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https://www.readbyqxmd.com/read/28334757/perturbations-in-cell-signaling-elicit-early-cardiac-defects-in-mucopolysaccharidosis-type-ii
#1
Roberto Costa, Andrea Urbani, Marika Salvalaio, Stefania Bellesso, Domenico Cieri, Ilaria Zancan, Mirella Filocamo, Paolo Bonaldo, Ildiko Szabò, Rosella Tomanin, Enrico Moro
Morphogens release and activity can be negatively affected by an impaired glycosaminoglycans (GAGs) turnover and proteoglycans assembly in the extracellular matrix, leading to altered tissue morphogenesis. In this work, we show that loss of Iduronate-2-sulfatase (IDS) activity, affecting GAGs catabolism and responsible for a life-threatening valvulopathy in mucopolysaccharidosis type II (MPSII), triggers early Sonic Hedgehog (Shh) and Wnt/β-catenin signaling defects, leading to aberrant heart development and atrioventricular valve formation in a zebrafish model...
February 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28332491/corrigendum-endocytic-recycling-protein-ehd1-regulates-primary-cilia-morphogenesis-and-shh-signaling-during-neural-tube-development
#2
Sohinee Bhattacharyya, Mark A Rainey, Priyanka Arya, Bhopal C Mohapatra, Insha Mushtaq, Samikshan Dutta, Manju George, Matthew D Storck, Rodney D McComb, David Muirhead, Gordon L Todd, Karen Gould, Kaustubh Datta, Janee Gelineau-van Waes, Vimla Band, Hamid Band
No abstract text is available yet for this article.
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332184/primary-cilium-alterations-and-expression-changes-of-patched1-proteins-in-niemann-pick-type-c-disease
#3
Patrizia Formichi, Carla Battisti, Maria Margherita De Santi, Raffaella Guazzo, Sergio Antonio Tripodi, Elena Radi, Benedetta Rossi, Ermelinda Tarquini, Antonio Federico
Niemann-Pick type C disease (NPC) is a disorder characterized by abnormal intracellular accumulation of unesterified cholesterol and glycolipids. Two distinct disease-causing genes have been isolated, NPC1 and NPC2. The NPC1 protein is involved in the sorting and recycling of cholesterol and glycosphingolipids in the late endosomal/lysosomal system. It has extensive homology with the Patched 1 (Ptc1) receptor, a transmembrane protein localized in the primary cilium and involved in the Hedgehog signaling (Shh) pathway...
March 23, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28320842/stat3-controls-the-long-term-survival-and-phenotype-of-repair-schwann-cells-during-nerve-regeneration
#4
Cristina Benito, Catherine M Davis, Jose A Gomez-Sanchez, Mark Turmaine, Dies Meijer, Valeria Poli, Rhona Mirsky, Kristjan R Jessen
After nerve injury, Schwann cells convert to a phenotype specialised to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signalling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role...
March 20, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28318003/small-molecule-hedgehog-pathway-antagonists
#5
Trieu N Trinh, Eileen A McLaughlin, Christopher P Gordon, Ilana R Bernstein, Victoria J Pye, Kate A Redgrove, Adam McCluskey
Leveraging our quinolone-1-(2H)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: l-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine. Synthesis of focused compound libraries identified six l-tryptophan based inhibitors, and two stimulators, of Gli at 10 μM compound concentration. 2,4-Dichloro-13 and indole 16 suppressed mRNA expression of Ptch1 in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli2 mRNA expression...
March 20, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#6
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28302010/discovery-of-hedgehog-antagonists-for-cancer-therapy
#7
Harleen Khatra, Chandra Bose, Surajit Sinha
BACKGROUND: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28296537/microfluidic-mobility-shift-assay-for-real-time-analysis-of-peptide-n-palmitoylation
#8
Thomas Lanyon-Hogg, Neki V Patel, Markus Ritzefeld, Katherine J Boxall, Rosemary Burke, Julian Blagg, Anthony I Magee, Edward W Tate
The Hedgehog pathway is a key developmental signaling pathway but is also implicated in many types of cancer. The extracellular signaling protein Sonic hedgehog (Shh) requires dual lipidation for functional signaling, whereby N-terminal palmitoylation is performed by the enzyme Hedgehog acyltransferase (Hhat). Hhat is an attractive target for small-molecule inhibition to arrest Hedgehog signaling, and methods for assaying Hhat activity are central to understanding its function. However, all existing assays to quantify lipidation of peptides suffer limitations, such as safety hazards, high costs, extensive manual handling, restriction to stopped-assay measurements, or indirect assessment of lipidation...
April 2017: SLAS Discov
https://www.readbyqxmd.com/read/28293554/sonic-hedgehog-signaling-in-limb-development
#9
REVIEW
Cheryll Tickle, Matthew Towers
The gene encoding the secreted protein Sonic hedgehog (Shh) is expressed in the polarizing region (or zone of polarizing activity), a small group of mesenchyme cells at the posterior margin of the vertebrate limb bud. Detailed analyses have revealed that Shh has the properties of the long sought after polarizing region morphogen that specifies positional values across the antero-posterior axis (e.g., thumb to little finger axis) of the limb. Shh has also been shown to control the width of the limb bud by stimulating mesenchyme cell proliferation and by regulating the antero-posterior length of the apical ectodermal ridge, the signaling region required for limb bud outgrowth and the laying down of structures along the proximo-distal axis (e...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28292438/maoa-dependent-activation-of-shh-il6-rankl-signaling-network-promotes-prostate-cancer-metastasis-by-engaging-tumor-stromal-cell-interactions
#10
Jason Boyang Wu, Lijuan Yin, Changhong Shi, Qinlong Li, Peng Duan, Jen-Ming Huang, Chunyan Liu, Fubo Wang, Michael Lewis, Yang Wang, Tzu-Ping Lin, Chin-Chen Pan, Edwin M Posadas, Haiyen E Zhau, Leland W K Chung
Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28286175/cilia-dependent-gli-processing-in-neural-crest-cells-is-required-for-tongue-development
#11
Grethel Millington, Kelsey Elliott, Ya-Ting Chang, Ching-Fang Chang, Andrzej Dlugosz, Samantha A Brugmann
Ciliopathies are a class of diseases caused by the loss of a ubiquitous, microtubule-based organelle called a primary cilium. Ciliopathies commonly result in defective development of the craniofacial complex, causing midfacial defects, craniosynostosis, micrognathia and aglossia. Herein, we explored how the conditional loss of primary cilia on neural crest cells (Kif3a(f/f);Wnt1-Cre) generated aglossia. On a cellular level, our data revealed that aglossia in Kif3a(f/f);Wnt1-Cre embryos was due to a loss of mesoderm-derived muscle precursors migrating into and surviving in the tongue anlage...
March 9, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28284480/copy-number-variations-found-in-patients-with-a-corpus-callosum-abnormality-and-intellectual-disability
#12
Solveig Heide, Boris Keren, Thierry Billette de Villemeur, Sandra Chantot-Bastaraud, Christel Depienne, Caroline Nava, Cyril Mignot, Aurélia Jacquette, Eric Fonteneau, Elodie Lejeune, Corinne Mach, Isabelle Marey, Sandra Whalen, Didier Lacombe, Sophie Naudion, Caroline Rooryck, Annick Toutain, Cédric Le Caignec, Damien Haye, Laurence Olivier-Faivre, Alice Masurel-Paulet, Christel Thauvin-Robinet, Fabien Lesne, Anne Faudet, Dorothée Ville, Vincent des Portes, Damien Sanlaville, Jean-Pierre Siffroi, Marie-Laure Moutard, Delphine Héron
OBJECTIVE: To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays. RESULTS: In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype...
March 8, 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/28283405/coordination-of-limb-development-by-crosstalk-among-axial-patterning-pathways
#13
REVIEW
Irene Delgado, Miguel Torres
Vertebrate limb development relies on the activity of signaling centers that promote growth and control patterning along three orthogonal axes of the limb bud. The apical ectodermal ridge, at the distal rim of the limb bud ectoderm, produces WNT and FGF signals, which promote limb bud growth and progressive distalization. The zone of polarizing activity, a discrete postero-distal mesenchymal domain, produces SHH, which stimulates growth and organizes patterning along the antero-posterior axis. The dorsal and ventral ectoderms produce, respectively, WNT7A and BMPs, which induce dorso-ventral limb fates...
March 7, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28277196/downregulation-of-rab23-in-prostate-cancer-inhibits-tumor-growth-in-vitro-and-in-vivo
#14
Junkai Chang, Weibo Xu, Guangchao Liu, Xinyi Du, Xiaodong Li
Rab23, a novel member of the Rab GTPase family, was found to be implicated in the progression of some human cancers. However, what role Rab23 plays in prostate cancer (PCa) remains to be illustrated. In the present study, we investigated the expression pattern and roles of Rab23 in PCa. The study results showed that Rab23 was upregulated in PCa tissues and cell lines. Moreover, downregulation of Rab23 remarkably suppressed the proliferation, migration, and invasion of PCa cells. In addition, downregulation of Rab23 significantly downregulated the protein expression levels of Shh and Gli1...
January 26, 2017: Oncology Research
https://www.readbyqxmd.com/read/28276480/selective-targeting-of-hdac1-2-elicits-anticancer-effects-through-gli1-acetylation-in-preclinical-models-of-shh-medulloblastoma
#15
Sonia Coni, Anna Barbara Mancuso, Laura Di Magno, Giulia Sdruscia, Simona Manni, Silvia Maria Serrao, Dante Rotili, Eleonora Spiombi, Francesca Bufalieri, Marialaura Petroni, Monika Kusio-Kobialka, Enrico De Smaele, Elisabetta Ferretti, Carlo Capalbo, Antonello Mai, Pawel Niewiadomski, Isabella Screpanti, Lucia Di Marcotullio, Gianluca Canettieri
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275687/hedgehog-signaling-links-chronic-inflammation-to-gastric-cancer-precursor-lesions
#16
REVIEW
Juanita L Merchant, Lin Ding
Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation...
March 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28273832/more-insight-into-bdnf-against-neurodegeneration-anti-apoptosis-anti-oxidation-and-suppression-of-autophagy
#17
REVIEW
Shang-Der Chen, Chia-Lin Wu, Wei-Chao Hwang, Ding-I Yang
In addition to its well-established neurotrophic action, brain-derived neurotrophic factor (BDNF) also possesses other neuroprotective effects including anti-apoptosis, anti-oxidation, and suppression of autophagy. We have shown before that BDNF triggers multiple mechanisms to confer neuronal resistance against 3-nitropropionic acid (3-NP)-induced mitochondrial dysfunction in primary rat cortical cultures. The beneficial effects of BDNF involve the induction of anti-oxidative thioredoxin with the resultant expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) as well as erythropoietin (EPO)-dependent stimulation of sonic hedgehog (SHH)...
March 3, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28270602/integration-of-shh-and-fgf-signaling-in-controlling-hox-gene-expression-in-cultured-limb-cells
#18
Alan R Rodrigues, Nayuta Yakushiji-Kaminatsui, Yuji Atsuta, Guillaume Andrey, Patrick Schorderet, Denis Duboule, Clifford J Tabin
During embryonic development, fields of progenitor cells form complex structures through dynamic interactions with external signaling molecules. How complex signaling inputs are integrated to yield appropriate gene expression responses is poorly understood. In the early limb bud, for instance, Sonic hedgehog (Shh) is expressed in the distal posterior mesenchyme, where it acts as a mediator of anterior to posterior (AP) patterning, whereas fibroblast growth factor 8 (Fgf8) is produced by the apical ectodermal ridge (AER) at the distal tip of the limb bud to direct outgrowth along the proximal to distal (PD) axis...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28267495/emulsifying-and-physicochemical-properties-of-soy-hull-hemicelluloses-soy-protein-isolate-conjugates
#19
Li Wang, Min Wu, Hua-Min Liu
Protein-polysaccharide conjugates could potentially combine the excellent emulsification properties of the protein with the stabilizing effect of the polysaccharide. The investigation aimed to prepare soy hull hemicelluloses-soy protein isolate (SHH-SPI) conjugates by Maillard reaction in a controlled dry state condition and assess the suitability of the conjugates in stabilizing oil-in-water (O/W) emulsion. Results indicated that Maillard reactions occurred between amino groups and carbonyl, resulting in consumption of some functional groups and the appearance of new groups in the conjugates...
May 1, 2017: Carbohydrate Polymers
https://www.readbyqxmd.com/read/28264835/ift56-regulates-vertebrate-developmental-patterning-by-maintaining-iftb-integrity-and-ciliary-microtubule-architecture
#20
Daisy Xin, Kasey J Christopher, Lewie Zeng, Yong Kong, Scott D Weatherbee
Cilia are key regulators of animal development and depend on intraflagellar transport (IFT) proteins to form and function, yet the roles of individual IFTs are still unclear. We examined the Ift56(hop) mouse mutant and reveal novel insight into the function of IFT56, a poorly understood IFTB protein. Ift56(hop) mice have normal cilia distribution but display defective cilia structure including abnormal positioning and number of ciliary microtubule doublets. Furthermore, we show that Ift56(hop) cilia are unable to accumulate Gli proteins efficiently, resulting in developmental patterning defects in Shh signaling-dependent tissues such as the limb and neural tube...
March 6, 2017: Development
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