPOSE: p27(KIP1) (p27), originally identified as a cell cycle inhibitor, is now known to have multifaceted roles beyond cell cycle regulation. p27 is required for the normal histogenesis of the RPE, but the role of p27 in the mature RPE remains elusive. To define the role of p27 in the maintenance and function of the RPE, we investigated the effects of p27 deletion on the responses of the RPE after photoreceptor damage. METHODS: Photoreceptor damage was induced in wild-type (WT) and p27 knockout (KO) mice with N-methyl-N-nitrosourea (MNU) treatment...
2016: Molecular Vision
Asha Rani, Subhadeep Roy, Manjari Singh, Uma Devi, Rajnish K Yadav, Swetlana Gautam, Jitendra K Rawat, Mohd Nazam Ansari, Abdulaziz S Saeedan, Anand Prakash, Gaurav Kaithwas
This study was undertaken to investigate the effect of α-chymotrypsin on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized into four groups (six animals in each). Group I (sham control 0.9 % normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v.); Group III (α-chymotrypsin, 5 mg/kg, p.o.); Group IV (α-chymotrypsin, 10 mg/kg p.o.). Toxicity was induced by single i.v. injection of MNU followed by α-chymotrypsin supplementation therapy for 100 days...
October 2016: Inflammopharmacology
Qi Wang, Kaishi Satomi, Ji Eun Oh, Barbara Hutter, Benedikt Brors, Nicolle Diessl, Hai-Kun Liu, Stephan Wolf, Otmar Wiestler, Paul Kleihues, Bernd Koelsch, Andrea Kindler-Röhrborn, Hiroko Ohgaki
A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T->A mutations in the transmembrane domain of the Neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas remains enigmatic. We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one...
October 2016: American Journal of Pathology
Kuo-Chen Wei, Feng-Wei Lin, Chiung-Yin Huang, Chen-Chi M Ma, Ju-Yu Chen, Li-Ying Feng, Hung-Wei Yang
To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2)...
2016: International Journal of Nanomedicine
Ye Tao, Tao Chen, Zhong-Yu Liu, Li-Qiang Wang, Wei-Wei Xu, Li-Min Qin, Guang-Hua Peng, Huang Yi-Fei
PURPOSE: To quantify the transcorneal electrical stimulation (TES)-induced effects on regional photoreceptors and visual signal pathway of N-methyl-N-nitrosourea (MNU)-treated retinas via topographic measurements. METHODS: N-methyl-N-nitrosourea-administered mice received TES or sham stimulations and were subsequently subjected to electroretinography (ERG), multielectrode array (MEA), and histologic and immunohistochemistry examinations. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were also performed to determine the mRNA levels of Bax, Bcl-2, Calpain-2, Caspase-3, brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF)...
September 1, 2016: Investigative Ophthalmology & Visual Science
William J Valente, Nolan G Ericson, Alexandra S Long, Paul A White, Francesco Marchetti, Jason H Bielas
The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed Muta(TM)Mouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays...
October 14, 2016: Nucleic Acids Research
Robert S McNeill, David M Irvin, C Ryan Miller
This commentary highlights the article by Wang et al that describes a preclinical model for targeting BRAF-mutant gliomas.
October 2016: American Journal of Pathology
Hyung Il Kim, Sun-Sook Paik, Gyu Hyun Kim, Muyan Kim, Soon Ha Kim, In-Beom Kim
NecroX-5 is a derivative of cyclopentylamino carboxymethylthiazolylindole (NecroX), an inhibitor of necrosis/necroptosis. NecroX-5 has been shown to scavenge mitochondrial reactive oxygen and nitrogen species, and thus preventing necrotic cell death against various kinds of oxidative stress in several tissues, including the brain. To examine the effect of NecroX-5 on retinal degeneration (RD), RD was induced in Sprague-Dawley rats by an intraperitoneal injection of N-methyl-N-nitrosourea and in BALB/c mice by blue light-emitting diode exposure...
October 19, 2016: Neuroreport
Ryosuke Fujikane, Kayoko Komori, Mutsuo Sekiguchi, Masumi Hidaka
O(6)-Methylguanine produced in DNA can pair with thymine during DNA replication, thus leading to a G-to-A transition mutation. To prevent such outcomes, cells harboring O(6)-methylguanine-containing mispair undergo apoptosis that requires the function of mismatch repair (MMR) protein complex. To identify the genes involved in the induction of apoptosis, we performed gene-trap mutagenesis and isolated a clone of mouse cells exhibiting an increased resistance to the killing effect of an alkylating agent, N-methyl-N-nitrosourea (MNU)...
2016: Scientific Reports
Paul K Potter, Michael R Bowl, Prashanthini Jeyarajan, Laura Wisby, Andrew Blease, Michelle E Goldsworthy, Michelle M Simon, Simon Greenaway, Vincent Michel, Alun Barnard, Carlos Aguilar, Thomas Agnew, Gareth Banks, Andrew Blake, Lauren Chessum, Joanne Dorning, Sara Falcone, Laurence Goosey, Shelley Harris, Andy Haynes, Ines Heise, Rosie Hillier, Tertius Hough, Angela Hoslin, Marie Hutchison, Ruairidh King, Saumya Kumar, Heena V Lad, Gemma Law, Robert E MacLaren, Susan Morse, Thomas Nicol, Andrew Parker, Karen Pickford, Siddharth Sethi, Becky Starbuck, Femke Stelma, Michael Cheeseman, Sally H Cross, Russell G Foster, Ian J Jackson, Stuart N Peirson, Rajesh V Thakker, Tonia Vincent, Cheryl Scudamore, Sara Wells, Aziz El-Amraoui, Christine Petit, Abraham Acevedo-Arozena, Patrick M Nolan, Roger Cox, Anne-Marie Mallon, Steve D M Brown
Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged...
2016: Nature Communications
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