Department of Biomedical Sciences and NCEED, College of Medicine, Inha University, Jung-gu, Incheon, South Korea.
Biomaterials. 2011 Feb;32(5):1438-45. doi: 10.1016/j.biomaterials.2010.10.023. Epub 2010 Nov 12.
Low molecular weight heparin (LH) has been reported to have anti-fibrotic and anti-cancer effects. To enhance the efficacy and minimize adverse effects of LH, a low molecular weight heparin-pluronic nanogel (LHP) was synthesized by conjugating carboxylated pluronic F127 to LH. The LHP reduced anti-coagulant activity by about 33% of the innate activity. Liver fibrosis was induced by the injection of 1% dimethylnitrosamine (DMN) in rats, and LH or LHP (1000 IU/kg body weight) was treated once daily for 4 weeks. LHP administration prevented DMN-mediated liver weight loss and decreased the values of aspartate transaminase, alanine transaminase, total bilirubin, and direct bilirubin. LHP markedly reduced the fibrotic area compared to LH. Also, LHP potently inhibited mRNA or protein expression of alpha-smooth muscle actin, collagen type I, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-1 compared to LH, in DMN-induced liver fibrosis. In addition, LHP decreased the expression of transforming growth factor-β(1) (TGF-β(1)), p-Smad 2, and p-Smad 3, which are all important molecules of the TGF-β/Smad signaling pathway. The results support an LHP shows anti-fibrotic effect in the liver via inhibition of the TGF-β/Smad pathway as well as by the elimination of the extracellular matrix.
低分子量肝素（LH）具有抗纤维化和抗癌作用。为了提高 LH 的疗效并降低其不良反应，通过将羧基化的 Pluronic F127 与 LH 偶联，合成了低分子量肝素-Pluronic 纳米凝胶（LHP）。LHP 将抗凝血活性降低到固有活性的约 33%。通过向大鼠注射 1%二甲基亚硝胺（DMN）诱导肝纤维化，然后每天用 LH 或 LHP（1000 IU/kg 体重）治疗一次，共 4 周。LHP 给药可预防 DMN 介导的肝重量减轻，并降低天冬氨酸转氨酶、丙氨酸转氨酶、总胆红素和直接胆红素的值。与 LH 相比，LHP 显著减少了纤维化面积。此外，与 LH 相比，LHP 可强力抑制 DMN 诱导的肝纤维化中α-平滑肌肌动蛋白、I 型胶原、基质金属蛋白酶-2 和金属蛋白酶组织抑制剂-1 的 mRNA 或蛋白表达。此外，LHP 降低了转化生长因子-β(1)（TGF-β(1)）、p-Smad 2 和 p-Smad 3 的表达，它们都是 TGF-β/Smad 信号通路的重要分子。结果表明，LHP 通过抑制 TGF-β/Smad 通路以及消除细胞外基质，在肝脏中表现出抗纤维化作用。
