委陵菜酸调节Keap-1/Nrf2和NLRP3炎症小体信号通路对乙醇诱导GES-1细胞损伤的保护作用及机制研究

doi:10.12092/j.issn.1009-2501.2026.08.004

中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (8): 1034-1052.doi: 10.12092/j.issn.1009-2501.2026.08.004

• 基础研究 • 上一篇

委陵菜酸调节Keap-1/Nrf2和NLRP3炎症小体信号通路对乙醇诱导GES-1细胞损伤的保护作用及机制研究

周如凤¹^,²(), 张颖¹^,², 孟子元², 刘杰², 石孟琼¹^,*(), 廖勇³, 许杰⁴, 李浩然⁴, 谈燕清⁴, 覃慧林⁴, 贾亮亮⁵, 游艳³^,*()

1. 三峡大学基础医学院&肿瘤微环境与免疫治疗湖北省重点实验室，宜昌 443002，湖北
2. 三峡大学天然产物研究与利用湖北省重点实验室 & 药食同源大健康产品开发利用宜昌市重点实验室，宜昌 443002，湖北
3. 三峡大学附属仁和医院，宜昌 443001，湖北
4. 三峡大学中医医院 & 湖北省功能性消化系统疾病中医临床医学研究中心，宜昌 443002，湖北
5. 宜昌市中心人民医院 & 三峡大学第一临床医学院，宜昌 443002，湖北

收稿日期:2025-09-23 修回日期:2025-11-09 出版日期:2026-08-26 发布日期:2026-09-09
通讯作者: 石孟琼,游艳 E-mail:2826720856@qq.com;shmq0212@126.com;497091164@qq.com
作者简介:周如凤，女，硕士研究生，主要从事中药防治消化系统疾病、皮肤疾病基础研究。E-mail：2748894048@qq.com
基金资助:
湖北省科技厅重点研发项目（2025BCB067）；湖北省科技厅重点研发大健康计划项目（2022BCE017）；湖北省卫生健康委员会中医药重点项目（ZY2023Z015）；湖北省科技厅自然科学基金项目（2025AFB805，2025AFB839，2025AFD301，2025AFD294，2023AFB600，2022CFB357，2022CFB427）；宜昌市医疗卫生研究项目（A22-2-059，A23-1-061）；湖北省卫生健康委员会科研资助项目（WJ2023M153）；湖北省功能性消化系统疾病中医临床医学研究中心开放基金（SXZ202303，SXZ202308，SXZ202311）

Tormentic acid protects alcohol induced GES-1 cells via regulating Keap-1/Nrf2 and NLRP3 inflammasome signaling pathways

Rufeng ZHOU¹^,²(), Ying ZHANG¹^,², Ziyuan MENG², Jie LIU², Mengqiong SHI¹^,*(), Yong LIAO³, Jie XU⁴, Haoran LI⁴, Yanqing TAN⁴, Huilin QIN⁴, Liangliang JIA⁵, Yan YOU³^,*()

1. Basic Medical College of China Three Gorges University & Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Yichang 443002, Hubei, China
2. Hubei Key Laboratory of Natural Products Research and Development, Yichang Laboratory of Development and Utilization of Health Products with Drug and Food Homology, China Three Gorges University, Yichang 443002, Hubei, China
3. Renhe Hospital Affiliated to China Three Gorges University, Yichang 443001, Hubei, China
4. Traditional Chinese Medicine Hospital & Hubei Clinical Research Center for Functional Digestive Diseases of Traditional Chinese Medicine, China Three Gorges University, Yichang 443002, Hubei, China
5. Yichang Central People's Hospital & The First College of Clinical Medical Science, China Three Gorges University, Yichang 443002, Hubei, China

Received:2025-09-23 Revised:2025-11-09 Online:2026-08-26 Published:2026-09-09
Contact: Mengqiong SHI,Yan YOU E-mail:2826720856@qq.com;shmq0212@126.com;497091164@qq.com

摘要/Abstract

摘要：

目的: 研究委陵菜酸（TA）对乙醇诱导GES-1细胞损伤的保护作用及其机制。方法: 建立乙醇诱导GES-1细胞损伤模型，实验设置对照组、模型组、TA（12.5 μg/mL）组、Nrf2抑制剂（ML385，10 μmol/L）组和NLRP3抑制剂（MCC950，8 μmol/L）组。药物干预组细胞加入相应药物培养22 h后，除对照组外，加入7%乙醇处理后继续培养细胞2 h，然后收集上清液和细胞。采用MTT检测细胞活力；采用细胞划痕和Transwell检测细胞迁移；AnnexinV-FITC/PI双染检测细胞凋亡，免疫荧光检测细胞MMP和细胞中ROS水平；比色法和ELISA检测细胞上清液中LDH、IL-4、IL-1β、IL-6、IL-10、IL-18、NO、TNF-α含量；比色法检测细胞中CAT、GSH、MDA、MPO、SOD、T-AOC及胞浆和线粒体中cytochrome C含量；采用免疫荧光检测NLRP3、ASC、caspase-1共定位；电子显微镜观察细胞内超微结构；实时荧光定量PCR测定GES-1细胞中Apaf-1、ASC、Bcl-2、Bcl-xl、Bad、Bax、caspase-1、COX-1、COX-2、GCLC、HO-1、iNOS、Keap-1、NEK7、NLRP3、NQO1、Nrf2、PGE2、TXNIP mRNA表达；Western blot测定GES-1细胞中Apaf-1、ASC、Bcl-2、Bcl-xl、Bad、Bax、caspase-1、cleaved-caspase-3、cleaved-caspase-9、PARP-1、cleaved-PARP-1、GCLC、HO-1、Keap-1、NEK7、NLRP3、NQO1、pro-caspase-1、pro-caspase-3、pro-caspase-9、pro-IL-18、pro-IL-1β、总Nrf2、TXNIP蛋白表达。结果: 与模型组比较，TA可显著促进乙醇诱导的GES-1细胞迁移；显著抑制细胞凋亡和LDH释放；降低细胞内ROS水平，上清液中IL-1β、IL-6、IL-18、NO、TNF-α水平，细胞中MDA、MPO水平和胞浆中cytochrome C含量（P<0.01）；升高MMP，上清液中IL-4、IL-10水平，细胞中CAT、GSH、SOD、T-AOC水平和线粒体中cytochrome C含量（P<0.01）；下调乙醇诱导的GES-1细胞中ASC、Apaf-1、Bad、Bax、caspase-1、COX-2、iNOS、Keap-1、NEK7、NLRP3、TXNIP mRNA和ASC、Apaf-1、Bad、Bax、caspase-1、cleaved-caspase-3、cleaved-caspase-9、cleaved-PARP-1、Keap-1、NEK7、NLRP3、pro-caspase-1、pro-IL-1β、pro-IL-18、TXNIP蛋白表达，抑制GES-1细胞内NLRP3、ASC和caspase-1共定位；改善细胞核及核仁结构、减轻线粒体肿胀；上调乙醇诱导的GES-1细胞中COX-1、Bcl-2、Bcl-xl、GCLC、HO-1、NQO1、Nrf2、PGE2 mRNA和Bcl-2、Bcl-xl、GCLC、HO-1、NQO1、总Nrf2、胞核Nrf2、pro-caspase-3、pro-caspase-9蛋白表达及Bcl-2/Bax、Bcl-xl/Bad比率（P<0.01）。结论: TA对乙醇所致GES-1细胞损伤具有显著的保护作用，其作用机制与激活Keap-1/Nrf2通路、减轻氧化应激，抑制NLRP3炎症小体通路激活、减轻炎症反应，进而抑制线粒体凋亡通路激活密切相关。

关键词: 委陵菜酸, 胃细胞损伤, 氧化应激, 炎症反应, Keap1/Nrf2信号通路, NLRP3炎症小体信号通路

Abstract:

AIM: To investigate the protective effect and mechanisms of tormentic acid (TA) on GES-1 cells induced by alcohol. METHODS: The GES-1 cell injury model induced alcohol was established. The GES-1 cells were divided into control group, model group, TA (12.5 μg/mL) group, Nrf2 inhibitor group (ML385, 10 μmol/L) group and NLRP3 inhibitor (MCC950, 8 μmol/L) group. After adding the corresponding drugs to the drug intervention group cells and culturing them for 22 hours, cells were treated with 7% alcohol except for the control group and cultured for another 2 hours, and then the cell supernatant and cells were collected, respectively. MTT assay was used to test cell viability; Cell scratch and Transwell were utilized to detect cell migration; AnnexinV FITC/PI double staining was used to test cell apoptosis; Immunofluorescences were used to detect MMP and ROS level in alcohol induced GES-1 cells; Colorimetric and ELISA methods were used to test the levels of LDH, IL-4, IL-1β, IL-6, IL-10, IL-18, NO and TNF-α in the GES-1 cell supernatants; Colorimetric method was utilized to detect the levels of CAT, GSH, MDA, MPO, SOD, T-AOC in alcohol induced GES-1 cells, and cytochrome C in the cytosol and mitochondria of GES-1 cells; Immunofluorescence was utilized to detect the co-localization of NLRP3, ASC and caspase-1; The changes in intracellular ultrastructure were observed under an electron microscope; Real-time PCR was used to detect the mRNA expression levels of Apaf-1, ASC, Bcl-2, Bcl-xl, Bad, Bax, caspase-1, COX-1, COX-2, GCLC, HO-1, iNOS, Keap-1, NEK7, NLRP3, NQO1, Nrf2, PGE2 and TXNIP in alcohol induced GES-1 cells; Western blot was utilized to test the protein expression levels of Apaf-1, ASC, Bcl-2, Bcl-xl, Bad, Bax, caspase-1, cleaved-caspase-3, cleaved-caspase-9, PARP-1, cleaved-PARP-1, GCLC, HO-1, Keap-1, NEK7, NLRP3, NQO1, nuclear Nrf2, pro-caspase-1, pro-caspase-3, pro-caspase-9, pro-IL-18, pro-IL-1β, total Nrf2 and TXNIP in GES-1 cells. RESULTS: Compared with the model group, TA prominently promote alcohol induced GES-1 cell migration, depressed cell apoptosis and LDH release, substantially reduced intracellular ROS level, IL-1β, IL-6, IL-18, NO, TNF-α levels in the GES-1 cell supernatants, MDA, MPO levels in alcohol induced GES-1 cells and cytochrome C content in cytosol (P<0.01), substantially elevated mitochondrial membrane potential, IL-4, IL-10 levels in the GES-1 cell supernatants, CAT, GSH, SOD, T-AOC levels in alcohol induced GES-1 cells and cytochrome C content in the mitochondria (P<0.01). It dramatically down-regulated the ASC, Apaf-1, Bad, Bax, caspase-1, COX-2, iNOS, Keap-1, NEK7, NLRP3, TXNIP mRNA and ASC, Apaf-1, Bad, Bax, caspase-1, cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP-1, Keap-1, NEK7, NLRP3, pro-caspase-1, pro-IL-1β, pro-IL-18, TXNIP protein expressions in alcohol induced GES-1 cells, restrained co-localization of NLRP3, ASC and caspase-1 in alcohol induced GES-1 cells; The structure of the nucleus and nucleolus was intact, chromatin was uniform, and mitochondrial swelling was reduced; TA up-regulated the COX-1, Bcl-2, Bcl-xl, GCLC, HO-1, NQO1, Nrf2, PGE2 mRNA and Bcl-2, Bcl-xl, GCLC, HO-1, NQO1, total Nrf2, nuclear Nrf2, pro-caspase-3, pro-caspase-9 protein expressions and Bcl-2/Bax, Bcl-xl/Bad ratios in the alcohol induced GES-1 cells (P<0.01). CONCLUSION: TA has a significant protective effect on alcohol damaged GES-1 cells, and its mechanism is closely related to activating the Keap-1/Nrf2 pathway, reducing oxidative stress, inhibiting the activation of the NLRP3 inflammasome pathway, alleviating inflammatory response, and thereby suppressing the activation of the mitochondrial apoptosis pathway.

Key words: tormentic acid, gastric cell damage, oxidative stress, inflammatory response, Keap1/Nrf2 signaling pathway, NLRP3 inflammasome signaling pathway

中图分类号:

R285.5

周如凤, 张颖, 孟子元, 刘杰, 石孟琼, 廖勇, 许杰, 李浩然, 谈燕清, 覃慧林, 贾亮亮, 游艳. 委陵菜酸调节Keap-1/Nrf2和NLRP3炎症小体信号通路对乙醇诱导GES-1细胞损伤的保护作用及机制研究[J]. 中国临床药理学与治疗学, 2026, 31(8): 1034-1052.

Rufeng ZHOU, Ying ZHANG, Ziyuan MENG, Jie LIU, Mengqiong SHI, Yong LIAO, Jie XU, Haoran LI, Yanqing TAN, Huilin QIN, Liangliang JIA, Yan YOU. Tormentic acid protects alcohol induced GES-1 cells via regulating Keap-1/Nrf2 and NLRP3 inflammasome signaling pathways[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(8): 1034-1052.

图/表 13

图 1

Fig.1 TA?s chemical structure and effects of different concentrations of TA and alcohol on the viabilities of GES-1 cells ($ \overline{x} $±s, n=5) A: TAʼs chemical structure; B: effect of TA on the viability of GES-1 cells; C: effect of ethanol on the cell viability of GES-1 cells; D: effect of ethanol on the cell viability of GES-1 cells induced by alcohol; bP<0.05, cP<0.01, compared with control group; eP<0.05, fP<0.01, compared with model group.

表 1

Table 1 Primer sequences

Gene	F:(5′-3′)	R:(5′-3′)
Keap-1	AGCGTGGAGAGAGATATGAGCC	ATCATCCGCCACTCATTCCT
Nrf2	GGCTACGTTTCAGTCACTT	AGCTCCTCCCAAACTTGCTC
GCLC	TGGCAATGCAGTGGTGGAT	AACACACCTTCCTTCCCATTGA
HO-1	TGGCAGCTGTCTCAAACCTC	TGCCGTTAAACACCTCCCTC
NQO1	CAGTGGTTTGGAGTCCCTGC	CAGTGGTTTGGAGTCCCTGCA
TXNIP	CAGCAGTGCAAACAGACTTCGG	CTGAGGAAGCTCAAAGCCGAAC
NEK7	ATGGAGGAGCCCGAGAAGAG	CTCCTGCTCCAGCTTCTTCC
NLRP3	GCACTGTGTTTGGAGTGGGTTTCA	CCCGACAGTGGATATAGAACAGA
ASC	TGGATGCTCTGTACGGGAAG	CCAGGCTGGTGTGAAACTGAA
Caspase-1	TTTCCGCAAGGTTCGATTTTCA	GGCATCTGCGCTCTACCATC
COX-1	CTATCACTGGATCCGTTCAT	AAAGTTCCTACCCCCACCAAT
COX-2	CAAATCCTTGCTGTTCCCACCCAT	GCACTGTGTTTGGAGTGGGTTTCA
iNOS	GCAATGGGCAGACTCTGAAG	CGATGTCATGAGCAAAGGCA
PGE2	CTCCTTGCCTTTCACGATTT	ACAACAGAGGACTGAACGCAT
Bcl-2	CATGTGTGTGGAGAGCGTCAA	GCCGGTTCAGGTACTCAGTCA
Bcl-xl	TCCTTGTCTACGCTTTCCACG	GGTCGCATTGTGGCCTTT
Bax	ATGGGCTGGACATTGGAC	GGGACATCAGTCGCTTCAG
Bad	CCAGAGTTTGAGCCGAGTGAG	GATGATGCTTGCCGGAGCC
Apaf-1	AGGACACAGACGGTGGAAAC	ATCGCACTGACCAGCTTCTT
GAPDH	AACGGCACAGTCAAGGCTGA	ACG CCAGTAGACTCCACGACAT

图 2

Fig.2 Effect of TA on migration ability of GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: cell scratch assay for detecting cell migration (scale bar=50 µm); B: transwell assay for detecting cell migration (scale bar=100 µm); cP<0.01, compared with control group; eP<0.05, fP<0.01, compared with model group.

图 3

Fig.3 Effect of TA on apoptosis of GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) cP<0.01, compared with control group; fP<0.01, compared with model group.

图 4

Fig.4 Effects of TA on ROS level and MMP of GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: ROS levels (scale bar=100 µm); B:MMP (scale bar=100 µm); cP<0.01, compared with the control group; fP<0.01, compared with the model group.

图 5

Fig.5 Effect of TA on cytokine levels of the supernatant of GES-1 cells and GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: cytokine levels in cell supernatant; B: mRNA expressions of cytokines in cells; cP<0.01, compared with control group; fP<0.01, compared with model group.

图 6

Fig.6 Effects of TA on LDH level and oxidative stress index of GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: LDH release; B: MDA levels; C-G: endogenous antioxidant enzyme activity; cP<0.01, compared with control group; fP<0.01, compared with model group.

图 7

Fig.7 Effect of TA on co localization of NLRP3 inflammasome in GES-1 cells induced by alcohol (scale bar=200 μm)

图 8

Fig.8 Effect of TA on the ultrastructure in GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: mitochondrial ultrastructure of GES-1 cells under electron microscopy; B: quantitative comparison of mitochondrial area; C: comparison of mitochondrial count, with each count defined within the size range of 4 μm × 4 μm; D: comparison of mitochondrial aspect ratio, i.e. the ratio of mitochondrial long axis to short axis; The red arrow points to the mitochondria, and the yellow arrow points to the nucleus, scale bar=2 μm; cP<0.01, compared with control group; fP<0.01, compared with model group.

图 9

Fig.9 Effects of TA on the relative gene mRNA and protein expressions Keap1/Nrf2 pathway in GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: relative gene mRNA expressions of Keap-1/Nrf2 pathway; B: relative gene protein expressions of Keap-1/Nrf2 pathway; cP<0.01, compared with control group; eP<0.05, fP<0.01, compared with model group.

图 10

Fig.10 Effects of TA on the relative gene mRNA and protein expressions NLRP3 inflammasome pathway in GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: relative gene mRNA expressions of NLRP3 inflammasome pathway; B: relative gene protein expressions of NLRP3 inflammasome pathway; cP<0.01, compared with the control group; fP<0.01, compared with the model group.

图 11

Fig.11 Effects of TA on the relative gene mRNA and protein expressions of mitochondria-dependent apoptotic pathway in GES-1 cells induced by alcohol ($ \overline{x} $±s, n=5) A: cytochrome C content in cytosol and mitochondria; B: relative gene mRNA expressions of mitochondria-dependent apoptotic pathway; C: relative gene protein expressions of mitochondria-dependent apoptotic pathway; cP<0.01, compared with control group; fP<0.01, compared with model group.

图 12

Fig.12 The mechanism of TA regulating Keap-1/Nrf2 and NLRP3 inflammasome signaling pathways in protecting against ethanol induced GES-1 cell damage

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委陵菜酸调节Keap-1/Nrf2和NLRP3炎症小体信号通路对乙醇诱导GES-1细胞损伤的保护作用及机制研究

Tormentic acid protects alcohol induced GES-1 cells via regulating Keap-1/Nrf2 and NLRP3 inflammasome signaling pathways

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