Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses.
Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses.
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DOI：
10.1186/s11658-022-00318-8
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发表时间：
2022-03-19
影响因子：
8.3
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Li J;Deng SH;Li J;Li L;Zhang F;Zou Y;Wu DM;Xu Y
急性肺损伤（acute lung injury，ALI）是一种高死亡率的疾病，在重症监护领域受到了广泛的关注。Obacunone（OB）是一种广泛存在于柑橘类水果中的具有抗炎和抗氧化活性的天然化合物。然而，目前尚不清楚OB是否对脂多糖（LPS）诱导的ALI具有保护作用。因此，本研究旨在评价OB对LPS诱导的ALI和BEAS-2B细胞损伤的保护作用及其可能机制。建立BEAS-2B细胞损伤模型和LPS致小鼠急性肺损伤模型。对体外模型样品进行细胞死亡、细胞计数试剂盒-8和乳酸脱氢酶（LDH）释放测定。检测支气管肺泡灌洗液（BALF）中细胞总数、中性粒细胞总数、蛋白含量及IL-6、TNF-α和IL-1β水平。测定肺组织中的谷胱甘肽、活性氧和丙二醛水平。此外，免疫组化分析，免疫荧光，western blot，定量实时PCR和酶联免疫吸附试验进行了检查OB的影响。此外，用Nrf 2抑制剂（ML 385）处理小鼠以验证其在铁凋亡中的作用。采用单因素方差分析或配对t检验分析数据。与LPS组相比，OB能显著降低肺湿/干重比、活性氧和丙二醛的生成、超氧化物歧化酶和谷胱甘肽的消耗，从而减轻LPS诱导的ALI。此外，OB显著减轻肺组织病理学损伤，降低炎性细胞因子分泌和Fe 2+和4-HNE水平，并上调GPX 4、SLC 7A 11和Nrf 2表达。机械上，OB通过抑制Nrf 2泛素化蛋白酶体降解来激活Nrf 2。ML 385逆转OB对LPS诱导的ALI的保护作用。总体而言，OB可抑制LPS诱导的ALI，使其成为一种潜在的新型抗LPS诱导的ALI保护剂。
Acute lung injury (ALI) has received considerable attention in the field of intensive care as it is associated with a high mortality rate. Obacunone (OB), widely found in citrus fruits, is a natural bioactive compound with anti-inflammatory and antioxidant activities. However, it is not clear whether OB protects against lipopolysaccharide (LPS)-induced ALI. Therefore, in this study, we aimed to evaluate the protective effects of OB and the potential mechanisms against LPS-induced ALI and BEAS-2B cell injury. We established a model of BEAS-2B cell injury and a mouse model of ALI by treating with LPS. Samples of in vitro model were subjected to cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release assays. The total number of cells and neutrophils, protein content, and levels of IL-6, TNF-α, and IL-1β were determined in bronchoalveolar lavage fluid (BALF). Glutathione, reactive oxygen species, and malondialdehyde levels were determined in lung tissue. Additionally, immunohistochemical analysis, immunofluorescence, western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were conducted to examine the effects of OB. Furthermore, mice were treated with an Nrf2 inhibitor (ML385) to verify its role in ferroptosis. Data were analyzed using one-way analysis of variance or paired t-tests. Compared with the LPS group, OB effectively alleviated LPS-induced ALI by decreasing lung wet/dry weight ratio, reactive oxygen species and malondialdehyde production, and superoxide dismutase and glutathione consumption in vivo. In addition, OB significantly alleviated lung histopathological injury, reduced inflammatory cytokine secretion and Fe2+ and 4-HNE levels, and upregulated GPX4, SLC7A11, and Nrf2 expression. Mechanistically, OB activated Nrf2 by inhibiting Nrf2 ubiquitinated proteasome degradation. ML385 reversed the protective effects of OB against LPS-induced ALI. Overall, OB alleviates LPS-induced ALI, making it a potential novel protective agent against LPS-induced ALI.
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影响因子：
8
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
120.7
作者：
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影响因子：
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作者：
Qu M;Zhang H;Chen Z;Sun X;Zhu S;Nan K;Chen W;Miao C
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DOI：
10.3390/molecules26020318
发表时间：
2021-01-09
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bai Y;Wang W;Wang L;Ma L;Zhai D;Wang F;Shi R;Liu C;Xu Q;Chen G;Lu Z
通讯作者：
Lu Z