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酸枣仁提取物通过调控 TGF-β1/SMAD 通路抑制博来霉素诱导的肺纤维化:LC-MS/MS 代谢组学、化学成分和组织学研究。

Ziziphus spina-christi L. extract attenuates bleomycin-induced lung fibrosis in mice via regulating TGF-β1/SMAD pathway: LC-MS/MS Metabolic profiling, chemical composition, and histology studies.

机构信息

King Abdulaziz University Herbarium, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.

出版信息

Biomed Pharmacother. 2024 Jul;176:116823. doi: 10.1016/j.biopha.2024.116823. Epub 2024 Jun 3.

DOI:10.1016/j.biopha.2024.116823
PMID:38834008
Abstract

Ancient Egyptians (including Bedouins and Nubians) have long utilized Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, to alleviate swellings and inflammatory disorders. It is also mentioned in Christian and Muslim traditions. Ziziphus spina-christi L. (Family: Rhamnaceae) is a plentiful source of polyphenols, revealing free radical scavenging, antioxidant, metal chelating, cytotoxic, and anti-inflammatory activities. Herein, different classes of the existing bioactive metabolites in Z. spina-christi L. were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. The study also aimed to assess the anti-inflammatory and antifibrotic properties of Z. spina-christi L. extract against bleomycin-induced lung fibrosis in an experimental mouse model. 32 male Swiss Albino mice were assigned into 4 groups; the first and second were the normal control group and the bleomycin positive control (single 2.5 U/kg bleomycin intratracheal dose). The third and fourth groups received 100 and 200 mg/kg/day Z. spina-christi L. extract orally for 3 weeks, 2 weeks before bleomycin, and 1 week after. The bioactive metabolites in Z. spina-christi L. extract were identified as phenolic acids, catechins, flavonoids, chalcones, stilbenes, triterpenoid acids, saponins, and sterols. The contents of total phenolic compounds and flavonoids were found to be 196.62 mg GAE/gm and 33.29 mg QE/gm, respectively. In the experimental study, histopathological examination revealed that lung fibrosis was attenuated in both Z. spina-christi L.- treated groups. Z. spina-christi L. extract downregulated the expression of nuclear factor kappa B (NF-κB) p65 and decreased levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and c-Jun N-terminal kinase (JNK) in lung tissue. Z. spina-christi L. also downregulated the expression of the fibrotic parameters collagen-1, alpha-smooth muscle actin (α-SMA), transforming growth factor-beta 1 (TGF-β1), matrix metalloproteinase-9 (MMP-9) and SMAD3, with upregulation of the antifibrotic SMAD7 in lung tissue. Overall, the present study suggests a potential protective effect of Z. spina-christi L. extract against bleomycin-induced lung fibrosis through regulation of the TGF-β1/SMAD pathway.

摘要

古埃及人(包括贝都因人和努比亚人)长期以来一直使用枣棘(L.),一种传统的阿拉伯药用植物,来缓解肿胀和炎症性疾病。它在基督教和伊斯兰教传统中也有提及。枣棘(L.)(家族:鼠李科)是多酚的丰富来源,具有自由基清除、抗氧化、金属螯合、细胞毒性和抗炎作用。在此,首次使用液相色谱-串联质谱(LC-MS/MS)检测了枣棘(L.)中不同类别的现有生物活性代谢物。该研究还旨在评估枣棘(L.)提取物对博来霉素诱导的实验性小鼠肺纤维化的抗炎和抗纤维化特性。32 只雄性瑞士白化病小鼠被分为 4 组;第一组和第二组为正常对照组和博来霉素阳性对照组(单次 2.5 U/kg 博来霉素气管内剂量)。第三组和第四组分别给予 100 和 200 mg/kg/天枣棘(L.)提取物口服,连续 3 周,博来霉素前 2 周,博来霉素后 1 周。枣棘(L.)提取物中的生物活性代谢物被鉴定为酚酸、儿茶素、类黄酮、查耳酮、芪、三萜酸、皂苷和固醇。总酚类化合物和类黄酮的含量分别为 196.62 mg GAE/gm 和 33.29 mg QE/gm。在实验研究中,组织病理学检查显示,枣棘(L.)治疗组的肺纤维化均减轻。枣棘(L.)提取物下调核因子 kappa B(NF-κB)p65 的表达,并降低肺组织中炎症标志物肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)和 c-Jun N 末端激酶(JNK)的水平。枣棘(L.)还下调胶原-1、α-平滑肌肌动蛋白(α-SMA)、转化生长因子-β1(TGF-β1)、基质金属蛋白酶-9(MMP-9)和 SMAD3 的纤维化参数表达,同时上调肺组织中的抗纤维化 SMAD7。总的来说,本研究表明枣棘(L.)提取物通过调节 TGF-β1/SMAD 通路对博来霉素诱导的肺纤维化具有潜在的保护作用。

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