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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/28408402/poly-gp-in-cerebrospinal-fluid-links-c9orf72-associated-dipeptide-repeat-expression-to-the-asymptomatic-phase-of-als-ftd
#1
Carina Lehmer, Patrick Oeckl, Jochen H Weishaupt, Alexander E Volk, Janine Diehl-Schmid, Matthias L Schroeter, Martin Lauer, Johannes Kornhuber, Johannes Levin, Klaus Fassbender, Bernhard Landwehrmeyer, Martin H Schludi, Thomas Arzberger, Elisabeth Kremmer, Andrew Flatley, Regina Feederle, Petra Steinacker, Patrick Weydt, Albert C Ludolph, Dieter Edbauer, Markus Otto
The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non-conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain-of-function mechanism. Here, we established a poly-GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly-GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases...
April 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28396567/inhibition-of-pikfyve-prevents-myocardial-apoptosis-and-hypertrophy-through-activation-of-sirt3-in-obese-mice
#2
Helene Tronchere, Mathieu Cinato, Andrei Timotin, Laurie Guitou, Camille Villedieu, Helene Thibault, Delphine Baetz, Bernard Payrastre, Philippe Valet, Angelo Parini, Oksana Kunduzova, Frederic Boal
PIKfyve is an evolutionarily conserved lipid kinase that regulates pleiotropic cellular functions. Here, we identify PIKfyve as a key regulator of cardiometabolic status and mitochondrial integrity in chronic diet-induced obesity. In vitro, we show that PIKfyve is critical for the control of mitochondrial fragmentation and hypertrophic and apoptotic responses to stress. We also provide evidence that inactivation of PIKfyve by the selective inhibitor STA suppresses excessive mitochondrial ROS production and apoptosis through a SIRT3-dependent pathway in cardiomyoblasts...
April 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28396566/gene-therapy-for-ada-scid-the-first-marketing-approval-of-an-ex%C3%A2-vivo-gene-therapy-in-europe-paving-the-road-for-the-next-generation-of-advanced-therapy-medicinal-products
#3
Alessandro Aiuti, Maria Grazia Roncarolo, Luigi Naldini
No abstract text is available yet for this article.
April 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28396565/a-clinical-and-mechanistic-study-of-topical-borneol-induced-analgesia
#4
Shu Wang, Dan Zhang, Jinsheng Hu, Qi Jia, Wei Xu, Deyuan Su, Hualing Song, Zhichun Xu, Jianmin Cui, Ming Zhou, Jian Yang, Jianru Xiao
Bingpian is a time-honored herb in traditional Chinese medicine (TCM). It is an almost pure chemical with a chemical composition of (+)-borneol and has been historically used as a topical analgesic for millennia. However, the clinical efficacy of topical borneol lacks stringent evidence-based clinical studies and verifiable scientific mechanism. We examined the analgesic efficacy of topical borneol in a randomized, double-blind, placebo-controlled clinical study involving 122 patients with postoperative pain...
April 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28377496/ferrochelatase-is-a-therapeutic-target-for-ocular-neovascularization
#5
Halesha D Basavarajappa, Rania S Sulaiman, Xiaoping Qi, Trupti Shetty, Sardar Sheik Pran Babu, Kamakshi L Sishtla, Bit Lee, Judith Quigley, Sameerah Alkhairy, Christian M Briggs, Kamna Gupta, Buyun Tang, Mehdi Shadmand, Maria B Grant, Michael E Boulton, Seung-Yong Seo, Timothy W Corson
Ocular neovascularization underlies major blinding eye diseases such as "wet" age-related macular degeneration (AMD). Despite the successes of treatments targeting the vascular endothelial growth factor (VEGF) pathway, resistant and refractory patient populations necessitate discovery of new therapeutic targets. Using a forward chemical genetic approach, we identified the heme synthesis enzyme ferrochelatase (FECH) as necessary for angiogenesis in vitro and in vivo FECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown of Fech or partial loss of enzymatic function in the Fech(m1Pas) mouse model reduces choroidal neovascularization...
April 4, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28377495/rig-i-antiviral-signaling-drives-interleukin-23-production-and-psoriasis-like-skin-disease
#6
Huiyuan Zhu, Fangzhou Lou, Qianqian Yin, Yuanyuan Gao, Yang Sun, Jing Bai, Zhenyao Xu, Zhaoyuan Liu, Wei Cai, Fang Ke, Lingyun Zhang, Hong Zhou, Hong Wang, Gang Wang, Xiang Chen, Hongxin Zhang, Zhugang Wang, Florent Ginhoux, Chuanjian Lu, Bing Su, Honglin Wang
Retinoic acid inducible-gene I (RIG-I) functions as one of the major sensors of RNA viruses. DDX58, which encodes the RIG-I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG-I by 5'ppp-dsRNA, its synthetic ligand, directly causes the production of IL-23 and triggers psoriasis-like skin disease in mice. Repeated injections of IL-23 to the ears failed to induce IL-23 production and a full psoriasis-like skin phenotype, in either germ-free or RIG-I-deficient mice...
April 4, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28373218/hepatic-stellate-cells-limit-hepatocellular-carcinoma-progression-through-the-orphan-receptor-endosialin
#7
Carolin Mogler, Courtney König, Matthias Wieland, Anja Runge, Eva Besemfelder, Dorde Komljenovic, Thomas Longerich, Peter Schirmacher, Hellmut G Augustin
Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte cross talk, we hypothesized that HSC-expressed endosialin might similarly affect cell proliferation during hepatocarcinogenesis...
April 3, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28360091/transcriptional-response-to-hepatitis-c-virus-infection-and-interferon-alpha-treatment-in-the-human-liver
#8
Tujana Boldanova, Aleksei Suslov, Markus H Heim, Anamaria Necsulea
Hepatitis C virus (HCV) is widely used to investigate host-virus interactions. Cellular responses to HCV infection have been extensively studied in vitro However, in human liver, interferon (IFN)-stimulated gene expression can mask direct transcriptional responses to infection. To better characterize the direct effects of HCV infection in vivo, we analyze the transcriptomes of HCV-infected patients lacking an activated endogenous IFN system. We show that expression changes observed in these patients predominantly reflect immune cell infiltrates rather than cell-intrinsic pathways...
March 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28356312/an-intranasally-delivered-peptide-drug-ameliorates-cognitive-decline-in-alzheimer-transgenic-mice
#9
Yu-Sung Cheng, Zih-Ten Chen, Tai-Yan Liao, Chen Lin, Howard C-H Shen, Ya-Han Wang, Chi-Wei Chang, Ren-Shyan Liu, Rita P-Y Chen, Pang-Hsien Tu
Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed...
March 29, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28351932/seeding-and-transgenic-overexpression-of-alpha-synuclein-triggers-dendritic-spine-pathology-in-the-neocortex
#10
Sonja Blumenstock, Eva F Rodrigues, Finn Peters, Lidia Blazquez-Llorca, Felix Schmidt, Armin Giese, Jochen Herms
Although misfolded and aggregated α-synuclein (α-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long-term in vivo imaging of apical dendrites was performed in mice overexpressing wild-type human α-synuclein. Additionally, intracranial injection of preformed α-synuclein fibrils was performed to induce cortical α-syn pathology...
March 28, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28351931/antibodies-inhibit-transmission-and-aggregation-of-c9orf72-poly-ga-dipeptide-repeat-proteins
#11
Qihui Zhou, Carina Lehmer, Meike Michaelsen, Kohji Mori, Dominik Alterauge, Dirk Baumjohann, Martin H Schludi, Johanna Greiling, Daniel Farny, Andrew Flatley, Regina Feederle, Stephanie May, Franziska Schreiber, Thomas Arzberger, Christoph Kuhm, Thomas Klopstock, Andreas Hermann, Christian Haass, Dieter Edbauer
Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins...
March 28, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28341703/niacin-ameliorates-ulcerative-colitis-via-prostaglandin-d2-mediated-d-prostanoid-receptor-1-activation
#12
Juanjuan Li, Deping Kong, Qi Wang, Wei Wu, Yanping Tang, Tingting Bai, Liang Guo, Lumin Wei, Qianqian Zhang, Yu Yu, Yuting Qian, Shengkai Zuo, Guizhu Liu, Qian Liu, Sheng Wu, Yi Zang, Qian Zhu, Daile Jia, Yuanyang Wang, Weiyan Yao, Yong Ji, Huiyong Yin, Masataka Nakamura, Michael Lazarus, Richard M Breyer, Lifu Wang, Ying Yu
Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2 However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively...
March 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28341702/nras-destines-tumor-cells-to-the-lungs
#13
Anastasios D Giannou, Antonia Marazioti, Nikolaos I Kanellakis, Ioanna Giopanou, Ioannis Lilis, Dimitra E Zazara, Giannoula Ntaliarda, Danai Kati, Vasileios Armenis, Georgia A Giotopoulou, Anthi C Krontira, Marina Lianou, Theodora Agalioti, Malamati Vreka, Maria Papageorgopoulou, Sotirios Fouzas, Dimitrios Kardamakis, Ioannis Psallidas, Magda Spella, Georgios T Stathopoulos
The lungs are frequently affected by cancer metastasis. Although NRAS mutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross-examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1- and Cxcr2-deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes lung colonization by regulating interleukin-8-related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells...
March 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28298340/pre-clinical-validation-of-a-selective-anti-cancer-stem-cell-therapy-for-numb-deficient-human-breast-cancers
#14
Daniela Tosoni, Sarah Pambianco, Blanche Ekalle Soppo, Silvia Zecchini, Giovanni Bertalot, Giancarlo Pruneri, Giuseppe Viale, Pier Paolo Di Fiore, Salvatore Pece
The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy...
March 15, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28289079/deletion-of-f4l-ribonucleotide-reductase-in-vaccinia-virus-produces-a-selective-oncolytic-virus-and-promotes-anti-tumor-immunity-with-superior-safety-in-bladder-cancer-models
#15
Kyle G Potts, Chad R Irwin, Nicole A Favis, Desmond B Pink, Krista M Vincent, John D Lewis, Ronald B Moore, Mary M Hitt, David H Evans
Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high-grade disease, Bacillus Calmette-Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell-cycle-regulated small subunit of ribonucleotide reductase (RRM2). The F4L-deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor-selective replication and cell killing...
March 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28289078/delivery-is-key-lessons-learnt-from-developing-splice-switching-antisense-therapies
#16
REVIEW
Caroline Godfrey, Lourdes R Desviat, Bård Smedsrød, France Piétri-Rouxel, Michela A Denti, Petra Disterer, Stéphanie Lorain, Gisela Nogales-Gadea, Valentina Sardone, Rayan Anwar, Samir El Andaloussi, Taavi Lehto, Bernard Khoo, Camilla Brolin, Willeke Mc van Roon-Mom, Aurélie Goyenvalle, Annemieke Aartsma-Rus, Virginia Arechavala-Gomeza
The use of splice-switching antisense therapy is highly promising, with a wealth of pre-clinical data and numerous clinical trials ongoing. Nevertheless, its potential to treat a variety of disorders has yet to be realized. The main obstacle impeding the clinical translation of this approach is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre-clinical development, the gaps in current knowledge and the pertinent challenges facing the field...
March 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28283651/tfe3-regulates-whole-body-energy-metabolism-in-cooperation-with-tfeb
#17
Nunzia Pastore, Anna Vainshtein, Tiemo J Klisch, Andrea Armani, Tuong Huynh, Niculin J Herz, Elena V Polishchuk, Marco Sandri, Andrea Ballabio
TFE3 and TFEB are members of the MiT family of HLH-leucine zipper transcription factors. Recent studies demonstrated that they bind overlapping sets of promoters and are post-transcriptionally regulated through a similar mechanism. However, while Tcfeb knockout (KO) mice die during early embryonic development, no apparent phenotype was reported in Tfe3 KO mice. Thus raising the need to characterize the physiological role of TFE3 and elucidate its relationship with TFEB TFE3 deficiency resulted in altered mitochondrial morphology and function both in vitro and in vivo due to compromised mitochondrial dynamics...
March 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28283650/culturing-human-intestinal-stem-cells-for-regenerative-applications-in-the-treatment-of-inflammatory-bowel-disease
#18
REVIEW
Fredrik Eo Holmberg, Jakob B Seidelin, Xiaolei Yin, Benjamin E Mead, Zhixiang Tong, Yuan Li, Jeffrey M Karp, Ole H Nielsen
Both the incidence and prevalence of inflammatory bowel disease (IBD) is increasing globally; in the industrialized world up to 0.5% of the population are affected and around 4.2 million individuals suffer from IBD in Europe and North America combined. Successful engraftment in experimental colitis models suggests that intestinal stem cell transplantation could constitute a novel treatment strategy to re-establish mucosal barrier function in patients with severe disease. Intestinal stem cells can be grown in vitro in organoid structures, though only a fraction of the cells contained are stem cells with regenerative capabilities...
March 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28264935/stat3-promotes-ifn%C3%AE-tnf%C3%AE-induced-muscle-wasting-in-an-nf-%C3%AE%C2%BAb-dependent-and-il-6-independent-manner
#19
Jennifer F Ma, Brenda J Sanchez, Derek T Hall, Anne-Marie K Tremblay, Sergio Di Marco, Imed-Eddine Gallouzi
Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While the multifactorial nature of this syndrome and the implication of cytokines such as IL-6, IFNγ, and TNFα is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFNγ/TNFα promotes the phosphorylation of STAT3 on Y705 residue in the cytoplasm of muscle fibers by activating JAK kinases. Unexpectedly, this effect occurs both in vitro and in vivo independently of IL-6, which is considered as one of the main triggers of STAT3-mediated muscle wasting...
March 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28314782/moving-molecular-medicine
#20
EDITORIAL
Philippe J Sansonetti
No abstract text is available yet for this article.
April 2017: EMBO Molecular Medicine
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