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RANK ligand

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https://www.readbyqxmd.com/read/28643924/exosomes-novel-regulators-of-bone-remodelling-and-potential-therapeutic-agents-for-orthodontics
#1
REVIEW
L S Holliday, K P McHugh, J Zuo, J I Aguirre, J K Neubert, W J Rody
Recent studies suggest that exosomes are involved in intercellular communication required for the maintenance of healthy bone. Exosomes are small (30-150 nm in diameter) extracellular vesicles that are formed in multivesicular bodies and are released from cells as the multivesicular bodies fuse with the plasma membrane. Regulatory exosomes have the capacity to exert profound control over target cells. They can stimulate plasma membrane receptors and are also internalized by the target cell delivering proteins, lipids, small molecules and functional RNAs from the cell of origin...
June 2017: Orthodontics & Craniofacial Research
https://www.readbyqxmd.com/read/28629155/repositioning-fda-drugs-as-potential-cruzain-inhibitors-from-trypanosoma-cruzi-virtual-screening-in-vitro-and-in-vivo-studies
#2
Isidro Palos, Edgar E Lara-Ramirez, Julio Cesar Lopez-Cedillo, Carlos Garcia-Perez, Muhammad Kashif, Virgilio Bocanegra-Garcia, Benjamin Nogueda-Torres, Gildardo Rivera
Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies...
June 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28628309/dissecting-orthosteric-contacts-for-a-reverse-fragment-based-ligand-design
#3
Arun Chandramohan, Nikhil Kumar Tulsian, Ganesh Srinivasan Anand
Orthosteric sites on proteins are formed typically from non-contiguous interacting sites in three dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the protein fold. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD)...
June 19, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28627025/novel-rankl-de-loop-mutants-antagonize-rank-mediated-osteoclastogenesis
#4
Yizhou Wang, Aart H G van Assen, Carlos R Reis, Rita Setroikromo, Ronald van Merkerk, Ykelien L Boersma, Robbert H Cool, Wim J Quax
Bone is a dynamic tissue that is maintained by continuous renewal. An imbalance in bone resorption and bone formation can lead to a range of disorders, such as osteoporosis. The Receptor Activator of NF-κB (RANK)-RANK ligand (RANKL) pathway plays a major role in bone remodeling. Here, we investigated the effect of mutations at position I248 in the DE-loop of murine RANKL on the interaction of RANKL with RANK, and subsequent activation of osteoclastogenesis. Two single mutants, RANKL I248Y and I248K, were found to maintain binding and have the ability to reduce wild type RANKL-induced osteoclastogenesis...
June 19, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28626618/cytoplasmic-expression-of-c-myc-protein-is-associated-with-risk-stratification-of-mantle-cell-lymphoma
#5
Yi Gong, Xi Zhang, Rui Chen, Yan Wei, Zhongmin Zou, Xinghua Chen
AIM: To investigate the association of C-MYC protein expression and risk stratification in mantle cell lymphoma (MCL), and to evaluate the utility of C-MYC protein as a prognostic biomarker in clinical practice. METHODS: We conducted immunohistochemical staining of C-MYC, Programmed cell death ligand 1 (PD-L1), CD8, Ki-67, p53 and SRY (sex determining region Y) -11 (SOX11) to investigate their expression in 64 patients with MCL. The staining results and other clinical data were evaluated for their roles in risk stratification of MCL cases using ANOVA, Chi-square, and Spearman's Rank correlation coefficient analysis...
2017: PeerJ
https://www.readbyqxmd.com/read/28619088/chemokine-signals-are-crucial-for-enhanced-homing-and-differentiation-of-circulating-osteoclast-progenitor-cells
#6
Alan Sucur, Zrinka Jajic, Marinko Artukovic, Marina Ikic Matijasevic, Branimir Anic, Darja Flegar, Antonio Markotic, Tomislav Kelava, Sanja Ivcevic, Natasa Kovacic, Vedran Katavic, Danka Grcevic
BACKGROUND: The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy...
June 15, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28617323/osteoblast-role-in-rheumatic-diseases
#7
REVIEW
Addolorata Corrado, Nicola Maruotti, Francesco Paolo Cantatore
Alterations in osteoblast growth, differentiation and activity play a role in the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritides, osteoarthritis, and osteoporosis. In fact, in these rheumatic diseases, abnormal activity of Wnt signaling, receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) signaling, bone morphogenetic proteins (BMPs) pathway and other mechanisms have been described in osteoblasts. This review article is focused on current knowledge on the role of osteoblast dysregulation occurring in rheumatic diseases...
June 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28617091/fragment-based-virtual-screening-approach-and-molecular-dynamics-simulation-studies-for-identification-of-bace1-inhibitor-leads
#8
Prabu Manoharan, Nanda Ghoshal
Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point...
June 15, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28601508/design-synthesis-and-biological-evaluation-of-renin-inhibitors-guided-by-simulated-annealing-of-chemical-potential-simulations
#9
Ian S Cloudsdale, John K Dickson, Thomas E Barta, Brian S Grella, Emilie D Smith, John L Kulp, Frank Guarnieri, John L Kulp
We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development...
May 19, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28598377/3d-pharmacophore-based-virtual-screening-and-docking-approaches-toward-the-discovery-of-novel-hppd-inhibitors
#10
Ying Fu, Yi-Na Sun, Ke-Han Yi, Ming-Qiang Li, Hai-Feng Cao, Jia-Zhong Li, Fei Ye
p-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking-based virtual screening were performed to identify novel potential HPPD inhibitors. The complex-based pharmacophore model (CBP) with 0.721 of ROC used for screening compounds showed remarkable ability to retrieve known active ligands from among decoy molecules...
June 9, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28593808/polymorphism-rs2073618-of-the-osteoprotegerin-gene-as-a-potential-marker-of-subclinical-carotid-atherosclerosis-in-caucasians-with-type-2-diabetes-mellitus
#11
Aleš Pleskovič, Sara Mankoč Ramuš, Zala Jenko Pražnikar, Marija Šantl Letonja, Andreja Cokan Vujkovac, Katarina Gazdikova, Martin Caprnda, Ludovit Gaspar, Peter Kruzliak, Daniel Petrovič
BACKGROUND: The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor κB ligand/receptor-activator of nuclear factor κB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: 595 subjects with T2DM were enrolled in the cross-sectional study...
June 8, 2017: VASA. Zeitschrift Für Gefässkrankheiten
https://www.readbyqxmd.com/read/28585620/-treatment-of-bone-metastases-bisphosphonates-and-denosumab
#12
László Landherr, Tamás Nagykálnai
Some disseminated tumor cells (as "seeds") feel well in the skeletal tissue, as a "soil", but the humoral crosstalk between tumor cells and bone cells disrupts the normal bone homeostasis (remodeling), which leads to a vicious circle, the multiple bone metastatic disease. The tumor cells could stimulate bone resorption, bone neo-formation or both, characteristic of the primary tumor. This usually incurable condition involves serious consequences, as fractures, pain, surgeries, irradiations, plegias, hypercalcemia, etc...
June 6, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28577080/receptor-activator-of-nuclear-factor-kappa-b-rank-expression-in-primary-breast-cancer-correlates-with-recurrence-free-survival-and-development-of-bone-metastases-in-i-spy1-calgb-150007-150012-acrin-6657
#13
Neelima Vidula, Christina Yau, Jiali Li, Laura J Esserman, Hope S Rugo
PURPOSE: The receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis may contribute to the development of bone metastases (BM). We studied gene expression in this pathway in primary breast cancer (BC) to determine correlations with clinical characteristics and outcomes in the neoadjuvant I-SPY1 study. METHODS: We evaluated RANK/RANKL/OPG expression using expression microarrays in I-SPY1 (n = 149). Associations with clinical features were determined using t test and ANOVA...
June 2, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28576140/rank-rankl-opg-system-in-the-intervertebral-disc
#14
Norihiko Takegami, Koji Akeda, Junichi Yamada, Tomohiko Sano, Koichiro Murata, Jenny Huang, Koichi Masuda, Akihiro Sudo
BACKGROUND: The receptor activator of NF-κB ligand (RANKL), a member of the TNF ligand superfamily, is known to regulate bone metabolism. The expression of each component of the RANK/RANKL/osteoprotegerin (OPG) system in the intervertebral disc (IVD) has not been examined in detail. The purposes of this study were to examine the expression of the RANK/RANKL/OPG system and to evaluate the function of RANKL in the matrix metabolism of the rat IVD. METHODS: Sprague-Dawley, 12-week-old, male rats were used in this study...
June 2, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28575868/increased-breast-tissue-receptor-activator-of-nuclear-factor-%C3%AE%C2%BAb-ligand-rankl-gene-expression-is-associated-with-higher-mammographic-density-in-premenopausal-women
#15
Adetunji T Toriola, Ha X Dang, Ian S Hagemann, Catherine M Appleton, Graham A Colditz, Jingqin Luo, Christopher A Maher
Increased mammographic breast density is associated with a 4-6-fold increased risk of breast cancer, yet lifestyle factors that can reduce dense breasts are yet to be identified, and viable prevention strategies to reduce breast density-associated breast cancer development are yet to be developed. We investigated the associations of breast tissue receptor activator of nuclear factor-κB (RANK) pathway gene expression with mammographic density in 48 premenopausal women, with no previous history of cancer. Gene expression levels were measured in total RNA isolated from formalin-fixed paraffin-embedded breast tissue samples, using the NanoString nCounter platform...
May 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28565907/thermodynamic-characterization-of-hydration-sites-from-integral-equation-derived-free-energy-densities-application-to-protein-binding-sites-and-ligand-series
#16
Stefan Güssregen, Hans Matter, Gerhard Hessler, Evanthia Lionta, Jochen Heil, Stefan M Kast
Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design...
June 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28555225/bar-based-optimum-adaptive-sampling-regime-for-variance-minimization-in-alchemical-transformation
#17
Zhao X Sun, Xiao H Wang, John Z H Zhang
The efficiency of alchemical free energy simulations with the staging strategy is improved by adaptively manipulating the significance of each ensemble followed by importance sampling. The OBAR (optimum BAR) method introduced in this work with explicit consideration of the statistical inefficiency in each ensemble outperforms the traditional equal time rule which is used in standard applications of alchemical transformation with the window sampling regime in the sense of minimizing the total variance of the free energy estimate...
June 14, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28552987/contribution-of-systemic-and-somatic-factors-to-clinical-response-and-resistance-to-pd-l1-blockade-in-urothelial-cancer-an-exploratory-multi-omic-analysis
#18
Alexandra Snyder, Tavi Nathanson, Samuel A Funt, Arun Ahuja, Jacqueline Buros Novik, Matthew D Hellmann, Eliza Chang, Bulent Arman Aksoy, Hikmat Al-Ahmadie, Erik Yusko, Marissa Vignali, Sharon Benzeno, Mariel Boyd, Meredith Moran, Gopa Iyer, Harlan S Robins, Elaine R Mardis, Taha Merghoub, Jeff Hammerbacher, Jonathan E Rosenberg, Dean F Bajorin
BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance...
May 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28540603/positioning-novel-biologicals-in-ckd-mineral-and-bone-disorders
#19
REVIEW
Lida Tartaglione, Marzia Pasquali, Silverio Rotondi, Maria Luisa Muci, Adrian Covic, Sandro Mazzaferro
Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality. Aging people, frequently identified as early CKD, could suffer from either the classical age-related osteoporosis (OP) or ROD. Distinguishing between these two bone diseases may not be easy without bone biopsy...
May 24, 2017: Journal of Nephrology
https://www.readbyqxmd.com/read/28540505/retrospective-evaluation-of-serum-ctx-levels-after-denosumab-discontinuation-in-patients-with-or-without-prior-exposure-to-bisphosphonates
#20
B Uebelhart, R Rizzoli, S L Ferrari
Discontinuation of denosumab (Dmab) therapy is associated with lower serum CTX levels in osteoporotic patients previously exposed to bisphosphonates compared to those who were not. INTRODUCTION: Discontinuation of Dmab therapy is followed by a transient increase of bone turnover markers (BTMs) above pretreatment values, together with accelerated bone loss, and potentially an increased risk of multiple vertebral fractures. Since a substantial proportion of patients discontinuing Dmab have previously been exposed to bisphosphonates (BPs), we hypothesized that previous BP therapy could attenuate this increase in bone turnover because of the prolonged biological effects of BPs on bone...
May 24, 2017: Osteoporosis International
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