Targeting CD38/ ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment

被引：4

作者：

Liu, Yuanzhi ^{[1
,2
,3
]}

Zhang, Linwei ^{[4
]}

Wang, Long ^{[5
,6
]}

Tang, Xiaoqin ^{[5
,6
]}

Wan, Shengli ^{[2
,5
]}

Huang, Qianqian ^{[5
,6
]}

Ran, Mei ^{[5
,6
]}

Shen, Hongping ^{[7
]}

Yang, Yan ^{[6
]}

Chiampanichayakul, Sawitree ^{[1
,8
]}

Tima, Singkome ^{[1
,8
]}

Anuchapreeda, Songyot ^{[1
,8
]}

Wu, Jianming ^{[3
,6
]}

机构：

[1] Chiang Mai Univ, Fac Associated Med Sci, Dept Med Technol, Div Clin Microscopy, Chiang Mai 50200, Thailand

[2] Southwest Med Univ, Affiliated Hosp, Dept Pharm, Luzhou 646000, Sichuan, Peoples R China

[3] Southwest Med Univ, Sch Basic Med Sci, Luzhou 646000, Sichuan, Peoples R China

[4] Chengdu Univ Tradit Chinese Med, Sch Pharm, State Key Lab Southwestern Chinese Med Resources, Chengdu 611137, Sichuan, Peoples R China

[5] Southwest Med Univ, Sch Pharm, Luzhou 646000, Sichuan, Peoples R China

[6] Southwest Med Univ, Lab Drug Discovery & Druggabil Evaluat Sichuan Pro, Luzhou Key Lab Act Screening & Druggabil Evaluat C, Luzhou 646000, Sichuan, Peoples R China

[7] Southwest Med Univ, Affiliated Tradit Chinese Med Hosp, Luzhou 646000, Sichuan, Peoples R China

[8] Chiang Mai Univ, Ctr Excellence Pharmaceut Nanotechnol, Chiang Mai 50200, Thailand

来源：

PHARMACOLOGICAL RESEARCH | 2024年 / 200卷

基金：

中国国家自然科学基金;

关键词：

Virtual screening; ADP-ribosyl cyclase; Ziyuglycoside II; Brevifolincarboxylic acid; 3,4-dihydroxy-5-methoxybenzoic acid; Leukopenia; INTERFERON-GAMMA; HEMATOPOIETIC STEM; IFN-GAMMA; GM-CSF; CALCIUM; PROLIFERATION; CHEMOTHERAPY; NEUTROPHILS; DIFFERENTIATION; NEUTROPENIA;

D O I：

10.1016/j.phrs.2024.107068

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Leukopenia is the most common side effect of chemotherapy and radiotherapy. It potentially deteriorates into a life-threatening complication in cancer patients. Despite several agents being approved for clinical administration, there are still high incidences of pathogen-related disease due to a lack of functional immune cells. ADPribosyl cyclase of CD38 displays a regulatory effect on leukopoiesis and the immune system. To explore whether the ADP-ribosyl cyclase was a potential therapeutic target of leukopenia. We established a drug screening model based on an ADP-ribosyl cyclase-based pharmacophore generation algorithm and discovered three novel ADP-ribosyl cyclase agonists: ziyuglycoside II (ZGSII), brevifolincarboxylic acid (BA), and 3,4-dihydroxy-5-methoxybenzoic acid (DMA). Then, in vitro experiments demonstrated that these three natural compounds significantly promoted myeloid differentiation and antibacterial activity in NB4 cells. In vivo, experiments confirmed that the compounds also stimulated the recovery of leukocytes in irradiation-induced mice and zebrafish. The mechanism was investigated by network pharmacology, and the top 12 biological processes and the top 20 signaling pathways were obtained by intersecting target genes among ZGSII, BA, DMA, and leukopenia. The potential signaling molecules involved were further explored through experiments. Finally, the ADP-ribosyl cyclase agonists (ZGSII, BA, and DMA) has been found to regenerate microbicidal myeloid cells to effectively ameliorate leukopenia-associated infection by activating CD38/ADP-ribosyl cyclase-Ca2+-NFAT. In summary, this study constructs a drug screening model to discover active compounds against leukopenia, reveals the critical roles of ADP-ribosyl cyclase in promoting myeloid differentiation and the immune response, and provides a promising strategy for the treatment of radiation-induced leukopenia.

引用

页数：21

共 69 条

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