The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR) modulating poly(p-dioxanone-co-l-phenylalanine) prodrug
| Autor: | Le Luo, Bing Wang, Chengmin Feng, Jun Lei, Jiang Zhu, Lijing Niu, Chengyi Shen, Aiping Wen, Xiao Xin, Xiao-Ming Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Polymers Biomedical Engineering chemistry.chemical_element Apoptosis Phenylalanine 02 engineering and technology Calcium Biochemistry Cell Line Dioxanes Biomaterials Mice 03 medical and health sciences In vivo medicine Animals Prodrugs Calcium Signaling Receptor Fibroblast Molecular Biology Calcium signaling General Medicine Fibroblasts 021001 nanoscience & nanotechnology Fibrosis Molecular biology 030104 developmental biology medicine.anatomical_structure chemistry Female Rabbits Peptides 0210 nano-technology Receptors Calcium-Sensing Intracellular Biotechnology |
| Zdroj: | Acta Biomaterialia. 73:180-189 |
| ISSN: | 1742-7061 |
| Popis: | In present study, the apoptosis induction and proliferation suppression effects of l -phenylalanine ( l -Phe) on fibroblasts were confirmed. The action sites of l -Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca2+ stores; disruption of intracellular Ca2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l -Phe, and the results those l -Phe triggered the increasing of intracellular Ca2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l -Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co- l -phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l -Phe for the sustained release of l -Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-β1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. Statement of Significance We have previously demonstrated that poly(p-dioxanone-co- l -phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l -phenylalanine. In present study, the inhibition mechanism of l -phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l -phenylalanine, and then the ER Ca2+ stores were released. The released Ca2+ can simultaneously activate Ca2+/calcineurin and then trigger apoptosis and G1 arrest of fibroblast. Hence, l -phenylalanine could be seen as anti-fibrosis drug and PDPA which conjugate l -phenylalanine by hydrolytic covalent bonds could be seen as l -phenylalanine polymer prodrug. Based above, the in vivo anti-fibrotic function of PDPA were verified in three different animal models. |
| Databáze: | OpenAIRE |
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