Lung protective effects of dietary malate esters derivatives from Bletilla striata against SiO2 nanoparticles through activation of Nrf2 pathway

doi:https://doi.org/10.1016/j.chmed.2022.11.001

Archive > Volume 15 Issue 1 > 2023,15(1):76-85. DOI:https://doi.org/10.1016/j.chmed.2022.11.001 Prev Next

白及中可食用蘋果酸酯類衍生物利用Nrf2途徑對納米二氧化硅顆粒所致肺損傷的保護作用

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Lung protective effects of dietary malate esters derivatives from Bletilla striata against SiO2 nanoparticles through activation of Nrf2 pathway

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摘要:

目的：本文對白及中可食用蘋果酸酯衍生物對納米二氧化硅顆粒所致A549細胞的保護活性及其作用機制進行了研究。方法：采用1D NMR和2D NMR等譜學方法對白及中的成分進行結構鑒定，采用MTT法測試這些成分對A549細胞的存活率，并利用免疫印跡法測試ROS和其他蛋白水平。結果：從白及乙醇提取物的正丁醇萃取物中分離得到1個新的2-異丁基葡萄糖芐基酯和31個已知化合物，其中化合物3, 4, 11, 12和13對損傷細胞表現(xiàn)出明顯的保護活性，其ED50值分別為14.0, 13.1, 3.7, 11.6和11.5 μmol/L，陽性藥白藜蘆醇的ED50值為14.7 μmol/L?；衔?，militarine顯著的抑制細胞內ROS水平，增加了Nrf2和其下游基因蛋白HO-1和γ-GCSc的表達。此外，Nrf2激活介導化合物8對納米二氧化硅顆粒誘導的肺損傷的干預作用。在化合物8的作用下，可顯著降低納米二氧化硅顆粒滴注小鼠肺部的炎癥和氧化應激。同時分子對接實驗表明，8通過氫鍵相互作用與HO-1蛋白穩(wěn)定結合。結論：白及中可食用蘋果酸酯類衍生物可以顯著提高納米二氧化硅顆粒誘導A549細胞的存活率，并減少細顆粒誘導的細胞損傷。化合物militarine是具有前景的化合物，可以通過激活Nrf2通路來預防納米二氧化硅顆粒誘導的肺癌。

Abstract:

Objective: To study the protective activities of the dietary malate esters derivatives of Bletilla striata against SiO2 nanoparticles-induced A549 cell lines and its mechanism action. Methods: The components were isolated and elucidated by spectroscopic methods such as 1D NMR and 2D NMR. And MTT assays was used to tested these components on the A549 cell survival rates and ROS or proteins levels were detected by Western blotting. Results: A new glucosyloxybenzyl 2-isobutylmalate (a malate ester derivative), along with 31 known compounds were isolated and identified from n-BuOH extract of EtOH extract of B. striata. Among them, compounds 3, 4, 11, 12 and 13 possessed noteworthy proliferative effects for damaged cells, with ED50 of 14.0, 13.1, 3.7, 11.6 and 11.5 lmol/L, respectively, compared to positive control resveratrol (ED50, 14.7 lmol/L). Militarine (8) prominently inhibited the intracellular ROS level, and increased the expression of Nrf2 and its downstream genes (HO-1 and c-GCSc). Furthermore, Nrf2 activation mediates the interventional effects of compound 8 against SiO2 nanoparticles (nm SiO2)-induced lung injury. Moreover, treatment with compound 8 significantly reduced lung inflammation and oxidative stress in nm SiO2-instilled mice. Molecular docking experiment suggested that 8 bound stably to the HO-1 protein by hydrogen bond interactions. Conclusion: The dietary malate esters derivatives of B. striata could significantly increase the viability of nm SiO2-induced A549 cells and decrease the finer particles-induced cell damages. Militarine is especially promising compound for chemoprevention of lung cancer induced by nm SiO2 through activation of Nrf2 pathway.

關鍵詞:

白及;可食用蘋果酸酯類衍生物;肺癌化學預防;militarine;納米二氧化硅顆粒-誘導的A549細胞

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Project Supported:

This work was financially supported by National Natural Science Foundation of China, China (Grant No. 81872768, 81673323, 82003630), Scientific Research Fund of Liaoning Province Education Department, Liaoning (LJKZ0949), Special Fund of Research Institute of Drug Regulatory Science Research Shenyang Pharmaceutical University, Liaoning (2021jgkx010), State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University), Guangxi (CMEMR2022-B04).

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