靶向IGFBP-3的重组TMEM219黄原体：一种靶向给药改善肝纤维化的新方法

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-05-28 DOI:10.1016/j.lfs.2025.123748

Armin Mokhtariye , Jaleh Varshosaz , Adel Mohammadalipour , Mohammad Hashemnia , Mohammad Reza Mofid

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引用次数: 0

摘要

目的：胰岛素样生长因子结合蛋白3 （IGFBP-3）激活肝星状细胞，促进肝纤维化。本研究旨在制备IGFBP-3靶向负载跨膜蛋白219 （TMEM219）的黄原体，靶向肝纤维化中TGFβ/IGFBP-3信号通路。材料和方法：采用薄膜水合法表达、纯化重组TMEM219，并将重组TMEM219装入黄原体。MTT法对LX-2细胞系进行细胞毒性试验。通过胆管结痂诱导大鼠肝纤维化，然后静脉注射：假手术（SH）和纤维化(F)伴生理盐水、短期（ST）和长期（LT）靶黄原体（0.4 mg/kg）、空白靶黄原体（BST和BLT）和游离TMEM219 (free； 0.4毫克/公斤)。评估方法包括生化指标、组织病理学和免疫组织化学、α-SMA和COL1A1 mRNA表达、血清IGFBP-3水平和TGF-β1蛋白表达。主要发现：负载tmem219的黄原体粒径为149.9 nm， ζ电位为-11.4 mV，负载效率为71.5 %。MTT试验显示，与游离TMEM219相比，靶向黄原体的细胞毒性更低（p ）。意义：治疗参数的改善表明肝纤维化进展减少。本研究证实tmem219 -黄质体有效靶向IGFBP-3，显著减少肝纤维化。

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Xanthosomes loaded with recombinant TMEM219 for targeting IGFBP-3: A novel approach for targeted drug delivery to ameliorate liver fibrosis

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Xanthosomes loaded with recombinant TMEM219 for targeting IGFBP-3: A novel approach for targeted drug delivery to ameliorate liver fibrosis

Aims

Insulin-like growth factor binding protein-3 (IGFBP-3) activates hepatic stellate cells, enhancing hepatic fibrogenesis. This research aimed to fabricate IGFBP-3 targeted xanthosomes loaded with transmembrane-protein 219 (TMEM219) to target TGFβ/IGFBP-3 signaling pathway in liver fibrosis.

Materials and methods

Recombinant TMEM219 was expressed, purified, and loaded into xanthosomes using thin-film hydration method. MTT assay performed cytotoxicity on the LX-2 cell line. Liver fibrosis was induced in rats via bile duct ligation, followed by intravenous injection: Sham (SH) and Fibrotic (F) with saline, Short-term (ST) and Long-term (LT) TMEM219 loaded in targeted xanthosomes (0.4 mg/kg), Blank targeted xanthosomes (BST and BLT), and free TMEM219 (Free; 0.4 mg/kg). Evaluations included biochemical parameters, histopathology and immunohistochemistry, α-SMA and COL1A1 mRNA expression, serum IGFBP-3 levels, and TGF-β1 protein expression.

Key findings

TMEM219-loaded xanthosomes exhibited a particle size of 149.9 nm, zeta-potential of −11.4 mV, and loading efficiency of 71.5 %. MTT assay showed lower cytotoxicity of targeted xanthosomes compared to free TMEM219 (p < 0.05). ST and LT groups significantly improved AST and ALT levels, histopathology (reduced necrosis, fibrogenesis, inflammation), α-SMA and COL1A1 expression, serum IGFBP-3, p-AKT and TGF-β1 expression (p < 0.05, p < 0.01).

Significance

Improvements in therapeutic parameters indicated reduced liver fibrosis progression. This study demonstrates that TMEM219-xanthosomes effectively target IGFBP-3, significantly reducing liver fibrosis.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.