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Eugene Jennifer Jin, Ferdi Ridvan Kiral, Mehmet Neset Ozel, Lara Sophie Burchardt, Marc Osterland, Daniel Epstein, Heike Wolfenberg, Steffen Prohaska, Peter Robin Hiesinger
Neurons are highly polarized cells that require continuous turnover of membrane proteins at axon terminals to develop, function, and survive. Yet, it is still unclear whether membrane protein degradation requires transport back to the cell body or whether degradation also occurs locally at the axon terminal, where live observation of sorting and degradation has remained a challenge. Here, we report direct observation of two cargo-specific membrane protein degradation mechanisms at axon terminals based on a live-imaging approach in intact Drosophila brains...
March 3, 2018: Current Biology: CB
Priscilla Coutinho Romualdo, Marília P Lucisano, Francisco Wanderley G Paula-Silva, Graziela B Leoni, Manoel D Sousa-Neto, Raquel Assed B Silva, Lea Assed B Silva, Paulo Nelson-Filho
INTRODUCTION: The aim of this study was to evaluate the gene expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and cathepsin K in apical periodontitis (AP) and the volume of lesions in ovariectomized and sham-operated rats. METHODS: Twenty 12-week-old female Wistar rats were subjected to ovariectomy (OVX) or sham surgery. After 9 weeks, access cavities were prepared in the maxillary and mandibular first molars, pulp tissue was removed, and canals were exposed to the oral environment during 21 days for the induction of AP...
March 14, 2018: Journal of Endodontics
Palani Dinesh, MahaboobKhan Rasool
The current study investigated the therapeutic effect of berberine (BBR), an alkaloid derivative against IL-21/IL-21R mediated phosphotidyl inositol 3 kinase/protein kinase B (PI3K/Akt) signaling in adjuvant induced arthritic fibroblast-like synoviocytes (AA-FLS) isolated from rats and IL-21 mediated osteoclastogenesis in bone-marrow derived monocytes (BMMs). BBR (15-45 µM) treatment attenuated the gene and protein levels of IL-21R complex. BBR suppressed the levels of IL-21 (20 ng/ml) mediated production of inflammatory cytokines such as: tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and interleukin 23 (IL-23) in AA-FLS cells...
March 14, 2018: Cytokine
Daniel M P Ardisson-Araújo, Ana Maria Rodrigues da Silva, Fernando L Melo, Ethiane Rozo Dos Santos, Daniel R Sosa-Gómez, Bergmann M Ribeiro
In this report, we described the genome of a novel baculovirus isolated from the monocot insect pest Mocis latipes , the striped grass looper. The genome has 134,272 bp in length with a G + C content of 38.3%. Based on the concatenated sequence of the 38 baculovirus core genes, we found that the virus is a betabaculovirus closely related to the noctuid-infecting betabaculoviruses including Pseudaletia unipuncta granulovirus (PsunGV), Trichoplusia ni granulovirus (TnGV), Helicoverpa armigera granulovirus (HearGV), and Xestia c-nigrum granulovirus (XecnGV)...
March 16, 2018: Viruses
Da-Zhi Guo, Lin Xiao, Yi-Jun Liu, Chen Shen, Hui-Fang Lou, Yan Lv, Shu-Yi Pan
This study aimed to investigate the role of cathepsin D (CathD) in central nervous system (CNS) myelination and its possible mechanism. By using CathD knockout mice in conjunction with immunohistochemistry, immunocytochemistry and western blot assays, the myelination of the CNS and the development of oligodendrocyte lineage cells in vivo and in vitro were observed. Endocytosis assays, real-time-lapse experiments and total internal reflection fluorescence microscopy were used to demonstrate the location and movement of proteolipid protein in oligodendrocyte lineage cells...
March 16, 2018: Experimental & Molecular Medicine
Naira F Z Schneider, Claudia Cerella, Jin-Young Lee, Aloran Mazumder, Kyung Rok Kim, Annelise de Carvalho, Jennifer Munkert, Rodrigo M Pádua, Wolfgang Kreis, Kyu-Won Kim, Christo Christov, Mario Dicato, Hyun-Jung Kim, Byung Woo Han, Fernão C Braga, Cláudia M O Simões, Marc Diederich
Cardiac glycosides (CGs) are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV) out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+ /K+ -ATPase α subunit, assessed by computational docking...
2018: Frontiers in Pharmacology
Zonggong Song, Yongming Huang, Chao Liu, Ming Lu, Zhituo Li, Bei Sun, Weihui Zhang, Dongbo Xue
This study was performed to screen miRNAs and mRNAs that are differentially expressed during trypsinogen activation in acute pancreatitis and to verify their role in the process of trypsinogen activation. The function enrichment analysis showed that the functions of miR-352 and its regulatory targets lysosome-associated membrane protein 2 (LAMP2) and cathepsin L1 (CTSL1) were lysosome related. The results of the verification experiment showed that in the TLC-S-treated AR42J (pancreatic cell line) cells, miR-352 expression increased, expression levels of LAMP2 and CTSL1 were significantly reduced, trypsinogen activation was increased, and the autophagy pathway was blocked...
February 16, 2018: Oncotarget
Álvaro de Mingo Pulido, Estefanía de Gregorio, Shilpi Chandra, Anna Colell, Albert Morales, Mitchell Kronenberg, Montserrat Marí
Natural killer T (NKT) cells exhibit a specific tissue distribution, displaying the liver the highest NKT/conventional T cell ratio. Upon antigen stimulation, NKT cells secrete Th1 cytokines, including interferon γ (IFNγ), and Th2 cytokines, including IL-4 that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver. Cysteine cathepsins control hepatic inflammation by regulating κB-dependent gene expression. However, the contribution of cysteine cathepsins other than Cathepsin S to NKT cell activation has remained largely unexplored...
2018: Frontiers in Immunology
Heather Flanagan-Steet, Courtney Christian, Po-Nien Lu, Megan Aarnio-Peterson, Laura Sanman, Stephanie Archer-Hartmann, Parastoo Azadi, Matthew Bogyo, Richard A Steet
Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ß signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S)...
March 13, 2018: Cell Reports
Seung Un Seo, Seon Min Woo, Kyoung-Jin Min, Taeg Kyu Kwon
Inhibition of cathespsin S not only inhibits invasion and angiogenesis, but also induces apoptosis and autophagy in cancer cells. In present study, we revealed that pharmacological inhibitor [Z-FL-COCHO (ZFL)] of cathepsin S up-regulates pro-apoptotic protein Bim expression at the posttranslational levels. These effects were not associated with MAPKs and AMPK signal pathways. Interestingly, pretreatment with the chemical chaperones (TUDCA and PBA) and knockdown of protein phosphatase 2A (PP2A) markedly inhibited ZFL-induced Bim upregulation...
March 10, 2018: Biochemical and Biophysical Research Communications
Youngil Kwon, Hyunjung Ko, Soojung Kim, Miri Kim
BACKGROUND/AIM: Continuous research efforts have been focusing on promoting healing of delayed replantation of avulsed teeth. The aim of this in vivo study was to assess the effect of cathepsin K inhibitor surface treatment on delayed tooth replantation.Materials and Methods Thirty-four premolar roots of four beagle dogs were extracted and conventional root canal treatment was performed. The canals were filled with gutta-percha and cement. All extracted teeth were air-dried for 1 h. Teeth were divided into two groups according to the root surface treatment prior to replantation: control (n = 13) and cathepsin K inhibitor (n = 21)...
March 13, 2018: Dental Traumatology: Official Publication of International Association for Dental Traumatology
Cher-Pheng Ooi, Terry K Smith, Eva Gluenz, Nadina Vasileva Wand, Sue Vaughan, Gloria Rudenko
The predominant secretory cargo of bloodstream form Trypanosoma brucei is Variant Surface Glycoprotein (VSG), comprising ~10% total protein and forming a dense protective layer. Blocking VSG translation using Morpholino oligonucleotides triggered a precise pre-cytokinesis arrest. We investigated the effect of blocking VSG synthesis on the secretory pathway. The number of Golgi decreased, particularly in post-mitotic cells, from 3.5 ± 0.6 to 2.0 ± 0.04 per cell. Similarly, the number of ER exit sites (ERES) in post-mitotic cells dropped from (3...
March 13, 2018: Traffic
Antonello Storniolo, Vincenzo Alfano, Sabino Carbotta, Elisabetta Ferretti, Livia Di Renzo
Sensors of endoplasmic reticulum (ER) stress function in a co-ordinated manner. In the present study we investigated the relationship between IRE1α and PERK pathways and survival of ER stressed U937 cells and BC3 cells. To this end, we investigated the effects of a subcytotoxic concentration of Tunicamycin in IRE1α-proficient and in IRE1α-deficient cells, by pharmacological inhibition with 4μ8 C or down-regulation by specific siRNA. We show that either type of IRE1α deficiency affects eIF2α expression and causes cell death increase...
December 2018: Cell Death Discovery
Sabine Buhner, Hannes Hahne, Kerstin Hartwig, Qin Li, Sheila Vignali, Daniela Ostertag, Chen Meng, Gabriele Hörmannsperger, Breg Braak, Christian Pehl, Thomas Frieling, Giovanni Barbara, Roberto De Giorgio, Ihsan Ekin Demir, Güralp Onur Ceyhan, Florian Zeller, Guy Boeckxstaens, Dirk Haller, Bernhard Kuster, Michael Schemann
BACKGROUND & AIMS: The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC). METHOD: Effects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques...
2018: PloS One
Purushottam R Lomate, Bryony C Bonning
Management of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), an invasive, agricultural pest in the United States, has presented significant challenges. This polyphagous insect uses both extra-oral and gut-based digestion thwarting protein- or nucleotide-based control strategies. The objective of this study was to biochemically characterize the digestive enzymes (proteases and nucleases) from the saliva, salivary gland and the gut of H. halys. Enzyme profiles for the two tissues and saliva radically differ: The pH optimum for proteases in the gut was six, with cysteine proteases predominant...
March 12, 2018: Archives of Insect Biochemistry and Physiology
Erik Lindström, Biljana Rizoska, Karin Tunblad, Charlotte Edenius, Alison M Bendele, Don Maul, Michael Larson, Neha Shah, Valerie Yoder Otto, Chris Jerome, Urszula Grabowska
BACKGROUND: MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). METHODS: Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks...
March 9, 2018: Journal of Translational Medicine
Johann Schottler, Niklas Randoll, Ralph Lucius, Amke Caliebe, Johann Roider, Alexa Klettner
Anti-Vascular Endothelial Growth Factor (VEGF) therapy is given repeatedly for an extended period of time to patients when treated for age-related macular degeneration. While short-term effects of anti-VEGF agents on retinal pigment epithelial (RPE) cells have been investigated, the effects of long-term and repeated treatment on these cells are scarce. In this study, we have investigated the effects of anti-VEGF treatment after long-term, repeated treatment on cell aging and morphology. The experiments were conducted in primary porcine RPE cells passage one and two...
March 6, 2018: Experimental Eye Research
Sander Bekeschus, Jan-Wilm Lackmann, Denis Gümbel, Matthias Napp, Anke Schmidt, Kristian Wende
Non-healing wounds continue to be a clinical challenge for patients and medical staff. These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is therefore important to decipher molecular signatures that reflect the macroscopic process of wound healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy after surgical trauma to generate wound-derived protein profiles via global mass spectrometry. We confidently identified 311 proteins in exudates...
March 7, 2018: International Journal of Molecular Sciences
Awen Menou, JanWillem Duitman, Bruno Crestani
Idiopathic Pulmonary Fibrosis (IPF) is a devastating chronic, progressive and irreversible disease that remains refractory to current therapies. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the development of pulmonary fibrosis since decades. Coagulation signalling deregulation, which influences several key inflammatory and fibro-proliferative responses, is also essential in IPF pathogenesis, and a growing body of evidence indicates that Protease-Activated Receptors (PARs) inhibition in IPF may be promising for future evaluation...
March 5, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Mithun Ghosh, In Sook Kim, Young Min Lee, Seong Min Hong, Taek Hwan Lee, Ji Hong Lim, Trishna Debnath, Beong Ou Lim
This study aimed to determine the anti-osteoclastogenic effects of extracts from Aronia melanocarpa 'Viking' (AM) and identify the underlying mechanisms in vitro. Reactive oxygen species (ROS) are signal mediators in osteoclast differentiation. AM extracts inhibited ROS production in RAW 264.7 cells in a dose-dependent manner and exhibited strong radical scavenging activity. The extracts also attenuated the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. To attain molecular insights, the effect of the extracts on the signaling pathways induced by receptor activator of nuclear factor kappa B ligand (RANKL) were also investigated...
March 8, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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