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Annas Al-Sharea, Andrew J Murphy, L A Huggins, Y Hu, Ira J Goldberg, Prabhakara R Nagareddy
BACKGROUND AND AIMS: Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia...
March 2, 2018: Atherosclerosis
Thomas N Wight
The content of proteoglycans (PGs) is low in the extracellular matrix (ECM) of vascular tissue, but increases dramatically in all phases of vascular disease. Early studies demonstrated that glycosaminoglycans (GAGs) including chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and heparan sulfate (HS) accumulate in vascular lesions in both humans and in animal models in areas of the vasculature that are susceptible to disease initiation (such as at branch points) and are frequently coincident with lipid deposits...
February 27, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Giuseppe Condomitti, Joris de Wit
Neural circuits consist of distinct neuronal cell types connected in specific patterns. The specificity of these connections is achieved in a series of sequential developmental steps that involve the targeting of neurites, the identification of synaptic partners, and the formation of specific types of synapses. Cell-surface proteins play a critical role in each of these steps. The heparan sulfate proteoglycan (HSPG) family of cell-surface proteins is emerging as a key regulator of connectivity. HSPGs are expressed throughout brain development and play important roles in axon guidance, synapse development and synapse function...
2018: Frontiers in Molecular Neuroscience
Charmaine J Simeonovic, Sarah K Popp, Lora M Starrs, Debra J Brown, Andrew F Ziolkowski, Barbara Ludwig, Stefan R Bornstein, J Dennis Wilson, Alberto Pugliese, Thomas W H Kay, Helen E Thomas, Thomas Loudovaris, Fui Jiun Choong, Craig Freeman, Christopher R Parish
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage...
2018: PloS One
Galina M Kazanskaya, Alexandra Y Tsidulko, Alexander M Volkov, Roman S Kiselev, Anastasia V Suhovskih, Vyacheslav V Kobozev, Alexei S Gaytan, Svetlana V Aidagulova, Alexei L Krivoshapkin, Elvira V Grigorieva
Glycosaminoglycans are major components of brain extracellular matrix (ECM), although heparan sulfate (HS) contribution in brain physiology and carcinogenesis remains underinvestigated. This study examined HS content and distribution in glioblastoma multiforme (GBM) tissues in the context of potential molecular mechanisms underlying its deregulation in brain tumours. Totally, 42 tissue samples and paraffin-embedded tissues for 31 patients with different prognosis were investigated. HS expression was demonstrated in 50-55% of the GBM tumours by immunohistochemistry (IHC), while almost no HS content was detected in the surrounding paratumourous brain tissues...
January 10, 2018: Histochemistry and Cell Biology
James S Findlay, Graham P Cook, G Eric Blair
It has been proposed that blood coagulation factors, principally factor X (FX), enhance the uptake of human adenovirus type 5 (Ad5) into cultured epithelial cells by bridging the viral hexon capsid protein and cell-surface heparan sulphate proteoglycans (HSPGs). We studied the effects of FX on Ad transduction of lymphoid cell lines (NK92MI, a natural killer cell line; Daudi, a B-cell line and Jurkat, a T-cell line) as well as primary peripheral blood lymphocytes (PBL) and HeLa epithelial cells using either replication-deficient Ad5, or a derivative in which the Ad5 fiber was replaced with that of another Ad type, Ad35, termed Ad5F35...
January 3, 2018: Viruses
Valeria Cagno, Patrizia Andreozzi, Marco D'Alicarnasso, Paulo Jacob Silva, Marie Mueller, Marie Galloux, Ronan Le Goffic, Samuel T Jones, Marta Vallino, Jan Hodek, Jan Weber, Soumyo Sen, Emma-Rose Janeček, Ahmet Bekdemir, Barbara Sanavio, Chiara Martinelli, Manuela Donalisio, Marie-Anne Rameix Welti, Jean-Francois Eleouet, Yanxiao Han, Laurent Kaiser, Lela Vukovic, Caroline Tapparel, Petr Král, Silke Krol, David Lembo, Francesco Stellacci
Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them...
December 18, 2017: Nature Materials
Rhonda C Kines, Isabella Varsavsky, Sanghamitra Choudhary, Debaditya Bhattacharya, Sean Spring, Roger J McLaughlin, Shin J Kang, Hans E Grossniklaus, Demitrios G Vavvas, Stephen Monks, John R MacDougall, Elisabet de Los Pinos, John T Schiller
The work outlined herein describes AU-011, a novel recombinant papillomavirus-like particle (VLP) drug conjugate and its initial evaluation as a potential treatment for primary uveal melanoma. The VLP is conjugated with a phthalocyanine photosensitizer, IRDye 700DX, that exerts its cytotoxic effect through photo-activation with a near-infrared laser. We assessed the anti-cancer properties of AU-011 in vitro utilizing a panel of human cancer cell lines and in vivo using murine subcutaneous and rabbit orthotopic xenograft models of uveal melanoma...
December 14, 2017: Molecular Cancer Therapeutics
Solomon A Agere, Eugene Y Kim, Nahid Akhtar, Salahuddin Ahmed
Syndecans (SDCs) are a family of heparan sulfate proteoglycans (HSPGs) glycoproteins ubiquitously expressed on the cell surfaces and extracellular matrix of all mammalian tissues. There are four mammalian syndecans, SDC-1 thorough 4, which play a critical role in cell adhesion, migration, proliferation, differentiation, and angiogenesis through independent and growth factor mediated signaling. An altered expression of SDCs is often observed in autoimmune disorders, cancer, HIV infection, and many other pathological conditions...
December 11, 2017: Journal of Cellular Physiology
Zemin Ren, Harmen van Andel, Wim de Lau, Robin B Hartholt, Madelon M Maurice, Hans Clevers, Marie José Kersten, Marcel Spaargaren, Steven T Pals
Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate (HS) proteoglycan syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its HS chains...
March 1, 2018: Blood
Elena I Leonova, Elena S Sadovnikova, Elvira R Shaykhutdinova, Oxana V Galzitskaya, Arkady N Murashev, Alexandr S Solonin
Background: Heparan sulfate proteoglycan (HSPG) syndecan-1 (Sdc1) acts as a receptor for triglyceride-rich lipoproteins (TRLs), growth factors, chemokines and enzymes. Due to the disordered structure, its function is as diverse as its ligands. In this paper, we have analyzed hepatic and aortic arch expression of Sdc1 in ApoE(-/-) mice and examined their association with biochemical changes in plasma during the atheroma formation. Methods: ApoE knockout (ApoE(-/-)) mice as a model of atherosclerosis were used...
2017: Open Biochemistry Journal
Mary L Dear, Jarrod Shilts, Kendal Broadie
Matrix metalloproteinase (MMP) functions modulate synapse formation and activity-dependent plasticity. Aberrant MMP activity is implicated in fragile X syndrome (FXS), a disease caused by the loss of the RNA-binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling and that synaptogenic defects in the fly model of FXS are alleviated by either inhibition of Mmp or genetic reduction of Dlp...
November 7, 2017: Science Signaling
Chieh Yu, Lyn R Griffiths, Larisa M Haupt
Unspecialized, self-renewing stem cells have extraordinary application to regenerative medicine due to their multilineage differentiation potential. Stem cell therapies through replenishing damaged or lost cells in the injured area is an attractive treatment of brain trauma and neurodegenerative neurological disorders. Several stem cell types have neurogenic potential including neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs). Currently, effective use of these cells is limited by our lack of understanding and ability to direct lineage commitment and differentiation of neural lineages...
2017: Frontiers in Integrative Neuroscience
Michael K E Schäfer, Irmgard Tegeder
Traumatic injury of the central nervous system is one of the leading causes of death and disability in young adults. Failure of regeneration is caused by autonomous neuronal obstacles and by formation of the glial scar, which is essential to seal the injury but also constitutes a barrier for regrowing axons. The scar center is highly inflammatory and populated by NG2+ glia, whereas astrocytes form the sealing border and trap regrowing axons, suggesting that the non-permissive environment of activated astrocytes and extracellular matrix components is one of the reasons for the regenerative failure...
October 17, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
Iwao Takahashi, Shuhei Yamada, Koji Nata
Heparan sulfate proteoglycans (HSPGs) comprise a core protein to which extracellular glycosaminoglycan chains are attached. Syndecan-4, one of the major HS-containing core proteins, is distributed on the cell surface, where they interact with various protein ligands and regulate a wide range of biological activities. Here, we propose that the core protein of HSPGs is involved in the insulin secretory response. To investigate the participation of HSPGs in the insulin-secretion mechanism, MIN6 cells, a mouse pancreatic β-cell line, were subcloned...
October 16, 2017: Molecular and Cellular Endocrinology
Satoshi Aoki, Akiko Saito-Hakoda, Takeo Yoshikawa, Kyoko Shimizu, Kiyomi Kisu, Susumu Suzuki, Kiyoshi Takagi, Shuji Mizumoto, Shuhei Yamada, Toin H van Kuppevelt, Atsushi Yokoyama, Taiji Matsusaka, Hiroshi Sato, Sadayoshi Ito, Akira Sugawara
Background: Heparan sulphate proteoglycan (HSPG) is present in the glomerular basement membrane (GBM) and is thought to play a major role in the glomerular charge barrier. Reductions and structural alterations of HSPG are observed in different types of kidney diseases accompanied by proteinuria. However, their causal relations remain unknown. Methods: We generated podocyte-specific exostosin-like 3 gene (Extl3) knockout mice (Extl3KO) using a Cre-loxP recombination approach...
January 1, 2018: Nephrology, Dialysis, Transplantation
Amy Pei-Ling Chiu, Denise Bierende, Nathaniel Lal, Fulong Wang, Andrea Wan, Israel Vlodavsky, Bahira Hussein, Brian Rodriges
In the diabetic heart, there is excessive dependence on FA utilization to generate ATP. Lipoprotein lipase (LPL)-mediated hydrolysis of circulating triglyceride (TG) is suggested to be the predominant source of FA for cardiac utilization during diabetes. In the heart, majority of LPL is synthesized in cardiomyocytes, and secreted onto cell surface heparan sulfate proteoglycans (HSPG), where an endothelial cell (EC) releasable β-endoglycosidase, heparanase, cleaves the side chains of HSPG to liberate LPL for its onward movement across the EC...
October 6, 2017: American Journal of Physiology. Heart and Circulatory Physiology
Anissa Kempf, Enrica Boda, Jessica C F Kwok, Rafael Fritz, Valentina Grande, Andrea M Kaelin, Zorica Ristic, Andre Schmandke, Antonio Schmandke, Bjoern Tews, James W Fawcett, Olivier Pertz, Annalisa Buffo, Martin E Schwab
Heparan sulfate proteoglycans (HSPGs) critically modulate adhesion-, growth-, and migration-related processes. Here, we show that the transmembrane protein, Nogo-A, inhibits neurite outgrowth and cell spreading in neurons and Nogo-A-responsive cell lines via HSPGs. The extracellular, active 180 amino acid Nogo-A region, named Nogo-A-Δ20, binds to heparin and brain-derived heparan sulfate glycosaminoglycans (GAGs) but not to the closely related chondroitin sulfate GAGs. HSPGs are required for Nogo-A-Δ20-induced inhibition of adhesion, cell spreading, and neurite outgrowth, as well as for RhoA activation...
October 9, 2017: Developmental Cell
Amy R Poe, Lingfeng Tang, Bei Wang, Yun Li, Maria L Sapar, Chun Han
Neurons sometimes completely fill available space in their receptive fields with evenly spaced dendrites to uniformly sample sensory or synaptic information. The mechanisms that enable neurons to sense and innervate all space in their target tissues are poorly understood. Using Drosophila somatosensory neurons as a model, we show that heparan sulfate proteoglycans (HSPGs) Dally and Syndecan on the surface of epidermal cells act as local permissive signals for the dendritic growth and maintenance of space-filling nociceptive C4da neurons, allowing them to innervate the entire skin...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
Argyris Spyrou, Soumi Kundu, Lulu Haseeb, Di Yu, Tommie Olofsson, Keith Dredge, Edward Hammond, Uri Barash, Israel Vlodavsky, Karin Forsberg-Nilsson
Curative therapy for medulloblastoma and other pediatric embryonal brain tumors has improved, but the outcome still remains poor and current treatment causes long-term complications. Malignant brain tumors infiltrate the healthy brain tissue and, thus despite resection, cells that have already migrated cause rapid tumor regrowth. Heparan sulfate proteoglycans (HSPG), major components of the extracellular matrix (ECM), modulate the activities of a variety of proteins. The major enzyme that degrades HS, heparanase (HPSE), is an important regulator of the ECM...
August 2017: Molecular Cancer Therapeutics
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