Oxysophocarpine Inhibits Apoptosis of Lung Epithelial Cells to Alleviate Acute Lung Injury via KIT/PI3K Signaling Pathway.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-09-23 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S544479

Ziyao Qiao, Kaihua Long, Kairu Ding, Xiaoyan Zhang, Xiaoli Gao, Shanrong Han, Na Zheng, Yun Yang, Jingjing Li, Yaqiong Su, Hong Zhang, Ye Li, Wenbing Zhi, Yang Liu

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引用次数: 0

Abstract

Purpose: Acute lung injury (ALI) is an acute, diffuse, inflammatory lung injury caused by many factors. Oxysophocarpine (OSC), a quinoline alkaloid sourced from traditional Chinese herbs Sophora flavescens and Sophora davidii, possesses anti-inflammatory and antioxidant properties. However, its effects on ALI are still unclear. This study aims to investigate the role and potential mechanisms of OSC for the treatment of ALI.

Methods: The levels of TNF-α, IL-6, and IL-1β in bronchoalveolar lavage fluid (BALF) were measured with an enzyme-linked immunosorbent assay (ELISA). Lung tissue changes were examined through hematoxylin and eosin (HE) staining. Lung cell apoptosis was analyzed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Flow cytometry was utilized to detect neutrophil aggregation. Further, the network pharmacology and molecular docking was employed to predict the mechanisms. Key pathways and targets of OSC were confirmed using methods like immunohistochemistry (IHC), immunofluorescence (IF), real-time quantitative PCR (RT-qPCR), and Western blotting (WB).

Results: In vivo, OSC treatment significantly inhibited diffuse alveolar injury and interstitial edema compared to the LPS-induced model mice, reduced neutrophil infiltration, and lowered lung epithelial cell apoptosis. In vitro, OSC pretreatment enhanced lung epithelial cell viability and decreased LPS-induced apoptosis. Network pharmacology analysis suggested that OSC mainly targeted key proteins in the PI3K/AKT and apoptosis signaling pathways, such as KIT, PIK3CA, and Bcl-2. Molecular docking confirmed that OSC binds strongly to these targets. Further, PCR, WB, IF, and IHC assay demonstrated that OSC pretreatment elevated PI3K, KIT, and Bcl-2 expressions in BEAS-2B lung epithelial cells and lung tissues.

Conclusion: OSC reduced inflammatory cytokine production, neutrophil aggregation, and lung epithelial cell apoptosis via regulating the KIT/PI3K signaling pathway.

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氧磷卡平通过KIT/PI3K信号通路抑制肺上皮细胞凋亡减轻急性肺损伤

目的：急性肺损伤（Acute lung injury， ALI）是由多种因素引起的急性、弥漫性、炎性肺损伤。氧膦碱（OSC）是一种喹啉类生物碱，从传统中药苦参和苦参中提取，具有抗炎和抗氧化作用。然而，它对ALI的影响尚不清楚。本研究旨在探讨OSC在ALI治疗中的作用及其潜在机制。方法：采用酶联免疫吸附法（ELISA）检测支气管肺泡灌洗液（BALF）中TNF-α、IL-6、IL-1β的水平。苏木精和伊红（HE）染色检测肺组织变化。采用末端脱氧核苷酸转移酶dUTP镍端标记（TUNEL）法分析肺细胞凋亡。流式细胞术检测中性粒细胞聚集。进一步，利用网络药理学和分子对接对其机制进行了预测。采用免疫组织化学（IHC）、免疫荧光（IF）、实时荧光定量PCR （RT-qPCR）、Western blotting （WB）等方法确定OSC的关键通路和靶点。结果：在体内，与lps诱导的模型小鼠相比，OSC处理显著抑制弥漫性肺泡损伤和间质水肿，减少中性粒细胞浸润，降低肺上皮细胞凋亡。在体外，OSC预处理可提高肺上皮细胞活力，减少lps诱导的细胞凋亡。网络药理学分析表明，OSC主要靶向PI3K/AKT和凋亡信号通路中的关键蛋白，如KIT、PIK3CA、Bcl-2。分子对接证实了OSC与这些靶标紧密结合。此外，PCR、WB、IF和IHC分析表明，OSC预处理可提高BEAS-2B肺上皮细胞和肺组织中PI3K、KIT和Bcl-2的表达。结论：OSC通过调节KIT/PI3K信号通路减少炎症细胞因子的产生、中性粒细胞聚集和肺上皮细胞凋亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.