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https://www.readbyqxmd.com/read/28472820/clinical-value-of-r-spondins-in-triple-negative-and-metaplastic-breast-cancers
#1
F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni, I Bièche
BACKGROUND: RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). METHODS: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs...
May 4, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28467820/non-equivalence-of-wnt-and-r-spondin-ligands-during-lgr5-intestinal-stem-cell-self-renewal
#2
Kelley S Yan, Claudia Y Janda, Junlei Chang, Grace X Y Zheng, Kathryn A Larkin, Vincent C Luca, Luis A Chia, Amanda T Mah, Arnold Han, Jessica M Terry, Akifumi Ootani, Kelly Roelf, Mark Lee, Jenny Yuan, Xiao Li, Christopher R Bolen, Julie Wilhelmy, Paige S Davies, Hiroo Ueno, Richard J von Furstenberg, Phillip Belgrader, Solongo B Ziraldo, Heather Ordonez, Susan J Henning, Melissa H Wong, Michael P Snyder, Irving L Weissman, Aaron J Hsueh, Tarjei S Mikkelsen, K Christopher Garcia, Calvin J Kuo
The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28462013/stromal-progenitor-cells-in-mitigation-of-non-hematopoietic-radiation-injuries
#3
Shilpa Kulkarni, Timothy C Wang, Chandan Guha
PURPOSE OF REVIEW: Therapeutic exposure to high doses of radiation can severely impair organ function due to ablation of stem cells. Normal tissue injury is a dose-limiting toxicity for radiation therapy (RT). Although advances in the delivery of high precision conformal RT has increased normal tissue sparing, mitigating and therapeutic strategies that could alleviate early and chronic radiation effects are urgently needed in order to deliver curative doses of RT, especially in abdominal, pelvic and thoracic malignancies...
December 2016: Current Pathobiology Reports
https://www.readbyqxmd.com/read/28424979/studies-on-core-shell-nanocapsules-of-felodipine-in-vitro-in-vivo-evaluations
#4
Jerome K Geroge, Priya Ranjan Prasad Verma, Jayachandran Venkatesan, Jin-Young Lee, Dong-Han Yoon, Se-Kwon Kim, Sandeep Kumar Singh
The present study aimed for in vitro-in vivo-in silico simulation studies of experimentally designed (3(2)-factorial) Capmul PG-8-cored, Eudragit RSPO-Lutrol F 127 nanocapsules to ferry felodipine using GastroPlus™. The in silico parameter sensitivity analysis for pharmacokinetic parameters was initially assessed to justify the preparation of felodipine-loaded nanocapsules (FLNs) with enhanced solubility to overcome the bioavailability issues of felodipine. The overall integrated desirability ranged between 0...
April 19, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28273449/r-spondin1-controls-muscle-cell-fusion-through-dual-regulation-of-antagonistic-wnt-signaling-pathways
#5
Floriane Lacour, Elsa Vezin, C Florian Bentzinger, Marie-Claude Sincennes, Lorenzo Giordani, Arnaud Ferry, Robert Mitchell, Ketan Patel, Michael A Rudnicki, Marie-Christine Chaboissier, Anne-Amandine Chassot, Fabien Le Grand
Wnt-mediated signals are involved in many important steps in mammalian regeneration. In multiple cell types, the R-spondin (Rspo) family of secreted proteins potently activates the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We find that muscle progenitor cells lacking Rspo1 show delayed differentiation due to reduced activation of Wnt/β-catenin target genes...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28272338/evidence-of-the-role-of-r-spondin-1-and-its-receptor-lgr4-in-the-transmission-of-mechanical-stimuli-to-biological-signals-for-bone-formation
#6
Gui-Xun Shi, Xin-Feng Zheng, Chao Zhu, Bo Li, Yu-Ren Wang, Sheng-Dan Jiang, Lei-Sheng Jiang
The bone can adjust its mass and architecture to mechanical stimuli via a series of molecular cascades, which have been not yet fully elucidated. Emerging evidence indicated that R-spondins (Rspos), a family of secreted agonists of the Wnt/β-catenin signaling pathway, had important roles in osteoblastic differentiation and bone formation. However, the role of Rspo proteins in mechanical loading-influenced bone metabolism has never been investigated. In this study, we found that Rspo1 was a mechanosensitive protein for bone formation...
March 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28220828/rspo3-lgr4-regulates-osteogenic-differentiation-of-human-adipose-derived-stem-cells-via-erk-fgf-signalling
#7
Min Zhang, Ping Zhang, Yunsong Liu, Longwei Lv, Xiao Zhang, Hao Liu, Yongsheng Zhou
The four R-spondins (RSPOs) and their three related receptors, LGR4, 5 and 6, have emerged as a major ligand-receptor system with critical roles in development and stem cell survival. However, the exact roles of the RSPO-LGR system in osteogenesis remain largely unknown. In the present study, we showed that RSPO3-shRNA increased the osteogenic potential of human adipose-derived stem cells (hASCs) significantly. Mechanistically, we demonstrated that RSPO3 is a negative regulator of ERK/FGF signalling. We confirmed that inhibition of the ERK1/2 signalling pathway blocked osteogenic differentiation in hASCs, and the increased osteogenic capacity observed after RSPO3 knockdown in hASCs was reversed by inhibition of ERK signalling...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28219935/novel-insights-into-gastric-cancer-methylation-of-r-spondins-and-regulation-of-lgr5-by-sp1
#8
Franziska Wilhelm, Eva Simon, Christine Boger, Hans-Michael Behrens, Sandra Kruger, Christoph Rocken
Recently it was shown that leucine-rich repeat-containing receptor 5 (LGR5) expressing stem cells are the cellular origin of intestinal-type gastric cancer. The aim of our study was to uncover regulatory mechanisms of LGR5 expression in gastric mucosa and their implications for cancer development. Reporter assays identified a LGR5 promoter fragment, which is highly relevant for active LGR5 expression. Chromatin immunoprecipitation (ChIP) verified that SP1 is bound within this region and reporter activity increased in SP1 transfected cells...
February 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28213179/the-dispersion-releaser-technology-is-an-effective-method-for-testing-drug-release-from-nanosized-drug-carriers
#9
Christine Janas, Marc-Philip Mast, Li Kirsamer, Carlo Angioni, Fiona Gao, Werner Mäntele, Jennifer Dressman, Matthias G Wacker
The dispersion releaser (DR) is a dialysis-based setup for the analysis of the drug release from nanosized drug carriers. It is mounted into dissolution apparatus2 of the United States Pharmacopoeia. The present study evaluated the DR technique investigating the drug release of the model compound flurbiprofen from drug solution and from nanoformulations composed of the drug and the polymer materials poly (lactic acid), poly (lactic-co-glycolic acid) or Eudragit(®)RSPO. The drug loaded nanocarriers ranged in size between 185...
February 14, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28078320/lgr4-and-lgr5-function-redundantly-during-human-endoderm-differentiation
#10
Yu-Hwai Tsai, David R Hill, Namit Kumar, Sha Huang, Alana M Chin, Briana R Dye, Melinda S Nagy, Michael P Verzi, Jason R Spence
BACKGROUND & AIMS: The Lgr family of transmembrane proteins (Lgr4, 5, 6) act as functional receptors for R-spondin proteins (Rspo 1, 2, 3, 4), and potentiate Wnt signaling in different contexts. Lgr5 is arguably the best characterized of the Lgr family members in a number of adult and embryonic contexts in mice. However, the function of LGR family members in early embryonic development is unclear, and has not been explored during human development or tissue differentiation in detail. METHODS: We interrogated the function and expression of LGR family members using human pluripotent stem cell-derived tissues including definitive endoderm, mid/hindgut, and intestinal organoids...
September 2016: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/27784900/corrigendum-the-rspo-lgr4-5-znrf3-rnf43-module-controls-liver-zonation-and-size
#11
Lara Planas-Paz, Vanessa Orsini, Luke Boulter, Diego Calabrese, Monika Pikiolek, Florian Nigsch, Yang Xie, Guglielmo Roma, Adriana Donovan, Patricia Marti, Nicolau Beckmann, Michael T Dill, Walter Carbone, Sebastian Bergling, Andrea Isken, Matthias Mueller, Bernd Kinzel, Yi Yang, Xiaohong Mao, Thomas B Nicholson, Raffaella Zamponi, Paola Capodieci, Reginald Valdez, Daniel Rivera, Andreas Loew, Chinweike Ukomadu, Luigi M Terracciano, Tewis Bouwmeester, Feng Cong, Markus H Heim, Stuart J Forbes, Heinz Ruffner, Jan S Tchorz
No abstract text is available yet for this article.
October 27, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27595040/formulation-and-pharmacokinetic-evaluation-of-microcapsules-containing-pravastatin-sodium-using-rats
#12
Venkatesh Dinnekere Puttegowda, Roopa Karki, Divakar Goli, Sajal Kumar Jha, Manjunatha Panduranga Mudagal
Pravastatin Sodium has a cholesterol lowering agent. It has shorter half-life and undergoes first-pass metabolism. Frequent dose is required in case of conventional dosage form. The purpose of the study is to formulate and evaluate microcapsules containing Pravastatin Sodium by complex with cholestyramine resins coated with Eudragit RLPO and Eudragit RSPO polymers for achieving control release. Complexation of drug on resin was carried out by batch method. Microencapsulation was carried out by nonaqueous solvent evaporation method...
2016: Scientifica
https://www.readbyqxmd.com/read/27581568/wnt-pathway-regulation-of-intestinal-stem-cells
#13
Amanda T Mah, Kelley S Yan, Calvin J Kuo
Wnt signalling is involved in multiple aspects of embryonic development and adult tissue homeostasis, notably via controlling cellular proliferation and differentiation. Wnt signalling is subject to stringent positive and negative regulation to promote proper development and homeostasis yet avoid aberrant growth. Such multi-layer regulation includes post-translational modification and processing of Wnt proteins themselves, R-spondin (Rspo) amplification of Wnt signalling, diverse receptor families, and intracellular and extracellular antagonists and destruction and transcription complexes...
September 1, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27572318/rspos-facilitated-hsc-activation-and-promoted-hepatic-fibrogenesis
#14
Xinguang Yin, Huixing Yi, Linlin Wang, Wanxin Wu, Xiaojun Wu, Linghua Yu
Roof plate-specific spondin (RSPO) proteins are potent Wnt pathway agonists and involve in a broad range of developmental and physiological processes. This study investigated the activities and mechanisms of RSPOs in liver fibrogenesis, especially in hepatic stellate cell (HSC) activation. HSC activation was assessed by fibrosis biomarker (α-smooth muscle actin and Collagen-I), phenotypic change (accumulation of lipid droplets), and increased proliferation. Similarly, Wnt pathway activity was evaluated by the expression of nuclear β-catenin and T cell-specific transcription factors (TCF) activity...
September 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27511199/rspo3-expands-intestinal-stem-cell-and-niche-compartments-and-drives-tumorigenesis
#15
John Hilkens, Nikki C Timmer, Mandy Boer, Gerjon J Ikink, Matthias Schewe, Andrea Sacchetti, Martijn A J Koppens, Ji-Ying Song, Elvira R M Bakker
OBJECTIVE: The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models...
June 2017: Gut
https://www.readbyqxmd.com/read/27401612/novel-bispecific-domain-antibody-to-lrp6-inhibits-wnt-and-r-spondin-ligand-induced-wnt-signaling-and-tumor-growth
#16
Heather Jackson, David Granger, Gavin Jones, Louisa Anderson, Sarah Friel, Daniel Rycroft, William Fieles, James Tunstead, Michael Steward, Trevor Wattam, Adam Walker, Jeremy Griggs, Muhammad Al-Hajj, Christopher Shelton
UNLABELLED: Aberrant WNT signaling is associated with the formation and growth of numerous human cancer types. The low-density lipoprotein receptor-related protein 6 (LRP6) is the least redundant component of the WNT receptor complex with two independent WNT ligand-binding sites. Using domain antibody (dAb) technology, a bispecific antibody (GSK3178022) to LRP6 was identified that is capable of blocking stimulation in the presence of a range of WNT and R-spondin (RSPO) ligands in vitro GSK3178022 was also efficacious in reducing WNT target gene expression in vivo, in both cancer cell line and patient-derived xenograft models, and delays tumor growth in a patient-derived RSPO fusion model of colorectal cancer...
September 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27351137/heterogeneous-polymer-composite-nanoparticles-loaded-in-situ-gel-for-controlled-release-intra-vaginal-therapy-of-genital-herpes
#17
D Ramyadevi, K S Rajan, B N Vedhahari, K Ruckmani, N Subramanian
Herpes simplex virus causes serious and contagious genital infections in high percentage of female population world-wide. Acyclovir is a clinically successful antiviral molecule till date, in-spite of limitations as poor solubility, low half-life, reduced oral bioavailability and side effects at higher doses. In the present work, controlled release in situ gelling system loaded with polymeric nanoparticles of acyclovir containing a dose of drug equivalent to 105mg/day has been developed. The formulation containing drug loaded polyvinyl pyrrolidone-Eudragit RSPO hybrid polymeric nanoparticles (Size ∼99±3nm, Zeta ∼+26...
October 1, 2016: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/27314333/n-glycosylation-of-human-r-spondin-1-is-required-for-efficient-secretion-and-stability-but-not-for-its-heparin-binding-ability
#18
Chiung-Fang Chang, Li-Sung Hsu, Chieh-Yu Weng, Chih-Kai Chen, Shu-Ying Wang, Yi-Hwa Chou, Yan-Yu Liu, Zi-Xiu Yuan, Wen-Ying Huang, Ho Lin, Yau-Hung Chen, Jen-Ning Tsai
R-spondin 1 (Rspo1) plays an essential role in stem cell biology by potentiating Wnt signaling activity. Despite the fact that Rspo1 holds therapeutic potential for a number of diseases, its biogenesis is not fully elucidated. All Rspo proteins feature two amino-terminal furin-like repeats, which are responsible for Wnt signal potentiation, and a thrombospondin type 1 (TSR1) domain that can provide affinity towards heparan sulfate proteoglycans. Using chemical inhibitors, deglycosylase and site-directed mutagenesis, we found that human Rspo1 and Rspo3 are both N-glycosylated at N137, a site near the C-terminus of the furin repeat 2 domain, and Rspo2 is N-glycosylated at N160, a position near the N-terminus of TSR1 domain...
June 14, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27237581/the-role-of-r-spondins-and-their-receptors-in-bone-metabolism
#19
REVIEW
Gui-Xun Shi, Wei-Wei Mao, Xin-Feng Zheng, Lei-Sheng Jiang
R-spondins are a family of four secreted proteins and act as agonists of the canonical Wnt/β-catenin signaling pathway. They are broadly expressed in different phases of skeleton tissues. Recently, three closely related leucine-rich repeat containing G-protein-coupled receptors (Lgr4/5/6) have been identified as the new and exact receptors of R-spondins. On the cell surface, R-spondins binding with Lgr4/5/6 and Znrf3/Rnf43 lead to reduced turnover of Wnts-receptors and potentiate Wnt/β-catenin signaling pathway which is critical for the control of bone development and remodeling...
November 2016: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/27117330/orchestrating-wnt-signalling-for-metabolic-liver-zonation
#20
Walter Birchmeier
Wnt/β-catenin signalling is an important regulator of liver development, zonation and regeneration. The cell surface complex RSPO-LGR4/5-ZNF3/RNF43 is now shown to direct Wnt/β-catenin signalling in orchestrating the division of the liver into functionally distinct metabolic zones, providing insights into the mechanisms that influence organ development and regeneration.
April 27, 2016: Nature Cell Biology
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