d -环丝氨酸对IBD和CAC小鼠模型的治疗作用：靶向NLRP3炎性体和肠屏障完整性

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-07-14 DOI:10.1016/j.intimp.2025.115209

Shengwei Chen , Lizhuowen Yan , Jingtao Zeng , Wei Meng , Jionghan Zhuang , Fengying Chen , Yonglong Guo , A.M. Abd El-Aty , Xianghong Ju , Shihua Yang

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引用次数: 0

摘要

d-环丝氨酸（DCS）是一种广谱抗生素和NMDA受体调节剂，其免疫调节作用超出了其已知的神经和抗菌功能。本研究通过体外和体内模型研究了DCS在炎症性肠病（IBD）和结肠炎相关结直肠癌（CAC）中的治疗潜力。在脂多糖（LPS）刺激的NCM460细胞中，DCS抑制NLRP3炎性体的激活并恢复紧密连接蛋白的表达。在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎中，预防性和治疗性DCS方案均能减轻炎症，减少组织病理学损伤，并保持肠屏障的完整性。在azoxymethane (AOM)/ dss诱导的CAC中，DCS降低了肿瘤负荷，降低了Ki-67+细胞的增殖，无全身毒性。这些发现表明DCS是通过抑制NLRP3-caspase-1-GSDMD通路和维持上皮屏障来治疗IBD和CAC的有希望的双靶点候选药物。

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Therapeutic effects of D-cycloserine in mouse models of IBD and CAC: Targeting NLRP3 inflammasome and intestinal barrier integrity

D-Cycloserine (DCS), a broad-spectrum antibiotic and NMDA receptor modulator, exhibits immunomodulatory effects beyond its known neurological and antimicrobial functions. This study investigated DCS's therapeutic potential in inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) using in vitro and in vivo models. In lipopolysaccharide (LPS)-stimulated NCM460 cells, DCS inhibited NLRP3 inflammasome activation and restored tight junction protein expression. In dextran sulfate sodium (DSS)-induced murine colitis, both preventive and therapeutic DCS regimens attenuated inflammation, reduced histopathological damage, and preserved intestinal barrier integrity. In azoxymethane (AOM)/DSS-induced CAC, DCS decreased tumor burden and reduced Ki-67+ cell proliferation without systemic toxicity. These findings position DCS as a promising dual-target candidate for IBD and CAC management through NLRP3-caspase-1-GSDMD pathway inhibition and epithelial barrier maintenance.

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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.