KMID : 0043320230460030177
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Archives of Pharmacal Research 2023 Volume.46 No. 3 p.177 ~ p.191
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Engineered fibrotic liver-targeted truncated transforming growth factor ¥â receptor type II variant for superior anti-liver fibrosis therapy
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Manman Ma
Xiaohua Wang Xiaohui Liu Yang Han Yanhui Chu Yanzhong Guan Haifeng Liu
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Abstract
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Truncated transforming growth factor ¥â receptor type II (tT¥âRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-¥â1 by means of competing with wild type T¥âRII (wtT¥âRII). However, the widespread application of tT¥âRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tT¥âRII variant Z-tT¥âRII by fusing the platelet-derived growth factor ¥â receptor (PDGF¥âR)-specific affibody ZPDGF¥âR to the N-terminus of tT¥âRII. The target protein Z-tT¥âRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tT¥âRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGF¥âR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tT¥âRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-¥â1/Smad pathway-related protein levels in TGF-¥â1-stimiluated HSC-T6 cells. Furthermore, Z-tT¥âRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-¥â1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tT¥âRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tT¥âRII or former variant BiPPB-tT¥âRII (PDGF¥âR-binding peptide BiPPB modified tT¥âRII). In addition, Z-tT¥âRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tT¥âRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.
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KEYWORD
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Transforming growth factor ¥â1, Transforming growth factor ¥â receptor type II, Platelet-derived growth factor ¥â
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