An inulin-type fructan CP-A from Codonopsis pilosula attenuates experimental colitis in mice by promoting autophagy-mediated inactivation of NLRP3 inflammasome

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Chinese Journal of Natural Medicines Pub Date : 2024-03-01 DOI:10.1016/S1875-5364(24)60556-X
Jiangtao ZHOU , Jun WANG , Jiajing WANG , Deyun LI, Jing HOU, Jiankuan LI, Yun'e BAI, Jianping GAO
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Abstract

Inulin-type fructan CP-A, a predominant polysaccharide in Codonopsis pilosula, demonstrates regulatory effects on immune activity and anti-inflammation. The efficacy of CP-A in treating ulcerative colitis (UC) is, however, not well-established. This study employed an in vitro lipopolysaccharide (LPS)-induced colonic epithelial cell model (NCM460) and an in vivo dextran sulfate sodium (DSS)-induced colitis mouse model to explore CP-A's protective effects against experimental colitis and its underlying mechanisms. We monitored the clinical symptoms in mice using various parameters: body weight, disease activity index (DAI), colon length, spleen weight, and histopathological scores. Additionally, molecular markers were assessed through enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence (IF), immunohistochemistry (IHC), and Western blotting assays. Results showed that CP-A significantly reduced reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), and interleukins (IL-6, IL-1β, IL-18) in LPS-induced cells while increasing IL-4 and IL-10 levels and enhancing the expression of Claudin-1, ZO-1, and occludin proteins in NCM460 cells. Correspondingly, in vivo findings revealed that CP-A administration markedly improved DAI, reduced colon shortening, and decreased the production of myeloperoxidase (MPO), malondialdehyde (MDA), ROS, IL-1β, IL-18, and NOD-like receptor protein 3 (NLRP3) inflammasome-associated genes/proteins in UC mice. CP-A treatment also elevated glutathione (GSH) and superoxide dismutase (SOD) levels, stimulated autophagy (LC3B, P62, Beclin-1, and ATG5), and reinforced Claudin-1 and ZO-1 expression, thereby aiding in intestinal epithelial barrier repair in colitis mice. Notably, the inhibition of autophagy via chloroquine (CQ) diminished CP-A's protective impact against colitis in vivo. These findings elucidate that CP-A's therapeutic effect on experimental colitis possibly involves mitigating intestinal inflammation through autophagy-mediated NLRP3 inflammasome inactivation. Consequently, inulin-type fructan CP-A emerges as a promising drug candidate for UC treatment.

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通过促进自噬介导的 NLRP3 炎症小体失活,从党参中提取的菊粉型果聚糖 CP-A 可减轻小鼠的实验性结肠炎
菊粉型果聚糖 CP-A 是党参中的一种主要多糖,对免疫活性和抗炎具有调节作用。然而,CP-A 对治疗溃疡性结肠炎(UC)的疗效尚未得到充分证实。本研究采用体外脂多糖(LPS)诱导的结肠上皮细胞模型(NCM460)和体内葡聚糖硫酸钠(DSS)诱导的结肠炎小鼠模型来探讨 CP-A 对实验性结肠炎的保护作用及其内在机制。我们使用各种参数监测小鼠的临床症状:体重、疾病活动指数(DAI)、结肠长度、脾脏重量和组织病理学评分。此外,我们还通过酶联免疫吸附试验(ELISA)、实时定量聚合酶链式反应(qRT-PCR)、免疫荧光(IF)、免疫组织化学(IHC)和 Western 印迹法对分子标记物进行了评估。结果表明,CP-A 能明显降低 LPS 诱导细胞中的活性氧(ROS)、肿瘤坏死因子-α(TNF-α)和白细胞介素(IL-6、IL-1β、IL-18),同时提高 IL-4 和 IL-10 的水平,并增强 NCM460 细胞中 Claudin-1、ZO-1 和 occludin 蛋白的表达。相应地,体内研究结果表明,CP-A 能明显改善 UC 小鼠的 DAI,减少结肠缩短,并降低髓过氧化物酶 (MPO)、丙二醛 (MDA)、ROS、IL-1β、IL-18 和 NOD 样受体蛋白 3 (NLRP3) 炎症体相关基因/蛋白的产生。CP-A 还能提高谷胱甘肽(GSH)和超氧化物歧化酶(SOD)的水平,刺激自噬(LC3B、P62、Beclin-1 和 ATG5),增强 Claudin-1 和 ZO-1 的表达,从而帮助结肠炎小鼠修复肠上皮屏障。值得注意的是,通过氯喹(CQ)抑制自噬会削弱 CP-A 对体内结肠炎的保护作用。这些发现阐明了 CP-A 对实验性结肠炎的治疗作用可能涉及通过自噬介导的 NLRP3 炎性体失活来减轻肠道炎症。因此,菊粉型果聚糖 CP-A 成为治疗 UC 的一种有前途的候选药物。
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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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