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Jamie M O'Sullivan, Sonia Aguila, Emily McRae, Soracha E Ward, Orla Rawley, Padraic G Fallon, Teresa M Brophy, Roger J S Preston, Lauren Brady, Orla Sheils, Alain Chion, James S O'Donnell
BACKGROUND: Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. OBJECTIVE: To define the molecular mechanisms through which VWF N-glycan structures influence in vivo clearance. METHODS: Using a series of exoglycosidases, different pd-VWF glycoforms were generated...
October 12, 2016: Journal of Thrombosis and Haemostasis: JTH
Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk...
October 4, 2016: Journal of Clinical Investigation
Shuang Zhu, Soyoung Park, Yeseo Lim, Sunhye Shin, Sung Nim Han
BACKGROUND/OBJECTIVES: Consumption of pine nut oil (PNO) was shown to reduce weight gain and attenuate hepatic steatosis in mice fed a high-fat diet (HFD). The aim of this study was to examine the effects of PNO on both intestinal and hepatic lipid metabolism in mice fed control or HFD. MATERIALS/METHODS: Five-week-old C57BL/6 mice were fed control diets containing 10% energy fat from either Soybean Oil (SBO) or PNO, or HFD containing 15% energy fat from lard and 30% energy fat from SBO or PNO for 12 weeks...
October 2016: Nutrition Research and Practice
Jong Ah Kim, Tommaso Casalini, Davide Brambilla, Jean-Christophe Leroux
Interfering with the activity of β-secretase to reduce the production of Aβ peptides is a conceivable therapeutic strategy for Alzheimer's disease. However, the development of efficient yet safe inhibitors is hampered by secondary effects, usually linked to the indiscriminate inhibition of other substrates' processing by the targeted enzyme. Based on the spatial compartmentalization of the cleavage of the amyloid precursor protein by β-secretase, we hypothesized that by exploiting the endocytosis receptor low-density lipoprotein receptor-related protein it would be possible to direct an otherwise cell-impermeable inhibitor to the endosomes of neurons, boosting the drug's efficacy and importantly, sparing the off-target effects...
September 29, 2016: Scientific Reports
Rafael Escate, Teresa Padro, Maria Borrell-Pages, Rosa Suades, Rosa Aledo, Pedro Mata, Lina Badimon
Familial hypercholesterolaemia (FH) is a major risk for premature coronary heart disease due to severe long-life exposure to high LDL levels. Accumulation of LDL in the vascular wall triggers atherosclerosis with activation of the innate immunity system. Here, we have investigated (i) gene expression of LDLR and LRPs in peripheral blood cells (PBLs) and in differentiated macrophages of young FH-patients; and (ii) whether macrophage from FH patients have a differential response when exposed to high levels of atherogenic LDL...
September 29, 2016: Journal of Cellular and Molecular Medicine
K G F Gerritsen, N Bovenschen, T Q Nguyen, D Sprengers, M P Koeners, A N van Koppen, J A Joles, R Goldschmeding, R J Kok
CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min)...
September 19, 2016: Journal of Cell Communication and Signaling
Judicael G Fazavana, Vincent Muczynski, Valerie Proulle, Nikolett Wohner, Olivier D Christophe, Peter J Lenting, Cécile V Denis
BACKGROUND: Recent findings point to activated factor VII (FVIIa) being cleared predominantly (±65% of the injected protein) as part of a complex with the serpin antithrombin. FVIIa/antithrombin complexes are targeted to hepatocytes and liver macrophages. Both cells lines abundantly express LRP1, a scavenger-receptor mediating clearance of protease/serpin complexes. OBJECTIVES: To investigate whether the FVIIa/antithrombin complex is a ligand for LRP1. METHODS: Binding of FVIIa and pre-formed FVIIa/antithrombin complexes to purified LRP1-fragment Cluster-IV (sLRP1-cIV/Fc) and to human & murine macrophages was analyzed...
September 10, 2016: Journal of Thrombosis and Haemostasis: JTH
Christine M Doherty, Robert Visse, Deendayal Dinakarpandian, Dudley K Strickland, Hideaki Nagase, Linda Troeberg
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a central inhibitor of matrix-degrading and sheddase families of metalloproteinases. Extracellular levels of the inhibitor are regulated by the balance between its retention on the extracellular matrix and its endocytic clearance by the scavenger receptor low density lipoprotein receptor-related protein 1 (LRP1). Here, we used molecular modeling to predict TIMP-3 residues potentially involved in binding to LRP1 based on the proposed LRP1 binding motif of 2 lysine residues separated by about 21 Å and mutated the candidate lysine residues to alanine individually and in pairs...
October 14, 2016: Journal of Biological Chemistry
Dong-Chuan Guo, Megan L Grove, Siddharth K Prakash, Per Eriksson, Ellen M Hostetler, Scott A LeMaire, Simon C Body, Sherene Shalhub, Anthony L Estrera, Hazim J Safi, Ellen S Regalado, Wei Zhou, Michael R Mathis, Kim A Eagle, Bo Yang, Cristen J Willer, Eric Boerwinkle, Dianna M Milewicz
Acute aortic dissections are a preventable cause of sudden death if individuals at risk are identified and surgically repaired in a non-emergency setting. Although mutations in single genes can be used to identify at-risk individuals, the majority of dissection case subjects do not have evidence of a single gene disorder, but rather have the other major risk factor for dissections, hypertension. Initial genome-wide association studies (GWASs) identified SNPs at the FBN1 locus associated with both thoracic aortic aneurysms and dissections...
September 1, 2016: American Journal of Human Genetics
Emilia Laudati, Andrew S Gilder, Michael S Lam, Roberta Misasi, Maurizio Sorice, Steven L Gonias, Elisabetta Mantuano
LDL Receptor-related Protein-1 (LRP1) is an endocytic receptor for diverse ligands. In neurons and neuron-like cells, ligand-binding to LRP1 initiates cell-signaling. Herein, we show that in PC12 and N2a neuron-like cells, LRP1 distributes into lipid rafts and non-raft plasma membrane fractions. When lipid rafts were disrupted, using methyl-β-cyclodextrin or fumonisin B1, activation of Src family kinases and ERK1/2 by the LRP1 ligands, tissue-type plasminogen activator and activated α2-macroglobulin, was blocked...
October 2016: Molecular and Cellular Neurosciences
Yanlan Chen, Wen Huang, Wenlin Jiang, Xianghong Wu, Biao Ye, Xiaoting Zhou
HIV-1 transactivator protein (Tat) has been shown to play an important role in HIV-associated neurocognitive disorders. The aim of the present study was to evaluate the relationship between occludin and amyloid-beta (Aβ) transfer receptors in human cerebral microvascular endothelial cells (hCMEC/D3) in the context of HIV-1-related pathology. The protein expressions of occludin, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in hCMEC/D3 cells were examined using western blotting and immunofluorescent staining...
2016: Oxidative Medicine and Cellular Longevity
Tixieanna Dissmore, Cheikh I Seye, Denis M Medeiros, Gary A Weisman, Barry Bardford, Laman Mamedova
BACKGROUND AND AIMS: The internalization of aggregated low-density lipoproteins (agLDL) mediated by low-density lipoprotein receptor related protein (LRP1) may involve the actin cytoskeleton in ways that differ from the endocytosis of soluble LDL by the LDL receptor (LDLR). This study aims to define novel mechanisms of agLDL uptake through modulation of the actin cytoskeleton, to identify molecular targets involved in foam cell formation in vascular smooth muscle cells (VSMCs). The critical observation that formed the basis for these studies is that under pathophysiological conditions, nucleotide release from blood-derived and vascular cells activates SMC P2Y2 receptors (P2Y2Rs) leading to rearrangement of the actin cytoskeleton and cell motility...
September 2016: Atherosclerosis
B Shackleton, F Crawford, C Bachmeier
BACKGROUND: Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Aβ) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer's disease (AD). One of the receptors responsible for the transport of Aβ in the BBB is the low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at the cell surface, which prevents endocytic transport of ligands. Previously, we reported a strong inverse correlation between LRP1 shedding in the brain and Aβ transit across the BBB...
2016: Fluids and Barriers of the CNS
Hisham Qosa, Amal Kaddoumi
Novel animal models of Alzheimer's disease (AD) are relentlessly being developed and existing ones are being fine-tuned; however, these models face multiple challenges associated with the complexity of the disease where most of these models do not reproduce the full phenotypical disease spectrum. Moreover, different AD models express different phenotypes that could affect their validity to recapitulate disease pathogenesis and/or response to a drug. One of the most important and understudied differences between AD models is differences in the phenotypic characteristics of the background species...
April 2016: Journal of Systems and Integrative Neuroscience
Peter G W Gettins, Steven T Olson
Serpins are a widely distributed family of high molecular mass protein proteinase inhibitors that can inhibit both serine and cysteine proteinases by a remarkable mechanism-based kinetic trapping of an acyl or thioacyl enzyme intermediate that involves massive conformational transformation. The trapping is based on distortion of the proteinase in the complex, with energy derived from the unique metastability of the active serpin. Serpins are the favoured inhibitors for regulation of proteinases in complex proteolytic cascades, such as are involved in blood coagulation, fibrinolysis and complement activation, by virtue of the ability to modulate their specificity and reactivity...
August 1, 2016: Biochemical Journal
Edwin Hernandez-Garzón, Ana M Fernandez, Alberto Perez-Alvarez, Laura Genis, Pablo Bascuñana, Ruben Fernandez de la Rosa, Mercedes Delgado, Miguel Angel Pozo, Estefania Moreno, Peter J McCormick, Andrea Santi, Angel Trueba-Saiz, Cristina Garcia-Caceres, Matthias H Tschöp, Alfonso Araque, Eduardo D Martin, Ignacio Torres Aleman
Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side...
November 2016: Glia
Gregory M Vercellotti, Ping Zhang, Julia Nguyen, Fuad Abdulla, Chunsheng Chen, Phong Nguyen, Carlos Nowotny, Clifford J Steer, Ann Smith, John D Belcher
Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesize that in SCD mice, hepatic overexpression of hemopexin will scavenge the proximal mediator of vascular activation, heme, and will inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into Hpx(-/-) or Hpx(+/+) C57BL/6 mice. Dorsal skin fold chambers were implanted in week 13 post-transplant and microvascular stasis (% non-flowing venules) evaluated in response to heme infusion...
July 19, 2016: Molecular Medicine
Fernanda Craveiro Franco, Alessandro Arruda Alves, Fernanda Ribeiro Godoy, Juliana Boaventura Avelar, Douglas Dantas Rodrigues, Thays Millena Alves Pedroso, Aparecido Divino da Cruz, Fausto Nomura, Daniela de Melo E Silva
This is the first study demonstrating genotoxic effects and whole transcriptome analysis on community health agents (CHAs) occupationally exposed to pesticides in Central Brazil. For the transcriptome analysis, we found some genes related to Alzheimer's disease (LRP1), an insulin-like growth factor receptor (IGF2R), immunity genes (IGL family and IGJ), two genes related to inflammatory reaction (CXCL5 and CCL3), one gene related to maintenance of cellular morphology (NHS), one gene considered to be a strong apoptosis inductor (LGALS14), and several transcripts of the neuroblastoma breakpoint family (NBPF)...
October 2016: Environmental Science and Pollution Research International
Joni M Prasad, Patricia A Young, Dudley K Strickland
The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain...
August 26, 2016: Journal of Biological Chemistry
Tzu-Ying Chuang, Yong Guo, Scott M Seki, Abagail M Rosen, David M Johanson, James W Mandell, Claudia F Lucchinetti, Alban Gaultier
Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis...
2016: Acta Neuropathologica Communications
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