萨帕尼塞蒂布通过调节Wnt5a/mTOR信号来减轻肺纤维化
Zehui Xu1, Yunying Lv1, Dexin Kong1
1School of Pharmacy, Binzhou Medical University, Yantai, China.
Basic & clinical pharmacology & toxicology
|July 3, 2023
概括
作为一种mTOR抑制剂的萨帕尼塞尔蒂布通过阻断关键信号通路,如Wnt5a/mTOR/HIF-1α/p70S6K,有效地减少了大鼠的肺纤维化. 这种药物还抑制了癌细胞中的上皮质-介质细胞过渡.
科学领域:
- 药理学 药理学是指药理学的学科.
- 细胞生物学 细胞生物学
- 肺部医学 肺部医学
背景情况:
- 萨帕尼塞尔蒂布是一种口服生物可用抑制剂,向猛禽-mTOR (TORC1) 途径,以其抗瘤潜力而闻名.
- 转化生长因子-β1 (TGF-β1) 在纤维化过程和上皮-介质细胞转换 (EMT) 中发挥着关键作用.
- 在老鼠中,白胺诱导的肺纤维化是研究抗纤维治疗的标准模型.
研究的目的:
- 调查sapanisertib在改善实验性肺纤维化中的疗效.
- 为了确定sapanisertib对TGF-β1诱导的EMT在A549细胞中的影响.
- 评估sapanisertib对TGF-β1诱导的L929细胞细胞变化的影响及其在老鼠模型中的抗纤维作用.
主要方法:
- 用TGF-β1和sapanisertib对A549和L929细胞进行治疗.
- 在A549单元格中评估EMT标记物 (E-cadherin,vimentin).
- 在L929细胞中分析细胞增殖和蛋白质表达 (原I和III,光滑肌肉动蛋白,缺氧诱导因子,mTOR,p70S6K,Wnt5a).
- 通过连续输血给患有白素诱导的肺纤维化病的老鼠14天的sapanisertib.
主要成果:
- 在A549细胞中,sapanisertib抑制了TGF-β1诱导的EMT,使E-cadherin和vimentin的表达正常化.
- 在L929细胞中,sapanisertib抑制了TGF-β1诱导的增殖,并减少了参与ECM生产和信号通路的关键蛋白质.
- 在大鼠模型中,sapanisertib显著降低了白色素诱导的肺纤维化中的病理评分和原沉积.
结论:
- 在实验性肺纤维化中,Sapanisertib表现出显著的抗纤维活性.
- 该药物通过抑制Wnt5a/mTOR/HIF-1α/p70S6K信号轴来改善肺纤维化.
- 萨帕尼塞尔蒂布具有作为纤维化肺部疾病治疗剂的潜力.
相关概念视频
02:54Canonical Wnt Signaling Pathway
8.8K
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
8.8K
01:41Non-Canonical Wnt Signaling Pathways
7.3K
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
7.3K
01:20The JAK-STAT Signaling Pathway
9.0K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
9.0K
01:22PI3K/mTOR/AKT Signaling Pathway
3.7K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.7K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
01:16TGF - β Signaling Pathway
7.5K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.5K