Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy
Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2015-07, Vol.64 (7), p.2581-2592 |
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| creator | Rezzola, Sara Dal Monte, Massimo Belleri, Mirella Bugatti, Antonella Chiodelli, Paola Corsini, Michela Cammalleri, Maurizio Cancarini, Anna Morbidelli, Lucia Oreste, Pasqua Bagnoli, Paola Semeraro, Francesco Presta, Marco |
| description | Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR. |
| doi_str_mv | 10.2337/db14-1378 |
| format | Article |
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Coli K5 Polysaccharide in Diabetic Retinopathy</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Journals@Ovid Complete</source><creator>Rezzola, Sara ; Dal Monte, Massimo ; Belleri, Mirella ; Bugatti, Antonella ; Chiodelli, Paola ; Corsini, Michela ; Cammalleri, Maurizio ; Cancarini, Anna ; Morbidelli, Lucia ; Oreste, Pasqua ; Bagnoli, Paola ; Semeraro, Francesco ; Presta, Marco</creator><creatorcontrib>Rezzola, Sara ; Dal Monte, Massimo ; Belleri, Mirella ; Bugatti, Antonella ; Chiodelli, Paola ; Corsini, Michela ; Cammalleri, Maurizio ; Cancarini, Anna ; Morbidelli, Lucia ; Oreste, Pasqua ; Bagnoli, Paola ; Semeraro, Francesco ; Presta, Marco</creatorcontrib><description>Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db14-1378</identifier><identifier>PMID: 25695948</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Angiogenesis Inhibitors - therapeutic use ; Animals ; Bacterial Capsules ; Carbohydrates ; Chick Embryo ; CHO Cells ; Cricetulus ; Diabetic retinopathy ; Diabetic Retinopathy - drug therapy ; E coli ; Escherichia coli ; Heparin - metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Retinal Neovascularization - drug therapy ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors ; Vitreous Body - drug effects</subject><ispartof>Diabetes (New York, N.Y.), 2015-07, Vol.64 (7), p.2581-2592</ispartof><rights>2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.</rights><rights>Copyright American Diabetes Association Jul 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c346t-1486ff8d32f466f958aed256a50671b8c547867af58f38a4eb12d659aabd16163</citedby><cites>FETCH-LOGICAL-c346t-1486ff8d32f466f958aed256a50671b8c547867af58f38a4eb12d659aabd16163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25695948$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rezzola, Sara</creatorcontrib><creatorcontrib>Dal Monte, Massimo</creatorcontrib><creatorcontrib>Belleri, Mirella</creatorcontrib><creatorcontrib>Bugatti, Antonella</creatorcontrib><creatorcontrib>Chiodelli, Paola</creatorcontrib><creatorcontrib>Corsini, Michela</creatorcontrib><creatorcontrib>Cammalleri, Maurizio</creatorcontrib><creatorcontrib>Cancarini, Anna</creatorcontrib><creatorcontrib>Morbidelli, Lucia</creatorcontrib><creatorcontrib>Oreste, Pasqua</creatorcontrib><creatorcontrib>Bagnoli, Paola</creatorcontrib><creatorcontrib>Semeraro, Francesco</creatorcontrib><creatorcontrib>Presta, Marco</creatorcontrib><title>Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR.</description><subject>Angiogenesis Inhibitors - therapeutic use</subject><subject>Animals</subject><subject>Bacterial Capsules</subject><subject>Carbohydrates</subject><subject>Chick Embryo</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Diabetic retinopathy</subject><subject>Diabetic Retinopathy - drug therapy</subject><subject>E coli</subject><subject>Escherichia coli</subject><subject>Heparin - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Retinal Neovascularization - drug therapy</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors</subject><subject>Vitreous Body - drug effects</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctr3DAQh0VoSbZJDv0HiqCXFOpEsmQ9jsvm0ZIneUBvZmxLuwpeayPJh_3vI5O0h17CwIxAHx8z_BD6SslxyZg86RrKC8qk2kEzqpkuWCn_fEIzQmhZUKnlHvoS4zMhROTaRXtlJXSluZqh-LgyATZmTK7Fdz6ZITnosbd4nl_FfFg6vzRD_rwe--QShKVJ-ObnbfEw9haS6fDZMV743uHLKgv6bYS2XUFwncFuwKcOGjO573Mf_AbSanuAPlvoozl8n_vo6fzscfGruLq9-L2YXxUt4yIVlCthrepYabkQVlcKTJc3h4oISRvVVlwqIcFWyjIF3DS07ESlAZqOCirYPjp6826CfxlNTPXaxdb0PQzGj7GmilJNtNLqY1RoWirJuMzo9__QZz-GIR8yUUxoRTjL1I83qg0-xmBsvQluDWFbU1JPodVTaPUUWma_vRvHZm26f-TflNgrla-QNQ</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Rezzola, Sara</creator><creator>Dal Monte, Massimo</creator><creator>Belleri, Mirella</creator><creator>Bugatti, Antonella</creator><creator>Chiodelli, Paola</creator><creator>Corsini, Michela</creator><creator>Cammalleri, Maurizio</creator><creator>Cancarini, Anna</creator><creator>Morbidelli, Lucia</creator><creator>Oreste, Pasqua</creator><creator>Bagnoli, Paola</creator><creator>Semeraro, Francesco</creator><creator>Presta, Marco</creator><general>American Diabetes Association</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>7TK</scope></search><sort><creationdate>20150701</creationdate><title>Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. 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Coli K5 Polysaccharide in Diabetic Retinopathy</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>64</volume><issue>7</issue><spage>2581</spage><epage>2592</epage><pages>2581-2592</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of other proangiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the Escherichia coli polysaccharide K5 [K5-N,OS(H)] as a multitarget molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo, and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from patients with PDR. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an antiangiogenic multitarget molecule with potential implications for the therapy of pathologic neovessel formation in the retina of patients with PDR.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>25695948</pmid><doi>10.2337/db14-1378</doi><tpages>12</tpages></addata></record> |
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| subjects | Angiogenesis Inhibitors - therapeutic use Animals Bacterial Capsules Carbohydrates Chick Embryo CHO Cells Cricetulus Diabetic retinopathy Diabetic Retinopathy - drug therapy E coli Escherichia coli Heparin - metabolism Humans Mice Mice, Inbred C57BL Retinal Neovascularization - drug therapy Vascular endothelial growth factor Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vitreous Body - drug effects |
| title | Therapeutic Potential of Anti-Angiogenic Multitarget N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy |
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