Protective potential of nodakenin in high-fat diet-mediated colitis-associated cancer: Inhibition of STAT3 activation and Wnt/β-catenin pathway, and gut microbiota modulation

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-05-02 DOI:10.1016/j.intimp.2025.114734

Kyung-Sook Chung , So-Won Heo , Jung-Hun Lee , Hee-Soo Han , Gi-Hui Kim , Ye-Rin Kim , Min-Su Kim , Ju-Eun Hong , Ki-Jong Rhee , Kyung-Tae Lee

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Abstract

A high-fat diet (HFD) exerts complex effects on the risk of colitis-associated cancer (CAC). Nodakenin, a key phytochemical isolated from the dried roots of Angelicae gigas Nakai (Umbelliferae), possesses anti-inflammatory and anti-adipogenic properties and shows potential as a therapeutic agent for colorectal cancer (CRC). In this study, we investigated the protective effects and underlying molecular mechanisms of nodakenin in an animal model of CRC induced by HFD, azoxymethane (AOM), and dextran sodium sulfate (DSS). Oral administration of nodakenin significantly alleviated clinical symptoms, such as recovery of weight, spleen weight, and colon length, and suppressed tumor progression in the colonic tissues of HFD/AOM/DSS-induced CRC mice. Nodakenin inhibited the activation of STAT3-related inflammatory mediators and downregulated proteins involved in the Wnt/β-catenin signaling pathway. These effects contributed to the disruption of epithelial-mesenchymal transition (EMT) and the restoration of tight junction integrity within the colonic tissue. Furthermore, nodakenin treatment improved the composition of the gut microbiota, leading to observable species-level differences. Network analysis revealed significant correlations between clinical parameters, inflammatory markers, EMT and apoptotic factors, and the composition of the gut microbiota. Specifically, negative correlations were observed between spleen weight and Alistipes, as well as between MCP-1 and Clostridium_g21. Positive correlations with spleen weight were observed with species belonging to Anaerotruncus, Emergencia, and Parvibacter. Bacteroidaceae_uc and Bacteroides correlated positively with MCP-1, Streptococcus correlated positively with PUMA, and Harryflintia, Odoribacteraceae_uc, and Roseburia correlated positively with cleaved caspase-3. Overall, our findings suggested that nodakenin effectively alleviates HFD/AOM/DSS-induced CRC by targeting inflammatory pathways (STAT3 and Wnt/β-catenin), suppressing EMT, and restoring gut microbiota balance. These multiple mechanisms underscore its potential as a promising agent for the prevention and treatment of colitis-associated colorectal cancer.

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nodakenin在高脂肪饮食介导的结肠炎相关癌症中的保护潜力：STAT3激活和Wnt/β-catenin通路的抑制，以及肠道微生物群的调节

高脂肪饮食（HFD）对结肠炎相关癌症（CAC）的风险有复杂的影响。Nodakenin是一种从白芷（Angelicae gigas Nakai）干根中分离出来的重要植物化学物质，具有抗炎和抗脂肪生成的特性，有望成为结直肠癌（CRC）的治疗药物。在这项研究中，我们研究了nodakenin在HFD、偶氮氧甲烷（AOM）和葡聚糖硫酸钠（DSS）诱导的CRC动物模型中的保护作用和潜在的分子机制。口服nodakenin可显著缓解HFD/AOM/ dss诱导的结直肠癌小鼠体重、脾脏重量、结肠长度恢复等临床症状，抑制结肠组织肿瘤进展。Nodakenin抑制stat3相关炎症介质的激活和下调参与Wnt/β-catenin信号通路的蛋白。这些作用有助于破坏上皮-间质转化（EMT）和恢复结肠组织内紧密连接的完整性。此外，nodakenin处理改善了肠道微生物群的组成，导致可观察到的物种水平差异。网络分析显示，临床参数、炎症标志物、EMT和凋亡因子与肠道菌群组成之间存在显著相关性。具体而言，脾脏重量与Alistipes以及MCP-1与Clostridium_g21呈负相关。脾脏重量与属厌氧菌属、紧急菌属和细小杆菌属的菌种呈正相关。拟杆菌科（bacteroidace_uc）和拟杆菌科（Bacteroides）与MCP-1呈正相关，链球菌（Streptococcus）与PUMA呈正相关，Harryflintia、odoribacterace_uc和Roseburia与cleaved caspase-3呈正相关。总体而言，我们的研究结果表明，nodakenin通过靶向炎症通路（STAT3和Wnt/β-catenin）、抑制EMT和恢复肠道微生物群平衡，有效缓解HFD/AOM/ dss诱导的CRC。这些多重机制强调了其作为预防和治疗结肠炎相关结直肠癌的有希望的药物的潜力。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.