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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
Li Zhang, Zhihong Yang, Jocelyn Trottier, Olivier Barbier, Li Wang
: Bile acids (BAs) play critical physiological functions in cholesterol homeostasis and deregulation of BA metabolism causes cholestatic liver injury. Maternally expressed gene 3 (MEG3) was recently shown as a potential tumor suppressor, however its basic hepatic function remains elusive. Using RNA pull-down with biotin-labeled sense or anti-sense MEG3RNA followed by mass spectrometry, we identified RNA binding protein polypyrimidine tract-binding protein 1 (PTBP1) as a MEG3 interaction protein and validated their interaction by RNA immunoprecipitation (RIP)...
October 22, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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
Yafen Zhu, Shengguo Wang, Hu Long, Jingyi Zhu, Fan Jian, Niansong Ye, Wenli Lai
Recent research has demonstrated that static magnetic fields (SMF) can generate an analgesic effect in different conditions. The present study explored effects of SMF on pain levels and expressions of P2X3 receptors in trigeminal ganglion (TG) in mice after experimental tooth movement (tooth movement induced by springs between teeth). Experiments were performed in male mice (body mass: 25-30 g) and divided into SMF + force group, force group, and no force group. Exposure time was over 22 h per day. Mouse Grimace Scale was used for evaluating orofacial pain levels during experimental tooth movement at 4 h and 1, 3, 7, and 14 days...
October 21, 2016: Bioelectromagnetics
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
Mathias Kranz, Bernhard Sattler, Solveig Tiepolt, Stephan Wilke, Winnie Deuther-Conrad, Cornelius K Donat, Steffen Fischer, Marianne Patt, Andreas Schildan, Jörg Patt, René Smits, Alexander Hoepping, Jörg Steinbach, Osama Sabri, Peter Brust
BACKGROUND: Both enantiomers of [(18)F]flubatine are new radioligands for neuroimaging of α4β2 nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[(18)F]flubatine compared to (-)-[(18)F]flubatine was its higher binding affinity suggesting that (+)-[(18)F]flubatine might be able to detect also slight reductions of α4β2 nAChRs and could be more sensitive than (-)-[(18)F]flubatine in early stages of Alzheimer's disease...
December 2016: EJNMMI Physics
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
Carolina Anazco, Alberto J Lopez-Jimenez, Mohamed Rafi, Lorenzo Vega-Montoto, Ming-Zhi Zhang, Billy G Hudson, Roberto M Vanacore
The 7S dodecamer is recognized as an important structural crosslinking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent crosslinking, the molecular mechanism by which such crosslinks are formed has not been revealed. Here we aimed to identify the enzyme(s) that crosslinks the 7S dodecamer and characterize its expression in the kidney glomerulus...
October 21, 2016: Journal of Biological Chemistry
Alexis V Mickelson, Sampath K Gollapudi, Murali Chandra
The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation, A28V, in cardiac troponin T (TnT). The A28V mutation is located within the N-terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how α- and β-myosin heavy chain (MHC) isoforms differently alter the effect of the N-terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by α- and β-MHC isoforms...
October 21, 2016: American Journal of Physiology. Heart and Circulatory Physiology
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
Xuemei Lin, Gang Wei, Zhijun Huang, Zhongsen Qu, Xinfeng Huang, Hua Xu, Jianjun Liu, Zhixiong Zhuang, Xifei Yang
Mitochondrial dysfunction is involved in neurotoxicity caused by exposure of various chemicals such as copper. However, the effects of long-term low-dose copper exposure on mitochondrial proteome remain unclear. In this study, we found the treatment of copper (0.13ppm copper sulfate in drinking water) for 12 months caused abnormal expression of a total of 13 mitochondrial proteins (7 up-regulated and 6 down-regulated) as revealed by two-dimensional electrophoresis coupled with mass spectrometry in mouse cortex...
October 18, 2016: Toxicology Letters
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
Luisa Iacovelli, Luisa Di Menna, Daniel Peterlik, Christina Stangl, Rosamaria Orlando, Gemma Molinaro, Antonio De Blasi, Valeria Bruno, Giuseppe Battaglia, Peter J Flor, Nicole Uschold-Schmidt, Ferdinando Nicoletti
We studied the interaction between mGlu7 and α1-adrenergic receptors in heterologous expression systems, brain slices, and living animals. L-2-Amino-4-phosphonobutanoate (L-AP4), and l-serine-O-phosphate (L-SOP), which activate group III mGlu receptors, restrained the stimulation of polyphosphoinositide (PI) hydrolysis induced by the α1-adrenergic receptor agonist, phenylephrine, in HEK 293 cells co-expressing α1-adrenergic and mGlu7 receptors. The inibitory action of L-AP4 was abrogated by (i) the mGlu7 receptor antagonist, XAP044; (ii) the C-terminal portion of type-2 G protein coupled receptor kinase; and (iii) the MAP kinase inhibitors, UO126 and PD98059...
October 18, 2016: Neuropharmacology
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
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