Mechanistic study of the therapeutic effect of berberine on ulcerative colitis in mice based on the Bak/Bax/Caspase-9 pathway
-
摘要: 目的 探讨小檗碱通过Bak/Bax/Caspase-9通路对溃疡性结肠炎(ulcerative colitis，UC)小鼠保护作用的机制。方法 将32只C57BL/6小鼠随机分为正常组、模型组、美沙拉嗪组、小檗碱组，每组8只。除正常组外，其余组予以3%葡聚糖硫酸钠盐(dextran sulfate sodium salt，DSS)构建UC小鼠模型。记录各组小鼠的疾病活动指数(disease activity index，DAI)评分及体重；测量结肠长度、脾脏指数；通过苏木精-伊红染色观察结肠、脾脏组织病理变化；利用qRT-PCR和Western blot法分别检测结肠组织中Bak、Bax、Caspase-9的mRNA和蛋白表达。结果 与模型组比较，小檗碱组小鼠的DAI评分与脾脏指数显著降低(P < 0.05)，结肠及脾脏病理损伤显著缓解，体重变化率和结肠长度显著升高(P < 0.01)，结肠组织中Bak、Bax、Caspase-9的mRNA和蛋白表达显著降低(P < 0.05)。结论 小檗碱能够降低UC小鼠的炎症反应，改善结肠和脾脏病理损伤，其作用可能与调控Bak/Bax/Caspase-9通路相关。
-
关键词:
- 溃疡性结肠炎 /
- 小檗碱 /
- 凋亡 /
- Bak/Bax/Caspase-9通路
Abstract: Objective This study aimed to investigate the protective effect of berberine on mice with ulcerative colitis(UC) and the involvement of the Bak/Bax/Caspase-9 pathway.Methods A total of thirty-two C57BL/6 mice were divided into four groups: normal group, model group, mesalazine group, and berberine group. The mice were randomly assigned to these groups for the study. The UC mouse model was induced in all groups using 3% dextran sulfate sodium salt(DSS). Disease activity index(DAI) score and body weight were recorded daily. Colon length and spleen index were measured. HE staining examined colon and spleen tissue changes. Bak, Bax, and Caspase-9 mRNA/protein expression in colon was measured via qRT-PCR/Western blot.Results Compared to the model group, the berberine group exhibited a significant reduction in the DAI score and spleen index(P < 0.05), along with improved colon and spleen pathological damage, there were significant increases in percentage of body weight change and colon length(P < 0.01), mRNA and protein expression of Bak, Bax, and Caspase-9 in colon tissues were significantly decreased in the berberine group(P < 0.05).Conclusion Berberine reduced inflammation and improved colon and spleen pathological damage in UC mice, potentially through modulation of the Bak/Bax/Caspase-9 pathway.-
Key words:
- ulcerative colitis /
- berberine /
- apoptosis /
- Bak/Bax/Caspase-9 pathway
-
-
表 2 引物序列
基因 上游引物序列(5′-3′) 下游引物序列(5′-3′) GAPDH AGCTTGTCATCAACGGGAAG TTTGATGTTAGTGGGGTCTCG Bak GATGGACAACTTGCCCCTGGAAC AATTCTGGAACTCTGTGTCGTAGCG Bax GCTACAGGGTTTCATCCAGGATCG TGCTGTCCAGTTCATCTCCAATTCG Caspase-9 TGCTGTGTCAAGTTTGCCTACCC TGCTGTGTCAAGTTTGCCTACCC 
下载: 导出CSV
-
[1] Segal JP, LeBlanc JF, Hart AL. Ulcerative colitis: an update[J]. Clin Med(Lond), 2021, 21(2): 135-139.
[2] Wei SC, Sollano J, Hui YT, et al. Epidemiology, burden of disease, and unmet needs in the treatment of ulcerative colitis in Asia[J]. Expert Rev Gastroenterol Hepatol, 2021, 15(3): 275-289. doi: 10.1080/17474124.2021.1840976
[3] Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis[J]. Lancet, 2023, 402(10401): 571-584. doi: 10.1016/S0140-6736(23)00966-2
[4] Uniken VW, Voskuil MD, Dijkstra G, et al. The genetic background of inflammatory bowel disease: from correlation to causality[J]. J Pathol, 2017, 241(2): 146-158. doi: 10.1002/path.4817
[5] Calmejane L, Laharie D, Kirchgesner J, et al. Review article: Updated management of acute severe ulcerative colitis: From steroids to novel medical strategies[J]. United European Gastroenterol J, 2023, 11(8): 722-732. doi: 10.1002/ueg2.12442
[6] Gros B, Kaplan GG. Ulcerative Colitis in Adults: A Review[J]. JAMA, 2023, 330(10): 951-965. doi: 10.1001/jama.2023.15389
[7] Zhou R, Huang Y, Tian C, et al. Coptis chinensis and Berberine Ameliorate Chronic Ulcerative Colitis: An Integrated Microbiome-Metabolomics Study[J]. Am J Chin Med, 2023: 1-26.
[8] Wang M, Fu R, Xu D, et al. Traditional Chinese Medicine: A promising strategy to regulate the imbalance of bacterial flora, impaired intestinal barrier and immune function attributed to ulcerative colitis through intestinal microecology[J]. J Ethnopharmacol, 2024, 318(Pt A): 116879.
[9] 盛红艳, 张薇. 地榆槐花汤保留灌肠联合美沙拉嗪治疗脾虚湿蕴型溃疡性结肠炎的临床疗效及对患者内镜表现、肠黏膜屏障功能的影响[J]. 中国中西医结合消化杂志, 2023, 31(8): 577-582. doi: 10.3969/j.issn.1671-038X.2023.08.01 https://zxyxh.whuhzzs.com/article/doi/10.3969/j.issn.1671-038X.2023.08.01
[10] 韩啸, 傅智浩, 石磊, 等. 中医药治疗溃疡性结肠炎随机对照临床试验结局指标研究[J]. 中国中西医结合消化杂志, 2023, 31(4): 260-265, 273. doi: 10.3969/j.issn.1671-038X.2023.04.05 https://zxyxh.whuhzzs.com/article/doi/10.3969/j.issn.1671-038X.2023.04.05
[11] 中国中西医结合学会. 溃疡性结肠炎中西医结合诊疗专家共识[J]. 中国中西医结合杂志, 2023, 43(1): 5-11. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZXJ202301001.htm
[12] 张声生, 赵鲁卿. 中医药治疗溃疡性结肠炎的研究进展述评[J]. 北京中医药, 2022, 41(9): 944-950. https://www.cnki.com.cn/Article/CJFDTOTAL-BJZO202209001.htm
[13] 楼伟, 王伟东, 曹生辉. 芍药汤加减治疗溃疡性结肠炎效果及对YKL-40、IL-17变化的研究[J]. 中华中医药学刊, 2022, 40(1): 19-21. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYHS202201005.htm
[14] 周瑞, 项昌培, 张晶晶, 等. 黄连化学成分及小檗碱药理作用研究进展[J]. 中国中药杂志, 2020, 45(19): 4561-4573. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY202019004.htm
[15] Zhao L, Du X, Tian J, et al. Berberine-Loaded Carboxylmethyl Chitosan Nanoparticles Ameliorate DSS-Induced Colitis and Remodel Gut Microbiota in Mice[J]. Front Pharmacol, 2021, 12: 644387. doi: 10.3389/fphar.2021.644387
[16] Liu C, Zeng Y, Wen Y, et al. Natural Products Modulate Cell Apoptosis: A Promising Way for the Treatment of Ulcerative Colitis[J]. Front Pharmacol, 2022, 13: 806148. doi: 10.3389/fphar.2022.806148
[17] Zhang J, Cen L, Zhang X, et al. MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT[J]. Redox Biol, 2022, 56: 102469. doi: 10.1016/j.redox.2022.102469
[18] 陈晓, 王启之, 郦忆文, 等. NF-κB介导的促凋亡蛋白Bak表达在溃疡性结肠炎发病中的作用研究[J]. 中国免疫学杂志, 2016, 32(9): 1286-1290. doi: 10.3969/j.issn.1000-484X.2016.09.009
[19] Shen J, Cheng J, Zhu S, et al. Regulating effect of baicalin on IKK/IKB/NF-κB signaling pathway and apoptosis-related proteins in rats with ulcerative colitis[J]. Int Immunopharmacol, 2019, 73: 193-200. doi: 10.1016/j.intimp.2019.04.052
[20] Li X, Wu X, Wang Q, et al. Sanguinarine ameliorates DSS induced ulcerative colitis by inhibiting NLRP3 inflammasome activation and modulating intestinal microbiota in C57BL/6 mice[J]. Phytomedicine, 2022, 104: 154321. doi: 10.1016/j.phymed.2022.154321
[21] Wu D, Zhang Y, Zou B, et al. Shaoyao decoction alleviates TNBS-induced ulcerative colitis by decreasing inflammation and balancing the homeostasis of Th17/Treg cells[J]. BMC Complement Med Ther, 2023, 23(1): 424.
[22] Magro F, Lopes J, Borralho P, et al. Comparison of the Nancy Index With Continuous Geboes Score: Histological Remission and Response in Ulcerative Colitis[J]. J Crohns Colitis, 2020, 14(7): 1021-1025.
[23] Krugliak CN, Torres J, Rubin DT. What Does Disease Progression Look Like in Ulcerative Colitis, and How Might It Be Prevented?[J]. Gastroenterology, 2022, 162(5): 1396-1408.
[24] Wang X, Liang F, Dai Z, et al. Combination of Coptis chinensis polysaccharides and berberine ameliorates ulcerative colitis by regulating gut microbiota and activating AhR/IL-22 pathway[J]. J Ethnopharmacol, 2024, 318(Pt B): 117050.
[25] Xu L, Zhang Y, Xue X, et al. A PhaseⅠTrial of Berberine in Chinese with Ulcerative Colitis[J]. Cancer Prev Res (Phila), 2020, 13(1): 117-126.
[26] Sharma A, Tirpude NV, Kulurkar PM, et al. Berberis lycium fruit extract attenuates oxi-inflammatory stress and promotes mucosal healing by mitigating NF-kappaB/c-Jun/MAPKs signalling and augmenting splenic Treg proliferation in a murine model of dextran sulphate sodium-induced ulcerative colitis[J]. Eur J Nutr, 2020, 59(6): 2663-2681.
[27] 程红山. 盐酸小檗碱联合柳氮磺吡啶治疗溃疡性结肠炎的临床研究[J]. 中国肛肠病杂志, 2022, 42(2): 55-57. https://www.cnki.com.cn/Article/CJFDTOTAL-GCBZ202202023.htm
[28] Xu Y, Huang J, Fan Y, et al. Macrophage-Targeted Berberine-Loaded beta-Glucan Nanoparticles Enhance the Treatment of Ulcerative Colitis[J]. Int J Nanomedicine, 2022, 17: 5303-5314.
[29] 魏海梁, 李京涛, 陈志国, 等. 小檗碱与6-姜烯酚配伍对溃疡性结肠炎小鼠肠道炎症和菌群影响的实验研究[J]. 中国中药杂志, 2022, 47(16): 4418-4427. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY202216021.htm
[30] Yan S, Liu YC, Wang ZL, et al. Effect of Berberine from Coptis chinensis on Apoptosis of Intestinal Epithelial Cells in a Mouse Model of Ulcerative Colitis: Role of Endoplasmic Reticulum Stress[J]. Evid Based Complement Alternat Med, 2020, 2020: 3784671.
[31] Dong Y, Fan H, Zhang Z, et al. Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/beta-catenin pathway[J]. Int J Biol Sci, 2022, 18(4): 1381-1397.
[32] Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases[J]. Gastroenterology, 2011, 140(6): 1756-1767.
[33] Liu JL, Gao YY, Zhou J, et al. Changes in serum inflammatory cytokine levels and intestinal flora in a self-healing dextran sodium sulfate-induced ulcerative colitis murine model[J]. Life Sci, 2020, 263: 118587.
[34] Dai Y, Lu Q, Li P, et al. Xianglian Pill attenuates ulcerative colitis through TLR4/MyD88/NF-kappaB signaling pathway[J]. J Ethnopharmacol, 2023, 300: 115690.
[35] Fu YP, Yuan H, Xu Y, et al. Protective effects of Ligularia fischeri root extracts against ulcerative colitis in mice through activation of Bcl-2/Bax signalings[J]. Phytomedicine, 2022, 99: 154006.
[36] Zhu L, Dai LM, Shen H, et al. Qing Chang Hua Shi granule ameliorate inflammation in experimental rats and cell model of ulcerative colitis through MEK/ERK signaling pathway[J]. Biomed Pharmacother, 2019, 116: 108967.
-
图(5)
表(2)
计量
- 文章访问数: 1702
- PDF下载数: 1997
- 施引文献: 0