乌梅丸对乙酸诱导的溃疡性结肠炎大鼠的保护作用机制：通过调节炎性细胞因子及VEGF-PI3K/Akt-eNOS信号通路

Mechanism of Fructus Mume Pills Underlying Their Protective Effects in Rats with Acetic Acid-Inducedulcerative Colitis via the Regulation of Inflammatory Cytokines and the VEGF-PI3K/Akt-eNOS Signaling Pathway.

作者信息

Xu Zongying, Zhang Xueli, Lu Ruimin, Zhang Di, Zou Tianyuan, Chen Meng, Zhang Dongmei

机构信息

College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.

出版信息

Evid Based Complement Alternat Med. 2022 May 2;2022:4621131. doi: 10.1155/2022/4621131. eCollection 2022.

BACKGROUND

Fructus mume pills (FMPs) have been clinically proven to be effective for treating ulcerative colitis (UC). However, the therapeutic and protective mechanisms have not been fully studied.

AIM

We aimed to explore the mechanism of FMPs in an acetic acid (AA)-induced ulcerative colitis rat model.

METHODS

The targets, GO terms, and KEGG pathways for the FMPs and UC were screened and constructed using network pharmacology. A possible mechanism was verified in a 4% AA-induced colitis rat model. Colitis activity and state were evaluated using the disease activity index, and colon ulceration and intestinal mucosal damage were determined by histopathological observation through HE, AB-PAS, and Masson pathological staining. The concentrations of TNF-, IL-6, IL-8, IL-10, MPO, MMP9, CXCR1, eNOS, and VEGF were measured to evaluate vascular permeability effects.

RESULTS

The network pharmacology results showed 108 active compounds, and 139 FMP-related targets were identified. Twenty-nine targets were identified for FMPs against UC, which included MMP9, MMP3, ESR1, PTGS1, PPARA, MPO, and NOS2. A total of 1,536 GO terms and 41 pathways were associated with FMP treatment of UC. The pharmacological evaluation showed that FMPs attenuated inflammation in AA-induced colitis by reducing the serum concentrations of TNF-, IL-6, IL-8, and IL-10 and the colonic concentrations of MPO, MMP9, and CXCR1. FMPs ameliorated hyperpermeability by reducing the colonic VEGF and eNOS concentrations. FMPs also significantly decreased the VEGFA, VEGFR2, Src, and eNOS protein expressions in colon tissue through the VEGF-PI3K/Akt-eNOS signaling pathway.

CONCLUSION

These results suggest that FMPs control UC inflammation by regulating inflammatory cytokine concentrations. FMPs alleviate AA-induced UC by regulating microvascular permeability through the VEGF-PI3K/Akt-eNOS signaling pathway.

背景

乌梅丸（FMPs）已被临床证明对治疗溃疡性结肠炎（UC）有效。然而，其治疗和保护机制尚未得到充分研究。

目的

我们旨在探讨乌梅丸在乙酸（AA）诱导的溃疡性结肠炎大鼠模型中的作用机制。

方法

使用网络药理学筛选并构建乌梅丸和UC的靶点、基因本体（GO）术语和京都基因与基因组百科全书（KEGG）通路。在4%乙酸诱导的结肠炎大鼠模型中验证可能的机制。使用疾病活动指数评估结肠炎活动和状态，并通过苏木精-伊红（HE）、阿尔辛蓝-过碘酸雪夫（AB-PAS）和马松（Masson）病理染色的组织病理学观察确定结肠溃疡和肠黏膜损伤。测量肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、白细胞介素-10（IL-10）、髓过氧化物酶（MPO）、基质金属蛋白酶9（MMP9）、CXC趋化因子受体1（CXCR1）、内皮型一氧化氮合酶（eNOS）和血管内皮生长因子（VEGF）的浓度，以评估血管通透性效应。

结果

网络药理学结果显示108种活性化合物，并鉴定出139个与乌梅丸相关的靶点。确定了29个乌梅丸针对UC的靶点，包括MMP9、MMP3、雌激素受体1（ESR1）、前列腺素内过氧化物合酶1（PTGS1）、过氧化物酶体增殖物激活受体α（PPARA）、MPO和一氧化氮合酶2（NOS2）。共有1536个GO术语和41条通路与乌梅丸治疗UC相关。药理学评估表明，乌梅丸通过降低血清中TNF-α、IL-6、IL-8和IL-10的浓度以及结肠中MPO、MMP9和CXCR1的浓度来减轻乙酸诱导的结肠炎中的炎症。乌梅丸通过降低结肠VEGF和eNOS浓度改善高通透性。乌梅丸还通过VEGF-磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/Akt）-eNOS信号通路显著降低结肠组织中血管内皮生长因子A（VEGFA）、血管内皮生长因子受体2（VEGFR2）、肉瘤病毒癌基因同源物（Src）和eNOS的蛋白表达。