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Agnieszka Fiszer, Marianna E Ellison-Klimontowicz, Wlodzimierz J Krzyzosiak
Polyglutamine (polyQ) diseases comprise a group of nine genetic disorders that are caused by the expansion of the CAG triplet repeat, which encodes glutamine, in unrelated single genes. Various oligonucleotide (ON)-based therapeutic approaches have been considered for polyQ diseases. The very attractive CAG repeat-targeting strategy offers selective silencing of the mutant allele by directly targeting the mutation site. CAG repeat-targeting miRNA-like siRNAs have been shown to specifically inhibit the mutant gene expression, and their characteristic feature is the formation of mismatches in their interactions with the target site...
October 21, 2016: Acta Biochimica Polonica
Gordon X Wang, Stephen J Smith, Philippe Mourrain
The distribution of proteins within sub-synaptic compartments is an essential aspect of their neurological function. Current methodology such as electron microscopy (EM) and super-resolution imaging techniques can provide precise localization of proteins, but are often limited to a small number of one-time observations with narrow spatial and molecular coverage. The diversity of synaptic proteins and synapse types demands synapse analysis on a scale that is prohibitive with current methods. Here, we demonstrate SubSynMAP, a fast, multiplexed sub-synaptic protein analysis method using wide-field data from deconvolution array tomography (ATD)...
October 22, 2016: ELife
Muhammad Imran Rahim, Andreas Weizbauer, Florian Evertz, Andrea Hoffmann, Manfred Rohde, Birgit Glasmacher, Henning Windhagen, Gerhard Gross, Jan-Marten Seitz, Peter P Mueller
Magnesium alloys are presently under investigation as promising biodegradable implant materials with osteoconductive properties. To study the molecular mechanisms involved, the potential contribution of soluble magnesium corrosion products to the stimulation of osteoblastic cell differentiation was examined. However, no evidence for the stimulation of osteoblast differentiation could be obtained when cultured mesenchymal precursor cells were differentiated in the presence of metallic magnesium or in cell culture medium containing elevated magnesium ion levels...
October 22, 2016: Journal of Biomedical Materials Research. Part A
Jeannine Coburn, Jamie Harris, Alexander D Zakharov, Jennifer Poirier, Naohiko Ikegaki, Andre Kajdacsy-Balla, Monika Pilichowska, Alexander V Lyubimov, Hiroyuki Shimada, David L Kaplan, Bill Chiu
Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multi-cycle chemotherapies, resulting in short- and long-term toxicities. Here we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin, or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment...
October 22, 2016: International Journal of Cancer. Journal International du Cancer
Silvania da Silva Teixeira, Carly Filgueira, Douglas H Sieglaff, Cindy Benod, Rosa Villagomez, Laurie J Minze, Aijun Zhang, Paul Webb, Maria Tereza Nunes
AIM: Thyroid hormones regulate metabolic response. While triiodothyronine (T3) is usually considered to be the active form of thyroid hormone, one form of diiodothyronine (3,5-T2) exerts T3-like effects on energy consumption and lipid metabolism. 3,5-T2 also improves glucose tolerance in rats and 3,5-T2 levels correlate with fasting glucose in humans. Presently, however, little is known about mechanisms of 3,5-T2 effects on glucose metabolism. Here, we set out to compare effects of T3, 3,5-T2 and another form of T2 (3,3-T2) in a mouse model of diet induced obesity and determined effects of T3 and 3,5-T2 on markers of classical insulin sensitization to understand how diiodothyronines influence blood glucose...
October 22, 2016: Acta Physiologica
Xuehua Piao, Soh Yamazaki, Sachiko Komazawa-Sakon, Sanae Miyake, Osamu Nakabayashi, Takeyuki Kurosawa, Tetsuo Mikami, Minoru Tanaka, Nico Van Rooijen, Masaki Ohmuraya, Akira Oikawa, Yuko Kojima, Soichiro Kakuta, Yasuo Uchiyama, Masato Tanaka, Hiroyasu Nakano
: Tissue-resident macrophages and bone marrow (BM)-derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte-specific Cflar-deficient (Cflar(Hep-low) ) mice. Cellular FLICE-inhibitory protein (cFLIP) expression was downregulated in Cflar-deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor-induced apoptosis...
October 22, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Cho-Ming Chao, Faady Yahya, Alena Moiseenko, Caterina Tiozzo, Amit Shrestha, Negah Ahmadvand, Elie El Agha, Jennifer Quantius, Salma Dilai, Vahid Kheirollahi, Matthew Jones, Jochen Wilhem, Gianni Carraro, Harald Ehrhardt, Klaus-Peter Zimmer, Guillermo Barreto, Katrin Ahlbrecht, Rory E Morty, Susanne Herold, Rosanna G Abellar, Werner Seeger, Ralph Schermuly, Jin-San Zhang, Parviz Minoo, Saverio Bellusci
Inflammation-induced FGF10 protein deficiency is associated with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants characterized by arrested alveolar development. So far, experimental evidence for a direct role of FGF10 in lung disease is lacking. Using the hyperoxia-induced neonatal lung injury as a mouse model of BPD, the impact of Fgf10 deficiency in Fgf10(+/-) versus Fgf10(+/+) pups was investigated. In normoxia, no lethality of Fgf10(+/+) or Fgf10(+/-) pups was observed...
October 22, 2016: Journal of Pathology
Michael L Schulte, Matthew R Hight, Gregory D Ayers, Qi Liu, Yu Shyr, M Kay Washington, H Charles Manning
PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF (V600E) , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting...
October 21, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Shu-Yu Wu, Ping Zou, Alexandra W Fuller, Sanjay Mishra, Zhen Wang, Kevin L Schey, Hassane S Mchaourab
The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. While thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-crystallin mutants in the zebrafish lens, and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins...
October 21, 2016: Journal of Biological Chemistry
Jinke Xu, Mifong Tam, Sepideh Samadei, Sophie Lerouge, Jake Barralet, Mary M Stevenson, Marta Cerruti
Mucoadhesive drug delivery systems stick to mucosal tissues and prolong the local retention time of drugs. Since the colon is covered by a mucosal layer, mucoadhesive rectal formulations may improve treatment of such diseases as hypertension or colon cancer. Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation of the colonic mucosa. It is commonly treated with sulfasalazine (SSZ), which is metabolized by the intestinal flora into the therapeutic 5-aminosalicylic acid (5-ASA) and a toxic by-product sulfapyridine (SP)...
October 18, 2016: Acta Biomaterialia
Yoon Young Choi, Suji Kim, Jung-Hwa Han, Dae-Hwan Nam, Kwon Moo Park, Seong Yong Kim, Chang-Hoon Woo
Epidemiological studies suggested that diabetic patients are susceptible to develop cardiovascular complications along with having endothelial dysfunction. It has been suggested that methylglyoxal (MGO), a glycolytic metabolite, has more detrimental effects on endothelial dysfunction rather than glucose itself. Here, we investigated the molecular mechanism by which MGO induces endothelial dysfunction via the regulation of ER stress. Biochemical data showed that 4-PBA significantly inhibited MGO-induced protein cleavages of PARP-1 and caspase-3...
October 18, 2016: Biochemical and Biophysical Research Communications
Jing Xue, Qinglan Zhao, Vishal Sharma, Linh P Nguyen, Yvonne N Lee, Kim L Pham, Mouad Edderkaoui, Stephen J Pandol, Walter Park, Aida Habtezion
BACKGROUND & AIMS: Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP. METHODS: We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4+ T cells; levels of interleukin-22 (IL22) were measured by ELISA and smoking histories were collected...
October 18, 2016: Gastroenterology
Franziska Richter, Julia Gerstenberger, Anne Bauer, Chun-Chi Liang, Angelika Richter
Hereditary generalized dystonia is often caused by a GAG deletion in TOR1A (DYT1) that encodes for the protein torsinA. Although mutation carriers show alterations in neuronal connectivity and sensorimotor deficits, only 30% develop dystonia. Uncovering the factors triggering the dystonic symptoms and underlying pathophysiology would greatly benefit the development of more effective therapies. In DYT1 knock-in (KI) mice, the expression of torsinA mutant alters the connectivity of neurons and the function of striatal cholinergic interneurons...
October 18, 2016: Behavioural Brain Research
Yeohong Yoon, Jee Woong Lim, Jiyoung Kim, Younggi Kim, Keun Ho Chun
The aim of our study was to develop ursolic acid (UA) prodrugs in order to overcome UA's weakness, which has an extremely low bioavailability. UA-medoxomil (NX-201), one of our UA prodrugs, showed an improved bioavailability about 200times better than UA in rodent model. According to in vivo test performed with PANC-1 xenograft SCID mouse model, tumor growth rate decreased dose-dependently and 100mg/kg dose of NX-201 had an anticancer effect comparable to gemcitabine. Most of all the combination of NX-201 (50mg/kg, po, daily) and gemcitabine (40mg/kg, iv, 2timesperweek) even reduced tumor size after three weeks...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Juliet Richetto, Renaud Massart, Ulrike Weber-Stadlbauer, Moshe Szyf, Marco A Riva, Urs Meyer
BACKGROUND: Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution. METHODS: Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation...
August 12, 2016: Biological Psychiatry
Srikanth Appikonda, Kaushik N Thakkar, Michelle Craig Barton
Tripartite Motif-containing protein 24 (TRIM24) functions as an E3 ligase targeting p53 for ubiquitination, a histone 'reader' that interacts with a specific signature of histone post-translational modifications and a co-regulator of nuclear receptor-regulated transcription. Although mouse models of Trim24 depletion suggest that TRIM24 may be a liver-specific tumor suppressor, several studies show that human TRIM24 is an oncogene when aberrantly over expressed. This review focuses on the mechanisms of TRIM24 functions in oncogenesis and metabolic reprogramming, which underlie recent interest in therapeutic targeting of aberrant TRIM24 in human cancers...
March 2016: Drug Discovery Today. Technologies
Zhangguo Chen, Katherine Gowan, Sonia M Leach, Sawanee S Viboolsittiseri, Ameet K Mishra, Tanya Kadoishi, Katrina Diener, Bifeng Gao, Kenneth Jones, Jing H Wang
BACKGROUND: Whole genome next generation sequencing (NGS) is increasingly employed to detect genomic rearrangements in cancer genomes, especially in lymphoid malignancies. We recently established a unique mouse model by specifically deleting a key non-homologous end-joining DNA repair gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in germinal center B cells. This mouse model spontaneously develops mature B cell lymphomas (termed G1XP lymphomas). RESULTS: Here, we attempt to employ whole genome NGS to identify novel structural rearrangements, in particular inter-chromosomal translocations (CTXs), in these G1XP lymphomas...
October 21, 2016: BMC Genomics
Elena S Don, Alexandra G Emelyanova, Natalia N Yakovleva, Nataliia V Petrova, Marina V Nikiforova, Evgeniy A Gorbunov, Sergey A Tarasov, Sergey G Morozov, Oleg I Epstein
The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose-dependent manner (at doses of 0...
October 21, 2016: Journal of Medical Virology
Xiaodan Yu, Hiroko Kawakami, Naoyuki Tahara, Merissa Olmer, Shinichi Hayashi, Ryutaro Akiyama, Anindya Bagchi, Martin Lotz, Yasuhiko Kawakami
Increasing evidence supports the idea that bone morphogenetic proteins (BMPs) regulate cartilage maintenance in the adult skeleton. The aim of this study is to obtain insight into the regulation of BMP activities in the adult skeletal system. We analyzed expression of Noggin and Gremlin1, BMP antagonists that are known to regulate embryonic skeletal development, in the adult skeletal system by Noggin-LacZ and Gremlin1-LacZ knockin reporter mouse lines. Both reporters are expressed in the adult skeleton in a largely overlapping manner with some distinct patterns...
October 21, 2016: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Kathrin Fielitz, Kristina Althoff, Katleen De Preter, Julie Nonnekens, Jasmin Ohli, Sandra Elges, Wolfgang Hartmann, Günter Klöppel, Thomas Knösel, Marc Schulte, Ludger Klein-Hitpass, Daniela Beisser, Henning Reis, Annette Eyking, Elke Cario, Johannes H Schulte, Alexander Schramm, Ulrich Schüller
Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland...
October 19, 2016: Oncotarget
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