Heparan Sulfate Mimicking Glycopolymer Prevents Pancreatic β Cell Destruction and Suppresses Inflammatory Cytokine Expression in Islets under the Challenge of Upregulated Heparanase
| Autor: | Ravi S. Loka, Zhenfeng Song, Eric T. Sletten, Yasmin Kayal, Israel Vlodavsky, Kezhong Zhang, Hien M. Nguyen |
|---|---|
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.1c00908 |
| Popis: | Diabetes is a chronic disease in which the levels of blood glucose are too high because the body does not effectively produce insulin to meet its needs or is resistant to insulin. β Cells in human pancreatic islets produce insulin, which signals glucogen production by the liver and causes muscles and fat to uptake glucose. Progressive loss of insulin-producing β cells is the main cause of both type 1 and type 2 diabetes. Heparan sulfate (HS) is a ubiquitous polysaccharide found at the cell surface and in the extracellular matrix (ECM) of a variety of tissues. HS binds to and assembles proteins in ECM, thus playing important roles in the integrity of ECM (particularly basement membrane), barrier function, and ECM–cell interactions. Islet HS is highly expressed by the pancreatic β cells and critical for the survival of β cells. Heparanase is an endoglycosidase and cleaves islet HS in the pancreas, resulting in β-cell death and oxidative stress. Heparanase could also accelerate β-cell death by promoting cytokine release from ECM and secretion by activated inflammatory and endothelial cells. We demonstrate that HS-mimicking glycopolymer, a potent heparanase inhibitor, improves the survival of cultured mouse pancreatic β cells and protects HS contents under the challenge of heparanase in human pancreatic islets. Moreover, this HS-mimicking glycopolymer reduces the expression levels of cytokines (IL8, IL1β, and TNFα) and the gene encoding Toll-like Receptor 2 (TLR2) in human pancreatic islets. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|