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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
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
Yin Xinguang, Yi Huixing, Wang Linlin, Wu Wanxin, Wu Xiaojun, Yu Linghua
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...
August 27, 2016: Oncotarget
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...
August 10, 2016: Gut
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
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
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...
2016: International Journal of Molecular Sciences
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...
May 26, 2016: Progress in Biophysics and Molecular Biology
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
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
LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation...
May 2016: Nature Cell Biology
Linyan Zhou, Tapas Charkraborty, Qian Zhou, Sipra Mohapatra, Yoshitaka Nagahama, Yueguang Zhang
In contrast to our understanding of testicular differentiation, ovarian differentiation is less well understood in vertebrates. In mammals, R-spondin1 (Rspo1), an activator of Wnt/β-catenin signaling pathway, is located upstream of the female sex determination pathway. However, the functions of Rspo1 in ovarian differentiation remain unclear in non-mammalian species. In order to elucidate the detailed functions of Rspo/Wnt signaling pathway in fish sex determination/differentiation, the ectopic expression of the Rspo1 gene was performed in XY medaka (Oryzias latipes)...
2016: Scientific Reports
Hetal P Thakkar, Nirav Pancholi, Chintankumar V Patel
The present study aimed to prepare, optimize, and evaluate Tapentadol hydrochloride controlled porosity osmotic pump (CPOP) and to achieve the drug release at nearly zero-order. The CPOP was prepared by the coating of polymers (Eudragit RSPO and RLPO) on a directly compressed core tablet. A Box-behnken experimental design was applied to optimize the parameters for CPOP. The optimized batch was characterized for in vitro drug release study, effect of pH, osmolarity and agitation intensity, and surface morphology and stability study...
October 2016: AAPS PharmSciTech
Jonathan D Boone, Rebecca C Arend, Bobbi E Johnston, Sara J Cooper, Scott A Gilchrist, Denise K Oelschlager, William E Grizzle, Gerald McGwin, Abhishek Gangrade, J Michael Straughn, Donald J Buchsbaum
Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 μM WNT974±100 μM carboplatin. Viability was evaluated with the ATPlite assay. The IC50 was calculated using a dose-response analysis...
February 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Anh Q Vo, Xin Feng, Joseph T Morott, Manjeet B Pimparade, Roshan V Tiwari, Feng Zhang, Michael A Repka
Floating dosage forms are an important formulation strategy for drugs with a narrow absorption window and low intestinal solubility, and for localized gastric treatment. Novel floating pellets were prepared using the hot-melt extrusion (HME) technology. Uniformly foamed strands were created by liquid injection pumping and screw configuration modification. The ammonio methacrylate copolymer (Eudragit® RSPO) foaming structure was formed by a liquid-vapor phase transition inside the strand upon die exiting resulting from the sudden decrease in external pressure, vaporizing the liquid ethanol and vacating the extruded material...
January 2016: European Journal of Pharmaceutics and Biopharmaceutics
Nagendra Kumar, Sundeep Chaurasia, Ravi R Patel, Gayasuddin Khan, Vikas Kumar, Brahmeshwar Mishra
Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation...
November 11, 2015: Pharmaceutical Development and Technology
Gregory Michelotti, Xiaoyin Jiang, Julie Ann Sosa, Anna Mae Diehl, Brittany Bohinc Henderson
PURPOSE: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness. PATIENTS AND METHODS: Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions...
October 27, 2015: Oncotarget
B Madan, Z Ke, N Harmston, S Y Ho, A O Frois, J Alam, D A Jeyaraj, V Pendharkar, K Ghosh, I H Virshup, V Manoharan, E H Q Ong, K Sangthongpitag, J Hill, E Petretto, T H Keller, M A Lee, A Matter, D M Virshup
Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts...
April 28, 2016: Oncogene
Matthias Zebisch, E Yvonne Jones
The four secreted R-spondin (Rspo1-4) proteins of vertebrates function as stem cell growth factors and potentiate canonical Wnt signalling. Rspo proteins act by cross-linking members of two cell surface receptor families, complexing the stem cell markers LGR4-6 with the Frizzled-specific E3 ubiquitin ligases ZNRF3/RNF43. The consequent internalisation of the ternary LGR-Rspo-E3 complex removes the E3 ligase activity, which otherwise targets the Wnt receptor Frizzled for degradation, and thus enhances Wnt signalling...
August 2015: Journal of Structural Biology
Y Q Han, J Geng, H T Shi, X M Zhang, L L Du, F T Liu, M M Li, X T Wang, Y Y Wang, G Y Yang
Rspo1 belongs to the Rspo family, which is composed of 4 members (Rspo1-4) that share 40 to 60% sequence homology and similar domain organizations, and regulate the WNT signaling pathway via a common mechanism. Rspo1 plays a key role in vertebrate development and is an effective mitogenic factor of gastrointestinal epithelial cells. We report the cloning of chicken Rspo1 and its gene expression distribution among tissues. It contained an open reading frame of 783 bp encoding a protein of 260 amino acids, and its molecular weight was predicted to be 28...
2015: Genetics and Molecular Research: GMR
Samy Yassin, Ke Su, Hungyen Lin, Lynn F Gladden, J Axel Zeitler
Tablet dissolution is strongly affected by swelling and solvent penetration into its matrix. A terahertz-pulsed imaging (TPI) technique, in reflection mode, is introduced as a new tool to measure one-dimensional swelling and solvent ingress in flat-faced pharmaceutical compacts exposed to dissolution medium from one face of the tablet. The technique was demonstrated on three tableting excipients: hydroxypropylmethyl cellulose (HPMC), Eudragit RSPO, and lactose. Upon contact with water, HPMC initially shrinks to up to 13% of its original thickness before undergoing expansion...
May 2015: Journal of Pharmaceutical Sciences
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