详细信息

Guiqi Baizhu prescription ameliorates cytarabine-induced intestinal mucositis by targeting JAK2 to inhibit M1 macrophage polarization  ( SCI-EXPANDED收录)   被引量:3

文献类型:期刊文献

英文题名:Guiqi Baizhu prescription ameliorates cytarabine-induced intestinal mucositis by targeting JAK2 to inhibit M1 macrophage polarization

作者:Chu, Wei[1,2];Li, Ya-ling[1,2,3];Li, Jun-jie[1,2];Lin, Jia[4];Li, Mi[4];Wang, Jiao[4];He, Jian-zheng[1,2];Zhang, Yue-mei[5];Yao, Juan[4];Jin, Xiao-jie[1,2,4,8];Cai, Hui[6,7,9];Liu, Yong-qi[1,2,3,8]

第一作者:Chu, Wei

通信作者:Jin, XJ[1];Jin, XJ[2];Liu, YQ[2];Cai, H[3]

机构:[1]Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, Lanzhou 730000, Peoples R China;[2]Gansu Univ Chinese Med, Chinese Med Prevent & Treatment Major Dis, Lanzhou 730000, Peoples R China;[3]Gansu Univ Chinese Med, Key Lab Dun Huang Med & Transformat, Minist Educ Peoples Republ China, Lanzhou 730000, Peoples R China;[4]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[5]First Hosp Lanzhou Univ, Ophthalmol Dept, Lanzhou 730000, Peoples R China;[6]Gansu Prov Hosp, Key Lab Mol Diagnost & Precis Med Surg Oncol Gansu, Lanzhou 730000, Peoples R China;[7]Gansu Prov Hosp, NHC Key Lab Diag & Therapy Gastrointestinal Tumor, Lanzhou 730000, Peoples R China;[8]Gansu Univ Chinese Med, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[9]Gansu Prov Hosp, Lanzhou 730000, Peoples R China

第一机构:甘肃中医药大学

通信机构:[1]corresponding author), Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[3]corresponding author), Gansu Prov Hosp, Lanzhou 730000, Peoples R China.|[10735]甘肃中医药大学;[1073501e14fb35863569f]甘肃中医药大学药学院(西北中藏药协同创新中心办公室);

年份:2023

卷号:164

外文期刊名:BIOMEDICINE & PHARMACOTHERAPY

收录:;Scopus(收录号:2-s2.0-85159604520);WOS:【SCI-EXPANDED(收录号:WOS:001001926700001)】;

基金:This study was supported by the National Natural Science Foundation of China (No. 82260927, 82160857), the Youth Science and Technology Fund in Gansu (21JR11RA149), the Foundation of Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province (No. DHYX20-07) and Basic Research Innovation Group in Gansu (20JR10RA332).

语种:英文

外文关键词:Intestinal mucositis; JAK2; STAT1; Macrophage polarization; Acridine; Senkyunolide A

摘要:Background: Intestinal mucositis (IM) is characterized by damage to the intestinal mucosa resulting from inhi-bition of epithelial cell division and loss of renewal capacity following anticancer chemotherapy and radio-therapy. Cytarabine (Ara-C), the main chemotherapy drug for the treatment of leukemia and lymphoma, is a frequent cause of IM. Guiqi Baizhu prescription (GQBZP) is a traditional Chinese medicine with anti-cancer and anti-inflammatory effects.Purpose: To determine if GQBZP can ameliorate Ara-C induced IM and identify and characterize the pharma-cologic and pharmacodynamic mechanisms.Study design and methods: IM was induced in mice with Ara-C and concurrently treated with orally administered GQBZP. Body weight and food intake was monitored, with HE staining to calculate ileal histomorphometric scoring and villus length/crypt depth. Immunoblotting was used to detect intestinal tissue inflammatory factors. M1 macrophages (M1) were labeled with CD86 by flow cytometry and iNOS + F4/80 by immunofluorescence. Virtual screening was used to find potentially active compounds in GQBZP that targeted JAK2. In vitro, RAW264.7 cells were skewed to M1 macrophage polarization by lipopolysaccharide (LPS) and interferon-gamma (INF-gamma) and treated orally with GQBZP or potential active compounds. M1 was labeled with CD86 by flow cytometry and iNOS by immunofluorescence. ELISA was used to detect inflammatory factor expression. Active compounds against JAK2, p-JAK2, STAT1 and p-STAT1 were identified by western blotting and HCS fluorescence. Molecular dynamics simulations and pharmacokinetic predictions were carried out on representative active compounds.Results: Experimental results with mice in vivo suggest that GQBZP significantly attenuated Ara-C-induced ileal damage and release of pro-inflammatory factors by inhibiting macrophage polarization to M1. Molecular docking was used to identify potentially active compounds in GQBZP that targeted JAK2, a key factor in macrophage polarization to M1. By examining the main components of each herb and applying Lipinski's rules, ten poten-tially active compounds were identified. In vitro experimental results suggested that all 10 compounds of GQBZP targeted JAK2 and could inhibit M1 polarization in RAW264.7 cells treated with LPS and INF-gamma. Among them, acridine and senkyunolide A down-regulated the expression of JAK2 and STAT1. MD simulations revealed that acridine and senkyunolide A were stable in the active site of JAK2 and exhibited good interactions with the surrounding amino acids.Conclusions: GQBZP can ameliorate Ara-C-induced IM by reducing macrophage polarization to M1, and acridine and senkyunolide A are representative active compounds in GQBZP that target JAK2 to inhibit M1 polarization. Targeting JAK2 to regulate M1 polarization may be a valuable therapeutic strategy for IM.

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