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Heparin and Related Molecules: Antiproliferative and Anti-Inflammatory Effects in the Airways
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Stephen A. Kilfeather, Clive Page
Excision of GAG from proteoglycan provides a route for generation of free GAG, while reduction of chain length by glycosidases could provide a route for removal of GAG activity in which chain length is crucial (see Figure 2). The similarity between GAG species provides a source of competition between GAGs for glycosidases. Both heparin and chondroitin sulphate exhibit potent inhibition of tumour-derived heparanase activity against heparan sulphate37–39 and, thereby, preserve heparan sulphate on HS proteoglycan in the presence of glycosidases (see Figure 2). Such an action could be exhibited by heparin released at high concentrations from mast cells at inflammatory sites.
Active Targeting Strategies in Cancer with a Focus on Potential Nanotechnology Applications
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
The RES is composed of a series of sentinel cells located in several highly perfused organs, including the liver and spleen.27 Nanoparticles can be rapidly cleared from the blood if they are recognized by RES cells in a non-selective fashion, typically before achievement of effective targeting.13,42 In some instances, this inherent targeting can provide a means to selectively delivery materials.43 In most cases, it is possible to modify the physical and chemical characteristics of nanoparticles to reduce their default uptake by the RES.44 Methods to avoid the RES will be addressed in depth in other chapters in this text. In general, these measures follow principles initially outlined in the development of stealth liposomes that provided a means of extending the circulating half-life of a nanoparticle. Although PEG molecules of various lengths coupled using various chemistries45 are frequently used in this approach, heparan sulfate glycosaminoglycans (HSGs) have also been shown to provide a protective coating that reduces immune detection.46 Interestingly, HSGs might be shed at tumors by tumor-associated heparanase activity.
Amyloidosis In Vivo: From Molecular Interactions to Therapeutic Targets
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
Further evidence that heparan sulfate plays a critical role in amyloidogenesis in vivo was obtained from transgenic animals that over express human heparanase (10). One would predict that if heparan sulfate is a critical factor in AA amyloidogenesis that such transgenic mice would be resistant to AA amyloid induction. The results with such animals using the rapid murine induction protocol were both surprising and satisfying. Such mice developed splenic amyloid as rapidly and quantitatively equal to the wild-type controls. However, within the time frame examined, they failed to deposit AA amyloid in kidneys and liver, sites occupied by easily demonstrable AA amyloid in controls. Additional studies illustrated, with Northern blotting and immunohistochemistry, that the transgene was not expressed to any significant degree in the spleens of such mice but was expressed in the kidneys and livers. Analysis of the size of HS in these tissues demonstrated that the HS was fragmented in the liver and kidneys but not the spleen.. Thus there is an excellent correlation between the expression of tissue heparanase and a failure of such tissue to deposit AA amyloid.
Heparanase Deficiency Is Associated with Disruption, Detachment, and Folding of the Retinal Pigment Epithelium
Published in Current Eye Research, 2021
Tine Van Bergen, Isabelle Etienne, Juan Jia, Jin-Ping Li, Israël Vlodavsky, Alan Stitt, Elke Vermassen, Jean H.M. Feyen
Heparanase is an endo-β-D-glucuronidase which degrades heparan sulphate. Under physiological conditions, low levels of expression are restricted to keratinocytes, trophoblast, platelets, mast cells and leukocytes1 and is mainly involved in tissue remodeling by liberating cytokines and heparin-binding growth factors that are sequestered within the extracellular matrix (ECM) and basement membrane (BM).2 In specific stress-conditions, heparanase is overexpressed by inflammatory and endothelial cells, contributing to disease progression by modulating the bioavailability of cytokines (e.g., IL-6, TNF-a), chemokines (e.g., MCP-1, CXCL1) and growth factors (e.g., VEGF) that are bound to heparan sulphate.3 This single gene-encoded enzyme is overexpressed in most human cancers, promoting tumor metastasis and angiogenesis.4,5 Since heparanase is described as key player in inflammatory processes,6 it can be a potential therapeutic target in some retinopathies where BM and ECM histopathology is observed, such as diabetic retinopathy (vascular BM) or age-related macular degeneration (Bruch’s membrane).7
New classes of potent heparanase inhibitors from ligand-based virtual screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Daniele Pala, Laura Scalvini, Gian Marco Elisi, Alessio Lodola, Marco Mor, Gilberto Spadoni, Fabiana F. Ferrara, Emiliano Pavoni, Giuseppe Roscilli, Ferdinando M. Milazzo, Gianfranco Battistuzzi, Silvia Rivara, Giuseppe Giannini
The endo-β-D-glucuronidase heparanase (EC 3.2.1.166) is responsible for the cleavage of HS. Heparanase is present in the intracellular compartment and in the extracellular space, where hydrolysis of HSPG side chains leads to the release of bioactive components and oligosaccharide cofactors required for cellular signalling (e.g. allowing the formation of fibroblast growth factor FGF:HS:FGF receptor heterotrimers). Heparanase also exerts non-enzymatic activities which contribute to its complex role in both physiological and pathological conditions3. During adult life, heparanase is present in few tissues, with high levels only detected in some blood-borne cells. On the other hand, heparanase is overexpressed in several pathological conditions where alteration of HS affects tissue structure and integrity, cell adhesion and migration4,5. In particular, heparanase overexpression has been correlated with tumour survival and progression, angiogenesis, cell dissemination and metastasis, and with poor prognosis. Moreover, treatment with classical cytotoxic agents often induces heparanase expression, which concurs to the development of drug resistance6. Heparanase is highly active also in non-malignant pathologies, such as in a variety of inflammatory conditions in which HS degradation and the consequent extracellular matrix remodelling facilitate recruitment and migration of leukocytes and activation of innate immune cells7,8.
The role of extracellular matrix components in angiogenesis and fibrosis: Possible implication for Systemic Sclerosis
Published in Modern Rheumatology, 2018
Vasiliki Liakouli, Paola Cipriani, Paola Di Benedetto, Piero Ruscitti, Francesco Carubbi, Onorina Berardicurti, Noemi Panzera, Roberto Giacomelli
Heparanase is an endo-β-d-glucuronidase cleaving heparan sulfate side-chains of heparin sulfate PGs, involved in inflammation, wound healing, angiogenesis, and tumor growth through the ECM degradation and remodeling and the release of sequestered pro-angiogenic factors [88]. Serum heparanase levels are significantly higher in SSc patients than in HC and SSc patients with digital ulcers show significantly lower levels of this molecule, suggesting the contribution of heparanase-dependent biological processes to the SSc pathogenesis. SSc patients with high serum heparanase levels may be protected from the development of digital ulcers due to the increased release of sequestered pro-angiogenic factors such as VEGF [89].