PH-sensitive molybdenum (Mo)-based polyoxometalate nanoclusters have therapeutic efficacy in inflammatory bowel disease by counteracting ferroptosis. (February 2023)

• Record Type: Journal Article
• Authors: Yang, Fan; Chen, Yuechuan; Xiao, Yitai; Jiang, Hailong; Jiang, Zebo; Yang, Meilin; Li, Mengzhu; Su, Yonghui; Yan, Zhixiang; Lin, Yong; Li, Dan
• Is Part Of: Pharmacological research. Volume 188(2023)
• Publication Date: 2023-02
• Subjects: Molybdenum-based polyoxometalate nanocluster -- Reactive oxygen species -- Ferroptosis -- Metabolite analysis -- Ulcerative colitis therapy; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2023.106645
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Current therapeutic drugs for ulcerative colitis (UC) remained inadequate due to drug dependence and unacceptable adverse events. Reactive oxygen species (ROS) played a critical role in the occurrence and development of UC, which most likely benefited from treatment in scavenging ROS. In this study, we developed a pH-sensitive molybdenum-based polyoxometalate (POM) nanocluster, which might contribute to site specific colonic delivery and enhance systemic efficacy of UC treatment. Our results demonstrated that POM displayed robust ROS scavenging ability in vitro . POM could significantly alleviate the enteric symptoms and inflammatory indicators in DSS-induced UC mouse models. Flow cytometry showed an effective diminishment of macrophages, neutrophils and T cells infiltration after POM administration in UC models. Also, for the first time, we demonstrated that POM interfered with metabolic pathway associated to oxidative stress and partially improved the abnormal production of intestinal metabolites in UC to some extent. Benefiting from the ROS scavenging ability, POM attenuated ferroptosis in DSS induced UC, as evidenced by increase of GSH, down-expression of GPX4 and improvement in mitochondrial morphological changes. Meanwhile, there were no side effects on normal tissues. Thus, our powerful therapeutic effects pioneered the application of POM for safer and more effective POM-based UC therapy. Graphical Abstract: A pH-sensitive molybdenum-based POM that could contribute to site specific colonic delivery and enhance systemic efficacy of UC treatment. POM improved metabolic pathway associated to oxidative stress and reduced the abnormal production of intestinal metabolites in UC. Ferroptosis could be attenuated by POM, which alleviated the infiltration of macrophages and neutrophils. ga1 Highlights: We developed a pH-sensitive POM nanoclusters, which contributed to site-specific colonic delivery and UC alleviation in mice. POM interfered with metabolic oxidative stress pathway and improved the abnormal production of intestinal metabolites in UC. POM reduces the infiltration of macrophages and neutrophils by attenuating ferroptosis.