树莓酮通过STAT2-P2X7r/NLRP3信号通路缓解辐射性肺损伤

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-15 DOI:10.1016/j.phymed.2025.156984

Yu-Chen Jiang , Bin Zhao , Peng Jiang , Si-Ying Wang , Lin Ma , Guo-Li Wu , Man-Li Wang , Hai-Ming Sun

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引用次数: 0

摘要

背景：在接受放疗的乳腺癌患者中，辐射诱发的肺损伤（RILI）是一个常见的副作用。目前，还没有一种最佳的辐射防护剂被广泛用于RILI的治疗。树莓酮（RK）是在树莓（Rubus idaeus L.）中发现的一种天然芳香化合物。我们最近的一项研究表明，RK具有很强的抗炎和抗纤维化作用。然而，其在炎症相关性肺损伤中的实际作用机制尚不清楚。目的本研究旨在阐明RK是否可以缓解RILI，并确定可能的潜在机制。采用co γ射线照射C57BL/6小鼠，建立肺损伤模型。小鼠每天口服RK 14天，然后沉默STAT2基因。收集肺组织、血清和支气管肺泡灌洗液检测肺损伤相关生物标志物。检测肺组织中与ECM、炎症、EMT和焦亡相关的组织形态学变化和生物标志物表达。方法将sc57bl /6小鼠暴露于co γ射线下，建立肺损伤模型。小鼠每天口服RK 14天，然后沉默STAT2基因。在炎症条件下，用TGF-β或上清激活原代肺成纤维细胞，分别用RK或Nifuroxazide培养。BMDMs也用LPS和RK处理，形成条件培养基。原代肺成纤维细胞和bmdm注射siRNA-STAT2。结果rk能提高肺组织生化指标水平，抑制肺组织ECM标志物表达，下调肺组织炎症因子IL-1β水平。RK还可以调节辐射诱导的组织病理损伤和EMT进展，抑制热释热相关蛋白的上调。此外，RK抑制STAT2和P2 × 7r下游信号的表达。此外，STAT2的缺失抑制了ECM、炎症、EMT和焦亡的发生。值得注意的是，沉默STAT2基因导致P2 × 7r和NLRP3炎性体在RILI小鼠、原代肺成纤维细胞和bmdm肺组织中的低表达。用lps引物的BMDMs条件培养基激活原代肺成纤维细胞，导致EMT标记物和炎症细胞因子显著增强。结论RK通过STAT2-P2 × 7r/NLRP3信号通路改善RILI。RK可能是一种有前景的治疗候选药物，其机制可能是治疗RILI的新途径。

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Raspberry ketone alleviates radiation-induced lung injury through the STAT2-P2X7r/NLRP3 signaling pathway

Background

Radiation-induced lung injury (RILI) is a frequent side effect in patients with breast cancer receiving radiotherapy. Currently, there is no optimal radioprotective agent that is widely utilized for RILI treatment. Raspberry ketone (RK) is a natural aromatic compound found in raspberries (Rubus idaeus L.). A recent study by our research revealed that RK has strong anti-inflammatory and anti-fibrosis effects. However, its actual mechanism of action in inflammation-related lung injury remains elusive.

Purpose

This study aimed to clarify whether RK can alleviate RILI and determine the possible underlying mechanisms. C57BL/6 mice were exposed to Coγ-rays to establish a lung injury model. RK was orally administered to the mice daily for 14 days, followed by STAT2 gene silencing. Lung tissue, serum, and bronchoalveolar lavage fluid were collected to detect lung injury-related biomarkers. Tissue morphological changes and biomarker expression related to the ECM, inflammation, EMT, and pyroptosis in the lung tissue were detected.

Methods

C57BL/6 mice were exposed to Coγ-rays to establish a lung injury model. RK was orally administered to the mice daily for 14 days, followed by STAT2 gene silencing. Primary lung fibroblasts were activated with TGF-β or supernatant under inflammatory conditions and incubated with RK or Nifuroxazide, respectively. BMDMs were also treated with LPS and RK to form a conditioned medium. Primary lung fibroblasts and BMDMs were injected with siRNA-STAT2.

Results

RK could improve the levels of biochemical indicators in the lung tissue, suppress the expression of ECM markers, and downregulate the levels of inflammatory factors, such as IL-1β, in RILI. RK could also regulate radiation-induced histopathological damage and EMT progression and inhibit the upregulation of pyroptosis-related proteins. Furthermore, RK inhibited the expression of the downstream signals of STAT2 and P2 × 7r. In addition, STAT2 deletion inhibited the occurrence of ECM, inflammation, EMT, and pyroptosis. Notably, silencing the STAT2 gene led to a low expression of P2 × 7r and the NLRP3 inflammasome in the lung tissue of RILI mice, primary lung fibroblasts, and BMDMs. Primary lung fibroblasts were activated with conditioned medium from LPS-primed BMDMs, which resulted in significant enhance of EMT markers and inflammatory cytokines.

Conclusion

This study indicated that RK improved RILI through STAT2-P2 × 7r/NLRP3 signaling. RK might be a prospective therapeutic candidate, and its mechanism would be a novel approach for RILI treatment.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.