Journal articles: 'Ligand-trap'

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Kreutzkamp, Barbara. "„ligand trap“ als neue Therapieoption." InFo Onkologie 21, no. 4 (May 2018): 42. http://dx.doi.org/10.1007/s15004-018-6108-2.

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RAMESH, Vasudevan, and Tom BROWN. "1H-NMR characterization of l-tryptophan binding to TRAP, the trp RNA-binding attenuation protein of Bacillus subtilis." Biochemical Journal 315, no. 3 (May 1, 1996): 895–900. http://dx.doi.org/10.1042/bj3150895.

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A 1H-NMR study of the binding of L-tryptophan to the trp RNA-binding attenuation protein of Bacillus subtilis (TRAP), an ondecamer (91.6 kDa), has been implemented. The assignment of the aromatic indole ring proton resonances of the bound tryptophan ligand has been successfully carried out by two-dimensional chemical exchange experiments. The observation of only a single set of chemical shifts of the bound ligand demonstrates that the tryptophan binding site is identical in all the 11 subunits of the protein. Further, the large change in ligand chemical shifts suggests that the conformation of tryptophan ligand undergoes a significant rearrangement after complex formation with TRAP. This is further substantiated by the extensive ligand-induced chemical shift changes observed to the protein resonances and identification of several strong ligand–protein intermolecular nuclear Overhauser effects. A correlation of these preliminary NMR data with the X-ray crystal structure of the TRAP–tryptophan complex also suggests, tentatively, that the observed changes to the NMR spectra of the protein might correspond to changes associated with residues surrounding the tryptophan binding pocket owing to complex formation.

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Jahn, Olaf, Jelena Radulovic, Oliver Stiedl, Hossein Tezval, Klaus Eckart, and Joachim Spiess. "Corticotropin-Releasing Factor Binding Protein - A Ligand Trap?" Mini-Reviews in Medicinal Chemistry 5, no. 10 (October 1, 2005): 953–60. http://dx.doi.org/10.2174/138955705774329500.

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Malay, Ali D., Masahiro Watanabe, Jonathan G. Heddle, and Jeremy R. H. Tame. "Crystal structure of unliganded TRAP: implications for dynamic allostery." Biochemical Journal 434, no. 3 (February 24, 2011): 427–34. http://dx.doi.org/10.1042/bj20101813.

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Allostery is vital to the function of many proteins. In some cases, rather than a direct steric effect, mutual modulation of ligand binding at spatially separated sites may be achieved through a change in protein dynamics. Thus changes in vibrational modes of the protein, rather than conformational changes, allow different ligand sites to communicate. Evidence for such an effect has been found in TRAP (trp RNA-binding attenuation protein), a regulatory protein found in species of Bacillus. TRAP is part of a feedback system to modulate expression of the trp operon, which carries genes involved in tryptophan synthesis. Negative feedback is thought to depend on binding of tryptophan-bound, but not unbound, TRAP to a specific mRNA leader sequence. We find that, contrary to expectations, at low temperatures TRAP is able to bind RNA in the absence of tryptophan, and that this effect is particularly strong in the case of Bacillus stearothermophilus TRAP. We have solved the crystal structure of this protein with no tryptophan bound, and find that much of the structure shows little deviation from the tryptophan-bound form. These data support the idea that tryptophan may exert its effect on RNA binding by TRAP through dynamic and not structural changes, and that tryptophan binding may be mimicked by low temperature.

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Miao, Le-Ping, Qi Qi, Xiang-Bin Han, and Wen Zhang. "DCM self-trapping by the host deformation in flexible host–guest molecules." CrystEngComm 23, no. 23 (2021): 4136–42. http://dx.doi.org/10.1039/d1ce00301a.

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The desolvated structure can self-trap the DCM molecules to return to the 1·DCM state via ligand deformation even under weak host–guest interactions. The capture behavior of DCM is mostly due to the flexibility of the ligand.

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Tavakoli Dastjerdi, Hadi, Daniel Prochowicz, Pankaj Yadav, and Mohammad Mahdi Tavakoli. "Synergistic ligand exchange and UV curing of PbS quantum dots for effective surface passivation." Nanoscale 11, no. 47 (2019): 22832–40. http://dx.doi.org/10.1039/c9nr07854a.

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Gervasi, Christian F., Dmitry A. Kislitsyn, Thomas L. Allen, Jason D. Hackley, Ryuichiro Maruyama, and George V. Nazin. "Diversity of sub-bandgap states in lead-sulfide nanocrystals: real-space spectroscopy and mapping at the atomic-scale." Nanoscale 7, no. 46 (2015): 19732–42. http://dx.doi.org/10.1039/c5nr05236j.

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Dundas, Kirsten, Melanie J. Shears, Yi Sun, Christine S. Hopp, Cecile Crosnier, Tom Metcalf, Gareth Girling, Photini Sinnis, Oliver Billker, and Gavin J. Wright. "Alpha-v–containing integrins are host receptors for the Plasmodium falciparum sporozoite surface protein, TRAP." Proceedings of the National Academy of Sciences 115, no. 17 (April 9, 2018): 4477–82. http://dx.doi.org/10.1073/pnas.1719660115.

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Malaria-causing Plasmodium sporozoites are deposited in the dermis by the bite of an infected mosquito and move by gliding motility to the liver where they invade and develop within host hepatocytes. Although extracellular interactions between Plasmodium sporozoite ligands and host receptors provide important guidance cues for productive infection and are good vaccine targets, these interactions remain largely uncharacterized. Thrombospondin-related anonymous protein (TRAP) is a parasite cell surface ligand that is essential for both gliding motility and invasion because it couples the extracellular binding of host receptors to the parasite cytoplasmic actinomyosin motor; however, the molecular nature of the host TRAP receptors is poorly defined. Here, we use a systematic extracellular protein interaction screening approach to identify the integrin αvβ3 as a directly interacting host receptor for Plasmodium falciparum TRAP. Biochemical characterization of the interaction suggests a two-site binding model, requiring contributions from both the von Willebrand factor A domain and the RGD motif of TRAP for integrin binding. We show that TRAP binding to cells is promoted in the presence of integrin-activating proadhesive Mn2+ ions, and that cells genetically targeted so that they lack cell surface expression of the integrin αv-subunit are no longer able to bind TRAP. P. falciparum sporozoites moved with greater speed in the dermis of Itgb3-deficient mice, suggesting that the interaction has a role in sporozoite migration. The identification of the integrin αvβ3 as the host receptor for TRAP provides an important demonstration of a sporozoite surface ligand that directly interacts with host receptors.

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Bartual-Murgui, C., S. Vela, O. Roubeau, and G. Aromí. "Designed intramolecular blocking of the spin crossover of an Fe(ii) complex." Dalton Transactions 45, no. 36 (2016): 14058–62. http://dx.doi.org/10.1039/c6dt03047e.

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Ghosh, Ashta Chandra, Jakob Klaus Reinhardt, Markus Karl Kindermann, and Carola Schulzke. "The ring opening reaction of 1,3-dithiol-2-one systems is fully reversible." Chem. Commun. 50, no. 70 (2014): 10102–4. http://dx.doi.org/10.1039/c4cc04414b.

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The deprotection of a common precursor moiety in dithiolene chemistry was discovered to be fully reversible, which, besides being relevant for researchers working in very different fields with these non-innocent ligand systems, may even have an impact on CO₂ housekeeping, as the deprotected ligand acts as an efficient trap.

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Fukushima, H., E. Jimi, H. Kajiya, W. Motokawa, and K. Okabe. "Parathyroid-hormone-related Protein Induces Expression of Receptor Activator of NF-κB Ligand in Human Periodontal Ligament Cells via a cAMP/Protein Kinase A-independent Pathway." Journal of Dental Research 84, no. 4 (April 2005): 329–34. http://dx.doi.org/10.1177/154405910508400407.

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Periodontal ligament (PDL) cells play important roles in root resorption of human deciduous teeth by odontoclasts (osteoclast-like cells). However, it is unclear how PDL cells regulate osteoclastogenesis. We examined the effects of PTHrP, TGF-β, and EGF, which are all secreted by the tooth germ, on tartrate-resistant acid-phosphatase-positive (TRAP+) cell formation using co-cultures of human PDL cells and mouse spleen cells. Only PTHrP promoted TRAP+ cell formation in co-cultures. PTHrP induced receptor activator of NF-κB ligand (RANKL) mRNA expression and slightly reduced osteoprotegerin (OPG) expression in PDL cells. The cAMP/PKA inhibitors Rp-cAMP, H89, and PKI did not affect PTHrP-induced TRAP+ cell formation. The PKC inhibitor, Ro-32-0432, suppressed RANKL expression in PDL cells and PTHrP-induced TRAP+ cell formation. However, this inhibitor directly modulated the number of osteoclast precursors. Thus, PTHrP induces osteoclastogenesis by increasing the relative expression level of RANKL vs. OPG in PDL cells via a cAMP/PKA-independent pathway. Abbreviations: PTHrP, parathyroid-hormone-related protein; TGF-β, transforming growth factor-β; EGF, epidermal growth factor; RANKL, receptor activator of NF-κB ligand; OPG, osteoprotegerin; PDL, periodontal ligament; TRAP, tartrate-resistant acid phosphatase; PKA, protein kinase A; PKC, protein kinase C; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; cAMP, cyclic Adenosine 3′5′-Monophosphate.

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12

Tesfamariam, B. "Thrombin receptor-mediated vascular relaxation differentiated by a receptor antagonist and desensitization." American Journal of Physiology-Heart and Circulatory Physiology 267, no. 5 (November 1, 1994): H1962—H1967. http://dx.doi.org/10.1152/ajpheart.1994.267.5.h1962.

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The vasorelaxant actions of the serine protease, alpha-thrombin, are selectively blocked by the thrombin active site inhibitors, suggesting that proteolytic cleavage is required for alpha-thrombin-induced release of nitric oxide. Whether these relaxations are caused by interaction with a thrombin receptor was evaluated using a prototype thrombin receptor antagonist, a decapeptide analogue of the tethered ligand thrombin receptor [3-mercapto-propionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-amide (c186–65)]. In rings of pig coronary arteries with endothelium contracted submaximally with U-46619, the relaxation caused by extremely low concentrations of alpha-thrombin were mimicked by the synthetic thrombin receptor-activating peptide (TRAP-7: SFLLRNP). These relaxations were inhibited by C186–65. In contrast, C186–65 had no effect on the relaxations caused by bradykinin and serotonin. Exposure of arteries to alpha-thrombin or TRAP-7 caused heterologous desensitization to subsequent stimulation by alpha-thrombin or TRAP-7 but not by bradykinin. These studies support the hypothesis that alpha-thrombin-induced endothelium-dependent relaxations occur by activation of the cloned “tethered-ligand” thrombin receptor in vascular endothelium.

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13

Jang, Jun Young, and Se Won Suh. "Structure of STM3169, a tripartite ATP-independent periplasmic transporter." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1653. http://dx.doi.org/10.1107/s2053273314083466.

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Substrate-binding proteins (SBPs) form a group of proteins that are commonly related to membrane protein complexes for transport or cell signal transduction. SBPs are comprised of prokaryotic ATP-binding cassette (ABC)-transporters, prokaryotic tripartite ATP-independent periplasmic (TRAP)-transporters, prokaryotic two-component regulatory systems, eukaryotic guanylatecyclase-atrial natriuretic peptide receptors, G-protein coupled receptors (GPCRs) and ligand-gated ion channels (Berntsson et al., 2010).The TRAP transporters are less known as compared with ABC transporters but are ubiquitous in prokaryotes. The TRAP transporters are important elements of solute uptake systems in prokaryotes. These transporters contain two membrane protein components, predicted to have four and twelve transmembrane helices, respectively. In the TRAP transporters of DctP-type, substrate recognition is mediated through a well-conserved and specific arginine/carboxylate interaction in the SBP (Mulligan et al., 2011). Here we have determined the crystal structure of the TRAP transporter from Salmonella entericaserovarTyphimurium. Unexpectedly, this structure shows that various ligands can bind to the TRAP transporters. It provides insights into substrate binding mechanism in the TRAP transporter system.

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14

Suragani, Rajasekhar N. V. S., Sharon M. Cawley, Robert Li, Samantha Wallner, Mark J. Alexander, Aaron W. Mulivor, Sara Gardenghi, et al. "Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia." Blood 123, no. 25 (June 19, 2014): 3864–72. http://dx.doi.org/10.1182/blood-2013-06-511238.

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Key Points Modified ActRIIB ligand trap promotes terminal erythroid differentiation and mitigates ineffective erythropoiesis in murine β-thalassemia. This agent reduces anemia, α-globin aggregates, hemolysis, and disease complications such as iron overload, splenomegaly, and bone defects.

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15

Cole, P. "Dalantercept. ALK-1 ligand trap, Angiogenesis inhibitor, treatment of solid tumors." Drugs of the Future 40, no. 10 (2015): 633. http://dx.doi.org/10.1358/dof.2015.040.10.2386993.

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Yung, Lai-Ming, Ivana Nikolic, Samuel D. Paskin-Flerlage, R. Scott Pearsall, Ravindra Kumar, and Paul B. Yu. "A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension." American Journal of Respiratory and Critical Care Medicine 194, no. 9 (November 2016): 1140–51. http://dx.doi.org/10.1164/rccm.201510-1955oc.

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17

Sun, Bin, Maral Vafaie, Larissa Levina, Mingyang Wei, Yitong Dong, Yajun Gao, Hao Ting Kung, et al. "Ligand-Assisted Reconstruction of Colloidal Quantum Dots Decreases Trap State Density." Nano Letters 20, no. 5 (March 31, 2020): 3694–702. http://dx.doi.org/10.1021/acs.nanolett.0c00638.

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18

Graf, Daniel, Ulf Korthäuer, Hans W. Mages, Gabriele Senger, and Richard A. Kroczek. "Cloning of TRAP, a ligand for CD40 on human T cells." European Journal of Immunology 22, no. 12 (December 1992): 3191–94. http://dx.doi.org/10.1002/eji.1830221226.

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19

Liu, Yun, Karthik Tiruthani, Menglin Wang, Xuefei Zhou, Nasha Qiu, Yang Xiong, Chad V. Pecot, Rihe Liu, and Leaf Huang. "Tumor-targeted gene therapy with lipid nanoparticles inhibits tumor-associated adipocytes and remodels the immunosuppressive tumor microenvironment in triple-negative breast cancer." Nanoscale Horizons 6, no. 4 (2021): 319–29. http://dx.doi.org/10.1039/d0nh00588f.

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In breast cancer model, we identified C–C Motif Chemokine Ligand 2 (CCL2) as the key mediator which is secreted by tumor associated adipocytes, and developed targeted lipid-protamine-DNA (LPD) nanoparticles to locally “trap” CCL2 to ameliorate the immunosuppressive tumor microenvironment.

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Tay, J. Y. Y., B. H. Bay, J. F. Yeo, M. Harris, S. Meghji, and S. T. Dheen. "Identification of RANKL in Osteolytic Lesions of the Facial Skeleton." Journal of Dental Research 83, no. 4 (April 2004): 349–53. http://dx.doi.org/10.1177/154405910408300415.

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RANKL (receptor activator of nuclear factor κB ligand) promotes osteoclast differentiation, stimulates osteoclast activity, and prolongs osteoclast survival and adherence to bone. Abnormalities of the RANKL/RANK/osteoprotegerin system have been implicated in a range of diseases, including osteoporosis. To date, no work has been done in osteolytic lesions of the facial skeleton. In this study, specimens of ameloblastomas, dentigerous cysts, odontogenic keratocysts, and radicular cysts were subjected to immunohistochemical analysis for RANKL and tartrate-resistant acid phosphatase (TRAP). Immunofluorescence staining for TRAP was visualized under confocal microscopy. All specimens demonstrated distinct positive immunoreactivity to RANKL and TRAP. The TRAP-positive cells also stained with in situ hybridization for human calcitonin receptor, a definitive marker for osteoclasts. Mononuclear pre-osteoclasts were observed to migrate from blood to the connective tissue stroma and multinucleate toward the bone surface. It can be concluded that RANKL plays a role in bone resorption in osteolytic lesions of the facial skeleton.

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Jethwaney, Deepa, Timothy Lepore, Saria Hassan, Kerrianne Mello, Radha Rangarajan, Willi Jahnen-Dechent, Dyann Wirth, and Ali A. Sultan. "Fetuin-A, a Hepatocyte-Specific Protein That Binds Plasmodium berghei Thrombospondin-Related Adhesive Protein: a Potential Role in Infectivity." Infection and Immunity 73, no. 9 (September 2005): 5883–91. http://dx.doi.org/10.1128/iai.73.9.5883-5891.2005.

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ABSTRACT Malaria infection is initiated when the insect vector injects Plasmodium sporozoites into a susceptible vertebrate host. Sporozoites rapidly leave the circulatory system to invade hepatocytes, where further development generates the parasite form that invades and multiplies within erythrocytes. Previous experiments have shown that the thrombospondin-related adhesive protein (TRAP) plays an important role in sporozoite infectivity for hepatocytes. TRAP, a typical type-1 transmembrane protein, has a long extracellular region, which contains two adhesive domains, an A-domain and a thrombospondin repeat. We have generated recombinant proteins of the TRAP adhesive domains. These TRAP fragments show direct interaction with hepatocytes and inhibit sporozoite invasion in vitro. When the recombinant TRAP A-domain was used for immunoprecipitation against hepatocyte membrane fractions, it bound to α2-Heremans-Schmid glycoprotein/fetuin-A, a hepatocyte-specific protein associated with the extracellular matrix. When the soluble sporozoite protein fraction was immunoprecipitated on a fetuin-A-adsorbed protein A column, TRAP bound this ligand. Importantly, anti-fetuin-A antibodies inhibited invasion of hepatocytes by sporozoites. Further, onset of malaria infection was delayed in fetuin-A-deficient mice compared to that in wild-type C57BL/6 mice when they were challenged with Plasmodium berghei sporozoites. These data demonstrate that the extracellular region of TRAP interacts with fetuin-A on hepatocyte membranes and that this interaction enhances the parasite's ability to invade hepatocytes.

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Cyraniak, Adrianna, and Marcin Czapla. "Tripodal Podand Ligand with a Superhalogen Nature as an Effective Molecular Trap." Symmetry 12, no. 9 (September 1, 2020): 1441. http://dx.doi.org/10.3390/sym12091441.

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Tris(2-methoxyethyl) fluoroborate anion (TMEFA), anovel tripodal ligand based on the BF4− superhalogen anion, is proposed and was investigated theoretically using ab initio MP2 (second-order Møller-Plesset perturbational method) and OVGF (outer valence Green function) methods. The studied molecule comprises three 2-methoxyethoxy groups (-O-CH2-CH2-O-CH3) connected to a central boron atom, which results in the C3-symmetry of the compound. The resulting anion was stable against fragmentation processes and its vertical electron detachment energy was found to be 5.72 eV. Due to its equilibrium structure resembling that of classical tripodal podands, the [F-B(O-CH2-CH2-O-CH3)3]− anion is capable of binding metal cations using its three arms, and thus may form strongly bound ionic complexes such as [F-B(O-CH2-CH2-O-CH3)3]−/Li+ and [F-B(O-CH2-CH2-O-CH3)3]−/Mg2+. The binding energies predicted for such compounds far exceed those of the similar neutral classical podand ligands, which likely makes the [F-B(O-CH2-CH2-O-CH3)3]− system a more effective molecular trap or steric shielding agent with respect to selected metal cations.

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Jin, Pei, Juan Zhang, Malgorzata Beryt, Lisa Turin, Cathleen Brdlik, Ying Feng, Xiaomei Bai, Jim Liu, Brett Jorgensen, and H. Michael Shepard. "Rational Optimization of a Bispecific Ligand Trap Targeting EGF Receptor Family Ligands." Molecular Medicine 15, no. 1-2 (January 2009): 11–20. http://dx.doi.org/10.2119/molmed.2008.00103.

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24

Dussiot, Michael, Thiago T. Maciel, Aurélie Fricot, Céline Chartier, Olivier Negre, Joel Veiga, Damien Grapton, et al. "An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia." Nature Medicine 20, no. 4 (March 23, 2014): 398–407. http://dx.doi.org/10.1038/nm.3468.

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Kretzer, Balázs, Bálint Kiss, Hedvig Tordai, Gabriella Csík, Levente Herényi, and Miklós Kellermayer. "Single-Molecule Mechanics in Ligand Concentration Gradient." Micromachines 11, no. 2 (February 19, 2020): 212. http://dx.doi.org/10.3390/mi11020212.

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Single-molecule experiments provide unique insights into the mechanisms of biomolecular phenomena. However, because varying the concentration of a solute usually requires the exchange of the entire solution around the molecule, ligand-concentration-dependent measurements on the same molecule pose a challenge. In the present work we exploited the fact that a diffusion-dependent concentration gradient arises in a laminar-flow microfluidic device, which may be utilized for controlling the concentration of the ligand that the mechanically manipulated single molecule is exposed to. We tested this experimental approach by exposing a λ-phage dsDNA molecule, held with a double-trap optical tweezers instrument, to diffusionally-controlled concentrations of SYTOX Orange (SxO) and tetrakis(4-N-methyl)pyridyl-porphyrin (TMPYP). We demonstrate that the experimental design allows access to transient-kinetic, equilibrium and ligand-concentration-dependent mechanical experiments on the very same single molecule.

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Kim, Woon-Ki, Ok-Joo Sul, Eun-Kyung Choi, Mi-Hyun Lee, Choon-Soo Jeong, Hyun-Ju Kim, Shin-Yoon Kim, Jae-Hee Suh, Rina Yu, and Hye-Seon Choi. "Absence of Herpes Virus Entry Mediator (HVEM) Increases Bone Mass by Attenuating Receptor Activator of Nuclear Factor-κB ligand (RANKL)-Induced Osteoclastogenesis." Endocrinology 153, no. 10 (October 1, 2012): 4808–17. http://dx.doi.org/10.1210/en.2012-1079.

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Abstract Herpes virus entry mediator (HVEM), which is constitutively expressed at a high level on myeloid lineage cells, is also expressed on bone marrow-derived macrophages, suggesting that it may play a role in bone metabolism by affecting osteoclasts (OC) derived from bone marrow-derived macrophages. To address this question, we evaluated bone mass by micro-computed tomography and the number and activity of OC by tartrate-resistant acid phosphatase (TRAP) and pit formation on dentine slices, comparing HVEM-knockout mice with wild-type mice. The absence of HVEM led to a higher bone mass and to decreased levels of serum collagen type I fragments and serum TRACP5b in vivo. In vitro HVEM deficiency resulted in a reduced number and activity of OC and an impaired receptor activator of nuclear factor-κB ligand signaling through reduced activation of nuclear factor-κB and of nuclear factor of activated T-cells cytoplasmic 1. Exogenous soluble HVEM decreased expression of TRAP, whereas soluble LIGHT (a ligand of HVEM) increased it, indicating the occurrence of a positive signaling through HVEM during osteoclastogenesis. Our findings indicate that HVEM regulates bone remodeling via action on OC. The higher bone mass in the femurs of HVEM-knockout mice could be, at least in part, due to attenuated osteoclastogenesis and bone resorption resulting from decreased receptor activator of nuclear factor-κB ligand signaling in the OC.

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Yang, Ji Yeong, Shin-Hye Kim, HanGyeol Lee, Kwang-Sik Lee, Seung-Yeob Song, Mi Ja Lee, Hyun Young Kim, et al. "Oat Seedlings Extract Inhibits RANKL-Induced c-Fos/NFATc1 Transcription Factors in the Early Stage of Osteoclast Differentiation." Evidence-Based Complementary and Alternative Medicine 2022 (September 23, 2022): 1–10. http://dx.doi.org/10.1155/2022/5372459.

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Osteoporosis is a common disease that increases the risk of fractures due to decreased bone density and weakens the bone microstructure. Preventing and diagnosing osteoporosis using the available drugs can be a costly affair with possible side effects. Therefore, natural product-derived therapeutics are promising alternatives. Our study demonstrated that the oat seedlings’ extract (OSE) inhibited the receptor activator of the nuclear factor κB ligand (RANKL)-induced osteoclastogenesis from the bone marrow-derived macrophages (BMMs). The OSE treatment significantly attenuated the RANKL-mediated induction of the tartrate-resistant acid phosphatase (TRAP) activity as well as the number of TRAP-positive (TRAP+) multinucleated cells (MNCs) counted through the TRAP staining in a dose-dependent manner. It was also confirmed that the OSE suppressed the formation of the TRAP + MNCs in the early stage of differentiation and not in the middle and late stages. The results of the real-time quantitative polymerase chain reaction (qPCR) and the western blotting showed that the OSE dramatically inhibited the mRNA and protein expressions of the osteoclastogenesis-mediated transcription factors such as the c-Fos and the nuclear factor-activated T cells c1 (NFATc1). In addition, the OSE strongly attenuated the mRNA induction of the c-Fos/NFATc1-dependent molecules such as the TRAP, the osteoclast-associatedimmunoglobulin-like receptor (OSCAR), the dendritic cell-specific transmembrane protein (DC-STAMP), and the cathepsin K. These results suggest that the naturally derived OSE may be useful for preventing bone diseases.

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Koppensteiner, Renate, Alexandra Kaider, Beate Eichelberger, Christine Mannhalter, Simon Panzer, and Thomas Gremmel. "Impact of variables of the P-selectin – P-selectin glycoprotein ligand-1 axis on leukocyte-platelet interactions in cardiovascular disease." Thrombosis and Haemostasis 113, no. 04 (July 2015): 806–12. http://dx.doi.org/10.1160/th14-08-0690.

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SummaryThe formation of leukocyte-platelet aggregates (LPA), through the P-selectin – P-selectin glycoprotein ligand (PSGL)-1 axis, plays a pivotal role in atherothrombosis. In order to investigate the influence of platelet (pP-selectin) and soluble P-selectin (sP-selectin), and of variations in the genes encoding for P-selectin (SELP) and PSGL-1 (SELPLG) on LPA formation, we assessed monocyte (MPA)- and neutrophil-platelet aggregates (NPA) as well as pP-selectin by flow cytometry in 263 patients undergoing angioplasty and stenting. sP-selectin was determined by ELISA, the SELP Pro715 allele and the SELPLG Ile62 allele were determined by allele specific PCR. The Pro715 allele was significantly associated with lower levels of in vivo pP-selectin and sP-selectin, while agonists´ inducible pP-selectin was not influenced by the Pro715 allele. PP-selectin was significantly associated with MPA and NPA formation. The in vivo formation of MPA and NPA depended to 19 % and 7.4 %, respectively, on in vivo pP-selectin, irrespective of the Pro715 allele and the Ile62 allele carrier status. TRAP-6 inducible MPA and NPA depended to 34 % and 27 %, respectively, on TRAP-6 inducible pP-selectin, but were independent of the Pro715 allele carrier status. Carriers of the Ile62 allele showed a stronger correlation between TRAP-6 inducible pP-selectin and TRAP-6 inducible MPA/NPA than non-carriers. Furthermore, TRAP-6 inducible NPA were higher in Ile62 allele carriers, which suggests higher thrombin sensitivity. In conclusion, our findings point to the significant role of pP-selectin for MPA and NPA formation, while other variables like sP-selectin, the SELP Pro715 allele and the SELPLG Ile62 allele have less influence.

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SCHANG, GAUTHIER GS, EMILIE BRÛLÉ, JEAN-FRANÇOIS DENIS, MATHILDE POUJOL DE MOLLIENS, CRISTINA CHAUVET, VANNAKAMBADI GANESH, JULIA SCHOELERMANN, GILLES TREMBLAY, ILIA TIKHOMIROV, and MAUREEN O'CONNOR. "HS135: NOVEL ACTIVIN AND GDF LIGAND TRAP FOR TREATMENT OF PULMONARY HYPERTENSION (PH)." Chest 162, no. 4 (October 2022): A2365—A2366. http://dx.doi.org/10.1016/j.chest.2022.08.1947.

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Rose, Jason J., Kaitlin A. Bocian, Qinzi Xu, Ling Wang, Anthony W. DeMartino, Xiukai Chen, Catherine G. Corey, et al. "A neuroglobin-based high-affinity ligand trap reverses carbon monoxide–induced mitochondrial poisoning." Journal of Biological Chemistry 295, no. 19 (March 23, 2020): 6357–71. http://dx.doi.org/10.1074/jbc.ra119.010593.

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Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

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Azarov, I., L. Wang, J. J. Rose, Q. Xu, X. N. Huang, A. Belanger, Y. Wang, et al. "Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning." Science Translational Medicine 8, no. 368 (December 7, 2016): 368ra173. http://dx.doi.org/10.1126/scitranslmed.aah6571.

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Feigenson, Marina, Remya Nathan, Keith Babbs, Christopher Materna, Claire C. Tseng, Ffolliott Fisher, Jasbir Seehra, and Jenn Lachey. "Ker-050, a Modified Actriia Ligand Trap, Alleviates Cytopenia Arising from Multiple Etiologies." Blood 136, Supplement 1 (November 5, 2020): 38. http://dx.doi.org/10.1182/blood-2020-140167.

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Hemopoietic system control the production of circulating blood cells that have important functions from transport of oxygen and carbon dioxide, blood clotting to fighting infections. Not surprisingly, the system is tightly regulated and failure to replenish RBC can result in anemia and inadequate platelets increases the risk of bleeding. Impaired hematopoiesis and the consequential cytopenias are associated with aging, diseases characterized by ineffective hematopoiesis including myelodysplastic syndrome (MDS) and myelofibrosis and diseases that lead to loss of growth factors. A therapeutic that could act more globally on the hematopoietic pathway would have the potential to overcome cytopenia in many diseases. Signaling of the TGFβ superfamily regulates several stages of RBC maturation, and recent studies demonstrate that inhibition of TGFβ signaling can induce RBC production and increase circulating RBCs, HGB, and hematocrit (HCT). KER-050, a modified ActRIIA ligand trap, has been shown to increase RBCs in rodents and non-human primates, and to increase both RBCs and PLTs in healthy human volunteers. In the current studies, we aimed to test the efficacy of KER-050 in alleviating cytopenias caused by multiple conditions and to further delineate the effect of KER-050 on platelets. First, we examined whether RKER-050 (a research form of KER-050) can reverse anemia associated with aging and frailty. After 6 weeks of twice weekly treatment, 2-year-old aged, vehicle-treated (AV) mice had significantly lower RBCs, HGB, and HCT (-14.0%, -13.5%, -10.9%, respectively) relative to 11-week-old young vehicle-treated mice (YV). However, aged mice treated with RKER-050 had higher RBCs, HGB, and HCT (+12.3%, +10.0%, +9.1%, respectively) compared to AV, with levels indistinguishable from those of YV. These data support that RKER-050 can improve anemia that arises from aging. Next, we evaluated the efficacy of RKER-050 in the treatment of anemia in an animal model of MDS. NUP98-HOXD13 mice, a murine model of MDS, aged to 6 months and confirmed as anemic prior to treatment, were dosed twice weekly with either vehicle or RKER-050 for 6 weeks. Over this treatment period, vehicle-treated MDS mice continued to have significantly reduced RBCs, HGB, and HCT compared to wildtype controls. In contrast, RKER-050-treated MDS mice had increases in RBCs, HGB, and HCT (+10.9%, +11.2%, + 9.8%, respectively), achieving values comparable to the wild type control animal of the same age. These data support that RKER-050 reverses anemia in a mouse model of MDS. Finally, we evaluated whether RKER-050 can improve anemia after acute blood loss. Anemia was induced by bleeding 20% of total blood volume in Sprague Dawley rats followed by treatment with RKER-050 twice weekly. After phlebotomy, the RKER-050-treated group had early, robust increases in both RBCs and HGB that exceeded baseline levels, whereas decreased RBCs and HGB in the vehicle-treated group persisted longer. Moreover, while vehicle PLTs were unchanged over the study, RKER-050 treatment resulted in an increase in PLT count at Day 3 post-phlebotomy which remained elevated at Day 6. These data suggest that in cases of acute bleeding, RKER-050 not only rapidly increases RBCs but also PLTs, potentially demonstrating a pancytopenic effect of RKER-050. Our data suggest that RKER-050 is a fast-acting modulator of RBC maturation that rapidly increases RBCs, HGB, and HCT. The increases were observed in aged mice showing signs of age-associated anemia, as well as in mice with chronic conditions such as MDS. Moreover, RKER-050 showed rapid recovery in a model of acute bleeding with an effect on both erythropoiesis and thrombopoiesis. These results suggest that KER-050 could be developed for the treatment of anemias and potentially other cytopenias, including thrombocytopenia, arising from a variety of causes. Disclosures Feigenson: Keros Therapeutics: Current Employment. Nathan:Keros Therapeutics: Current Employment. Babbs:Keros Therapeutics: Current Employment. Materna:Keros Therapeutics: Current Employment. Tseng:Mitobridge: Current equity holder in private company; Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Fisher:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

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Miller, Brian R., Maureen Powers, Minkyu Park, Wolfgang Fischer, and Douglass J. Forbes. "Identification of a New Vertebrate Nucleoporin, Nup188, with the Use of a Novel Organelle Trap Assay." Molecular Biology of the Cell 11, no. 10 (October 2000): 3381–96. http://dx.doi.org/10.1091/mbc.11.10.3381.

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The study of the nuclear pore in vertebrates would benefit from a strategy to directly identify new nucleoporins and interactions between those nucleoporins. We have developed a novel two-step “organelle trap” assay involving affinity selection and in vitro pore assembly. In the first step, soluble proteins derived from Xenopusegg extracts are applied to a column containing a ligand of interest. The bound proteins are then tagged by biotinylation and eluted. In the second step, potential nucleoporins are selected for by virtue of their ability to assemble into annulate lamellae, a cytoplasmic mimic of nuclear pores. The incorporated proteins are then recognized by their biotin tag. Here we use the lectin wheat germ agglutinin (WGA) as ligand; WGA inhibits nuclear transport and has been shown to directly bind three known nucleoporins from Xenopus extract, Nup62, Nup98, and Nup214, all of which containN-acetylglucosamine residues. Under reduced-stringency conditions, three additional proteins bind to WGA–Sepharose and are revealed by the organelle trap assay. We identified all three as partner nucleoporins. Two were discovered to be XenopusNup93 and Nup205. The third is a novel vertebrate nucleoporin, Nup188. This new vertebrate protein, Xenopus Nup188, exists in a complex with xNup93 and xNup205. The Nup93-Nup188-Nup205 complex does not bind directly to WGA but binds indirectly via theN-acetylglucosamine–modified nucleoporins. A gene encoding human Nup188 was also identified. The discovery of vertebrate Nup188, related to a yeast nucleoporin, and its novel protein–protein interactions illustrates the power of the two-step organelle trap assay and identifies new building blocks for constructing the nuclear pore.

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AKHOURI, Reetesh Raj, Arindam BHATTACHARYYA, Priyabrata PATTNAIK, Pawan MALHOTRA, and Amit SHARMA. "Structural and functional dissection of the adhesive domains of Plasmodium falciparum thrombospondin-related anonymous protein (TRAP)." Biochemical Journal 379, no. 3 (May 1, 2004): 815–22. http://dx.doi.org/10.1042/bj20031500.

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TRAP (thrombospondin-related anonymous protein) is a sporozoite surface protein that plays a central role in hepatocyte invasion. We have developed procedures for recombinant production of the entire ECD (extracellular domain) and A domain of TRAP using bacterial- and baculovirus-expression systems respectively. The ECD and A domain were purified to homogeneity and migrated on gel-filtration columns as non-aggregated, monomeric proteins. These adhesive modules bound to HepG2 cells in a dose-dependent and bivalent cation-independent manner. The binding of ECD and the A domain to HepG2 cells was inhibited poorly by an excess of sulphatide analogues, suggesting the presence of as yet unidentified receptors for the A domain on hepatocytes. Using surface-plasmon-resonance-based sensor technology (Biacore), we demonstrate that TRAP ECD has higher affinity for heparin (KD=40 nM) compared with the A domain (KD=79 nM). We also present a three-dimensional structure of the A domain based on the crystal structure of the homologous von Willebrand factor A1 domain. The TRAP A domain shows two spatially distinct ligand-binding surfaces. One surface on the A domain contains the MIDAS (metal-ion-dependent adhesion site) motif, where point mutations of Thr131 and Asp162 correlate with impairment of cell infectivity by sporozoites. The other surface contains a putative heparin-binding site and consists of a basic residue cluster. Our studies suggest that TRAP interacts with multiple receptors during the hepatocyte invasion process. Our results also pave the way for inclusion of these high-quality recombinant TRAP domains in subunit-based vaccines against malaria.

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Tracey, Jayne, Michael Recht, Laura DeCastro, Christine Rinder, Colleen McHugh, Brian Smith, and Henry Rinder. "Differences in Platelet α-granule Release between Normals and Immune Thrombocytopenic Patients and between Young and Old Platelets." Thrombosis and Haemostasis 80, no. 09 (1998): 457–62. http://dx.doi.org/10.1055/s-0037-1615229.

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SummaryThe risk of serious bleeding in patients with immune thrombocytopenic purpura (ITP) appears to be less than in comparably thrombocytopenic patients with megakaryocytic hypoplasia. It has been proposed that this difference is due to enhanced hemostatic activity of young platelets, which are increased in the circulation during ITP. We examined α-granule release in reticulated platelets (RP), which are thought to be the youngest circulating platelets, and in older non-reticulated platelets (non-RP) in normal human controls and ITP patients. Normal controls had a mean RP of 7%, compared with 42% in ITP patients. The mean concentration of thrombin receptor agonist peptide (TRAP) causing 50% of control RP to express CD62P (EC50) was 0.82 ± 0.08 μM (SEM), significantly higher than the TRAP CD62P EC50 for RP in ITP, 0.57 ± 0.06 uM (p = 0.04). Similarly, the TRAP EC 50 for non-RP in controls, 0.84 ± 0.09 μM, was significantly higher than in ITP, 0.56 ± 0.07 μM (p = 0.03), suggesting that all platelets in ITP have an enhanced α-granule threshold response to TRAP compared with controls, while RP and older platelets within each patient group have similar threshold sensitivities to TRAP. By contrast, high-dose TRAP caused RP to express twice as much mean and total CD62P as non-RP in both ITP patients and controls (p <0.05 for both comparisons). We conclude that compared with controls, all platelets in ITP are primed to undergo α-granule release to TRAP, while in both ITP and controls, the newly circulating, reticulated platelets have the potential to contribute greater amounts of CD62P surface ligand compared with older platelets (non-RP) after stimulation. Both the increased RP% and enhanced platelet response to agonist in ITP may contribute to maintenance of hemostasis despite thrombocytopenia.

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Han, Sang-Yong, and Yun-Kyung Kim. "Yukmijihwang-Tang Suppresses Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-Induced Osteoclast Differentiation and Prevents Ovariectomy (OVX)-Mediated Bone Loss." Molecules 26, no. 24 (December 14, 2021): 7579. http://dx.doi.org/10.3390/molecules26247579.

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Yukmijihwang-tang (YJ) has been used to treat diabetes mellitus, renal disorders, and cognitive impairment in traditional medicine. This study aimed to evaluate the anti-osteoporotic effect of YJ on ovariectomy (OVX)-induced bone loss in a rat and receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs). YJ reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) in an osteoclast/osteoblast co-culture system by regulating the ratio of RANKL/osteoprotegerin (OPG) by osteoblasts. Overall, YJ reduced TRAP-positive cell formation and TRAP activity and F-actin ring formation. Analysis of the underlying mechanisms indicated that YJ inhibited the activation of the nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and c-Fos, resulting in the suppression of osteoclast differentiation-related genes such as TRAP, ATPase, H+ transporting, lysosomal 38 kDa, V0 subunit d2, osteoclast-associated receptor, osteoclast-stimulatory transmembrane protein, dendritic cell-specific transmembrane protein, matrix metalloproteinase-9, cathepsin K, and calcitonin receptor. YJ also inhibited the nuclear translocation of NFATc1. Additionally, YJ markedly inhibited RANKL-induced phosphorylation of signaling pathways activated in the early stages of osteoclast differentiation including the p38, JNK, ERK, and NF-κB. Consistent with these in vitro results, the YJ-administered group showed considerably attenuated bone loss in the OVX-mediated rat model. These results provide promising evidence for the potential novel therapeutic application of YJ for bone diseases such as osteoporosis.

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Maulu, Alberto, Juan Navarro-Arenas, Pedro Rodríguez-Cantó, Juan Sánchez-Royo, Rafael Abargues, Isaac Suárez, and Juan Martínez-Pastor. "Charge Transport in Trap-Sensitized Infrared PbS Quantum-Dot-Based Photoconductors: Pros and Cons." Nanomaterials 8, no. 9 (August 30, 2018): 677. http://dx.doi.org/10.3390/nano8090677.

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Control of quantum-dot (QD) surface chemistry offers a direct approach for the tuning of charge-carrier dynamics in photoconductors based on strongly coupled QD solids. We investigate the effects of altering the surface chemistry of PbS QDs in such QD solids via ligand exchange using 3-mercaptopropionic acid (MPA) and tetrabutylammonium iodide (TBAI). The roll-to-roll compatible doctor-blade technique was used for the fabrication of the QD solid films as the photoactive component in photoconductors and field-effect phototransistors. The ligand exchange of the QD solid film with MPA yields superior device performance with higher photosensitivity and detectivity, which is due to less dark current and lower noise level as compared to ligand exchange with TBAI. In both cases, the mechanism responsible for photoconductivity is related to trap sensitization of the QD solid, in which traps are responsible of high photoconductive gain values, but slow response times under very low incident optical power (<1 pW). At medium–high incident optical powers (>100 pW), where traps are filled, both MPA- and TBAI-treated photodevices exhibit similar behavior, characterized by lower responsivity and faster response time, as limited by the mobility in the QD solid.

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Ham, Ju, Ra-Yeong Choi, Hae-In Lee, and Mi-Kyung Lee. "Methoxsalen and Bergapten Prevent Diabetes-Induced Osteoporosis by the Suppression of Osteoclastogenic Gene Expression in Mice." International Journal of Molecular Sciences 20, no. 6 (March 14, 2019): 1298. http://dx.doi.org/10.3390/ijms20061298.

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This study evaluated whether bergapten and methoxsalen could prevent diabetes-induced osteoporosis and its underlying mechanism. For 10 weeks, bergapten or methoxsalen (0.02%, w/w) was applied to diabetic mice that were provided with a high-fat diet and streptozotocin. Bone mineral density (BMD) and microarchitecture quality were significantly reduced in the diabetic control group; however, both bergapten and methoxsalen reversed serum osteocalcin, bone-alkaline phosphatase and femur BMD. These coumarin derivatives significantly increased bone volume density and trabecular number, whereas they decreased the structure model index of femur tissue in diabetic mice. Conversely, tartrate-resistant acid phosphatase 5 (TRAP) staining revealed that these derivatives reduced osteoclast numbers and formation in diabetic bone tissue. Additionally, both bergapten and methoxsalen tended to downregulate the expression of osteoclast-related genes such as receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear of activated T-cells, cytoplasmic 1 (NFATc1) and TRAP in diabetic femurs, with NFATc1 and TRAP expression showing significant reductions. Our data suggest that both bergapten and methoxsalen prevent diabetic osteoporosis by suppressing bone resorption.

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Pérez-Otero, Yolanda, M. Isabel Fernández-García, Esther Gómez-Fórneas, Gustavo González-Riopedre, and Marcelino Maneiro. "Mimicking Peroxidase Activity by a Manganese(II) Complex Involving a New Asymmetric Tetradentate Ligand Containing Both Amino and Imino Groups." Journal of Chemistry 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/963152.

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The asymmetric ligand (E)-4-bromo-2-(((2-((5-bromo-2-hydroxybenzyl)(methyl)amino)ethyl)imino)methyl)phenol has been prepared by a novel seven-step route. All organic compounds isolated in each step have been characterised by elemental analysis, infrared and1H NMR spectroscopy, and mass spectrometry. Interaction of this ligand with manganese has been investigated employing an electrochemical method. This method leads to the formation of a neutral manganese(II) complex7in high yield and purity. The complex has been thoroughly characterised by elemental analysis, infrared spectroscopy, mass spectrometry, magnetic susceptibility measurements, and cyclic voltammetry. Complex7behaves as peroxidase mimic in the presence of the water-soluble trap ABTS, probably due to its ease to coordinate the substrate molecule.

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Malek, Mehnaz, Carla Heise, Rajesh Chopra, Tom O. Daniel, and Victoria Sung. "Sotatercept, An Activin Receptor-2a Ligand Trap, Modulates Hepcidin Levels In Primary Human Hepatocytes." Blood 122, no. 21 (November 15, 2013): 3441. http://dx.doi.org/10.1182/blood.v122.21.3441.3441.

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Abstract Sotatercept, a recombinant human fusion protein containing the extracellular domain of ActRIIA binds to and inhibits activin and other members of the TGFß superfamily to induce a rapid increase in red cell number and hemoglobin. We sought to investigate if RAP-011, the murine ortholog of sotatercept, might regulate iron availability, which is important for erythropoiesis, through modulating hepcidin levels. Hepcidin is a circulating peptide hormone that negatively regulates iron transport into the plasma membrane by binding the iron transporter, ferroportin, and causing degradation of the complex. Hepcidin is primarily secreted by hepatocytes and also by hematopoietic cells, macrophages, kidney, heart, pancreas, and adipose cells (Gantz, T., Blood, 2003). The hepcidin promoter can be activated by both SMAD-4 and STAT-3, downstream targets of BMP-6 and IL-6 respectively (Andriopoulos Jr, B., Nature Genetics, 2009). BMP-6 binds its receptor, triggering downstream SMAD-1/5/8 signaling leading to SMAD-4 activation and initiation of HAMP (the gene encoding hepcidin) transcription. SMAD-4 signaling is also implicated in STAT-3 activation of HAMP transcription downstream of inflammatory signals such as IL-6 (Wang, R.H., Cell Metabolism, 2005). In the current study, we evaluated the effect of RAP-011 on hepcidin expression and regulation in primary human hepatocytes. Consistent with its role as an activin receptor ligand trap, RAP-011 reduced baseline p-SMAD 1/5/8 expression and subsequently decreased HAMP expression. Next, we asked whether RAP-011 could also decrease HAMP expression under conditions of exogenous BMP-6 stimulation. When hepatocytes were treated with 50 ng BMP-6, an approximately 50-fold induction of HAMP was observed; interestingly, RAP-011 treatment decreased this induction by half. Similarly, treatment of the hepatocytes with the inflammatory cytokine IL-6 led to nearly a 7-fold induction of HAMP which was reduced to baseline levels following the addition of RAP-011. Hepcidin protein levels, although much more variable, mirrored that of HAMP expression following BMP-6 and combined BMP-6 + RAP-011 treatment. Protein changes following IL-6 stimulation were less apparent; this may be due to the fact that the peak of IL-6-stimulated HAMP expression occurred earlier than the 48 hours post-treatment at which the protein was assayed. Our data demonstrate that RAP-011 can modulate SMAD signaling and HAMP expression in primary human hepatocytes and suggests that RAP-011 may allow for increased iron availability for erythropoiesis. Importantly, RAP-011 was able to rescue IL-6-induced HAMP expression, suggesting that the drug might be able to restore iron availability in antinflammatory environment. Anemia of inflammation is associated with diseases such as renal, Castleman’s, and Rheumatoid arthritis. Hepcidin has been shown to play a role in restricting iron and promoting anemia in these pathologies (Steinbicker, A.U., Blood, 2011). In summary, RAP-011, through a yet unknown mechanism, may help to regulate iron availability by regulating hepcidin in pathological situations such as inflammation, iron restriction, or stress erythropoiesis. Disclosures: Malek: Celgene Corp.: Employment. Heise:Celgene: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Daniel:Celgene Corp.: Employment, Equity Ownership. Sung:Celgene Corp.: Employment, Equity Ownership.

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Graf, Daniel, Sabine Müller, Ulf Korthäuer, Cees van Kooten, Christoph Weise, and Richard A. Kroczek. "A soluble form of TRAP (CD40 ligand) is rapidly released after T cell activation." European Journal of Immunology 25, no. 6 (June 1995): 1749–54. http://dx.doi.org/10.1002/eji.1830250639.

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Langdon, Jacqueline M., Sangjucta Barkataki, Alan E. Berger, Chris Cheadle, Qian-Li Xue, Victoria Sung, and Cindy N. Roy. "RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice." American Journal of Hematology 90, no. 1 (October 25, 2014): 8–14. http://dx.doi.org/10.1002/ajh.23856.

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Clark, Daniel D. "Preliminary investigation of deoxyoligonucleotide binding to ribonuclease A using mass spectrometry: An attempt to develop a lab experience for undergraduates." F1000Research 7 (March 20, 2018): 340. http://dx.doi.org/10.12688/f1000research.14268.1.

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Deoxyoligonucleotide binding to bovine pancreatic ribonuclease A (RNase A) was investigated using electrospray ionization ion-trap mass spectrometry (ESI-IT-MS). Deoxyoligonucleotides included CCCCC (dC5) and CCACC (dC2AC2). This work was an attempt to develop a biochemistry lab experience that would introduce undergraduates to the use of mass spectrometry for the analysis of protein-ligand interactions. Titration experiments were performed using a fixed RNase A concentration and variable deoxyoligonucleotide concentrations. Samples at equilibrium were infused directly into the mass spectrometer under native conditions. For each deoxyoligonucleotide, mass spectra showed one-to-one binding stoichiometry, with marked increases in the total ion abundance of ligand-bound RNase A complexes as a function of concentration, but the accurate determination of dC5 and dC2AC2 dissociation constants was problematic.

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Clark, Daniel D. "Preliminary investigation of deoxyoligonucleotide binding to ribonuclease A using mass spectrometry: An attempt to develop a lab experience for undergraduates." F1000Research 7 (April 26, 2018): 340. http://dx.doi.org/10.12688/f1000research.14268.2.

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Deoxyoligonucleotide binding to bovine pancreatic ribonuclease A (RNase A) was investigated using electrospray ionization ion-trap mass spectrometry (ESI-IT-MS). Deoxyoligonucleotides included CCCCC (dC5) and CCACC (dC2AC2). This work was an attempt to develop a biochemistry lab experience that would introduce undergraduates to the use of mass spectrometry for the analysis of protein-ligand interactions. Titration experiments were performed using a fixed RNase A concentration and variable deoxyoligonucleotide concentrations. Samples at equilibrium were infused directly into the mass spectrometer under native conditions. For each deoxyoligonucleotide, mass spectra showed one-to-one binding stoichiometry, with marked increases in the total ion abundance of ligand-bound RNase A complexes as a function of concentration, but the accurate determination of dC5 and dC2AC2 dissociation constants was problematic.

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Lean, Jeny Maree, Karen Fuller, and Timothy John Chambers. "FLT3 ligand can substitute for macrophage colony-stimulating factor in support of osteoclast differentiation and function." Blood 98, no. 9 (November 1, 2001): 2707–13. http://dx.doi.org/10.1182/blood.v98.9.2707.

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Abstract Although bone resorption and osteoclast numbers are reduced in osteopetrotic (op/op) mice, osteoclasts are nevertheless present and functional, despite the absence of macrophage colony-stimulating factor (M-CSF). This suggests that alternative factors can partly compensate for the crucial actions of M-CSF in osteoclast induction. It was found that when nonadherent bone marrow cells were incubated in RANKL with Flt3 ligand (FL) without exogenous M-CSF, tartrate-resistance acid phosphatase (TRAP)–positive cells were formed, and bone resorption occurred. Without FL, only macrophagelike TRAP-negative cells were present. Granulocyte-macrophage CSF, stem cell factor, interleukin-3, and vascular endothelial growth factor could not similarly replace the need for M-CSF. TRAP-positive cell induction in FL was not due to synergy with M-CSF produced by the bone marrow cells themselves because FL also enabled their formation from the hemopoietic cells of op/op mice, which lack any M-CSF. FL appeared to substitute for M-CSF by supporting the differentiation of adherent cells that express mRNA for RANK and responsiveness to RANKL. To determine whether FL can account for the compensation for M-CSF deficiency that occurs in vivo, FL signaling was blockaded in op/op mice by the injection of soluble recombinant Flt3. It was found that the soluble receptor induced a substantial decrease in osteoclast number, strongly suggesting that FL is responsible for the partial compensation for M-CSF deficiency that occurs in these mice.

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Lee, Daye, Wan-Kyu Ko, Seong Jun Kim, In-Bo Han, Je Beom Hong, Seung Hun Sheen, and Seil Sohn. "Inhibitory Effects of Gold and Silver Nanoparticles on the Differentiation into Osteoclasts In Vitro." Pharmaceutics 13, no. 4 (March 29, 2021): 462. http://dx.doi.org/10.3390/pharmaceutics13040462.

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Gold nanoparticles (GNPs) have been widely studied to inhibit differentiation into osteoclasts. However, reports of the inhibitory effects of silver nanoparticles (SNPs) during the process of differentiation into osteoclasts are rare. We compared the inhibitory effect of GNPs and SNPs during the process of differentiation into osteoclasts. Bone marrow-derived cells were differentiated into osteoclasts by the receptor activator of the nuclear factor-kappa-Β ligand (RANKL). The inhibitory effect of GNPs or SNPs during the process of differentiation into osteoclasts was investigated using tartrate-resistant acid phosphatase (TRAP) and actin ring staining. The formation of TRAP positive (+) multinuclear cells (MNCs) with the actin ring structure was most inhibited in the SNP group. In addition, the expression of specific genes related to the differentiation into osteoclasts, such as c-Fos, the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), TRAP, and Cathepsin K (CTSK) were also inhibited in the SNP groups. As a result, the levels related to differentiation into osteoclasts were consistently lower in the SNP groups than in the GNP groups. Our study suggests that SNPs can be a useful material for inhibiting differentiation into osteoclasts and they can be applied to treatments for osteoporosis patients.

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Gu, Yanqing, Weimin Fan, and Guoyong Yin. "The Study of Mechanisms of Protective Effect of Rg1 against Arthritis by Inhibiting Osteoclast Differentiation and Maturation in CIA Mice." Mediators of Inflammation 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/305071.

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Ginsenoside Rg1 is a natural product extracted fromPanax ginsengC.A. Although Rg1 protects tissue structure and functions by inhibiting local inflammatory reaction, the mechanism remains poorly understood.In vitro, Rg1 dose-dependently inhibited TRAP activity in receptor activator of nuclear factor-κB ligand- (RANKL-) induced osteoclasts and decreased the number of osteoclasts and osteoclast resorption area. Rg1 also significantly inhibited the RANK signaling pathway, including suppressing the expression of Trap, cathepsin K, matrix metalloproteinase 9 (MMP9), and calcitonin receptor (CTR).In vivo, Rg1 dramatically decreased arthritis scores in CIA mice and effectively controlled symptoms of inflammatory arthritis. Pathologic analysis demonstrated that Rg1 significantly attenuated pathological changes in CIA mice. Pronounced reduction in synovial hyperplasia and inflammatory cell invasion were observed in CIA mice after Rg1 therapy. Alcian blue staining results illustrated that mice treated with Rg1 had significantly reduced destruction in the articular cartilage. TRAP and cathepsin K staining results demonstrated a significant reduction of numbers of OCs in the articular cartilage in proximal interphalangeal joints and ankle joints in Rg1-treated mice. In summary, this study revealed that Rg1 reduced the inflammatory destruction of periarticular bone by inhibiting differentiation and maturation of osteoclasts in CIA mice.

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Lozan, Vasile. "Stabilization of Unusual Substrate Coordination Modes in Dinuclear Macrocyclic Complexes." Chemistry Journal of Moldova 5, no. 1 (June 2010): 24–35. http://dx.doi.org/10.19261/cjm.2010.05(1).02.

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The steric protection offered by the macrobinucleating hexaazaditiophenolateligand (L) allows for the preparation of the first stable dinuclear nickel(II) borohydride bridged complex, which reacts rapidly with elemental sulphur producing a tetranuclear nickel(II) complex [{(L)Ni2}2(μ-S6)]2+ bearing a helical μ4-hexa- sulfide ligand. The [(L)CoII 2]2+ fragment have been able to trap a monomethyl orthomolybdate in the binding pocket. Unusual coordination modes of substrate in dinuclear macrocyclic compounds was demonstrated.

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Kim, Michael S., Christopher J. Day, and Nigel A. Morrison. "MCP-1 Is Induced by Receptor Activator of Nuclear Factor-κB Ligand, Promotes Human Osteoclast Fusion, and Rescues Granulocyte Macrophage Colony-stimulating Factor Suppression of Osteoclast Formation." Journal of Biological Chemistry 280, no. 16 (February 17, 2005): 16163–69. http://dx.doi.org/10.1074/jbc.m412713200.

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Abstract:

Human osteoclast formation from monocyte precursors under the action of receptor activator of nuclear factor-κB ligand (RANKL) was suppressed by granulocyte macrophage colony-stimulating factor (GM-CSF), with down-regulation of critical osteoclast-related nuclear factors. GM-CSF in the presence of RANKL and macrophage colony-stimulating factor resulted in mononuclear cells that were negative for tartrate-resistant acid phosphatase (TRAP) and negative for bone resorption. CD1a, a dendritic cell marker, was expressed in GM-CSF, RANKL, and macrophage colony-stimulating factor-treated cells and absent in osteoclasts. Microarray showed that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), was profoundly repressed by GM-CSF. Addition of MCP-1 reversed GM-CSF suppression of osteoclast formation, recovering the bone resorption phenotype. MCP-1 and chemokine RANTES (regulated on activation normal T cell expressed and secreted) permitted formation of TRAP-positive multinuclear cells in the absence of RANKL. However, these cells were negative for bone resorption. In the presence of RANKL, MCP-1 significantly increased the number of TRAP-positive multinuclear bone-resorbing osteoclasts (p= 0.008). When RANKL signaling through NFATc1 was blocked with cyclosporin A, both MCP-1 and RANTES expression was down-regulated. Furthermore, addition of MCP-1 and RANTES reversed the effects of cyclosporin A and recovered the TRAP-positive multinuclear cell phenotype. Our model suggests that RANKL-induced chemokines are involved in osteoclast differentiation at the stage of multinucleation of osteoclast precursors and provides a rationale for increased osteoclast activity in inflammatory conditions where chemokines are abundant.

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Xia, Hua, Xiaoyi Wang, and Yunhong Wang. "Three Azamacrocycle-Based Coordination Complexes Bearing a New Triazine Derived Carboxylic Ligand Via In Situ Ligand Hydrolysis: The Trap of Resonance Structure." Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry 46, no. 8 (March 16, 2016): 1212–19. http://dx.doi.org/10.1080/15533174.2015.1004450.

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Journal articles on the topic 'Ligand-trap'

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