PUBLICATION
Targeting CD38/cyclic ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment
- Authors
- Liu, Y., Zhang, L., Wang, L., Tang, X., Wan, S., Huang, Q., Ran, M., Shen, H., Yang, Y., Chiampanichayakul, S., Tima, S., Anuchapreeda, S., Wu, J.
- ID
- ZDB-PUB-240118-4
- Date
- 2024
- Source
- Pharmacological research 200: 107068 (Journal)
- Registered Authors
- Keywords
- (-)-gallocatechin (PubChem CID: 9882981), 3,4-dihydroxy-5-methoxybenzoic acid, 3,4-dihydroxy-5-methoxybenzoic acid (PubChem CID: 19829), ADP-ribosyl cyclase, Brevifolincarboxylic acid, Brevifolincarboxylic acid (PubChem CID: 9838995), Citric acid (PubChem CID: 311), Leukopenia, Oleanolic acid (PubChem CID: 10494), Procyanidin B3 (PubChem CID: 146798), Syringic acid (PubChem CID: 10742), Virtual screening, Ziyuglycoside II, Ziyuglycoside II (PubChem CID: 15984080)
- MeSH Terms
-
- Humans
- Antigens, Differentiation/genetics
- ADP-ribosyl Cyclase/metabolism
- Membrane Glycoproteins
- Leukopenia*/chemically induced
- Leukopenia*/drug therapy
- Mice
- ADP-ribosyl Cyclase 1
- Animals
- Antigens, CD*/genetics
- Zebrafish/metabolism
- PubMed
- 38232908 Full text @ Pharmacol. Res.
Citation
Liu, Y., Zhang, L., Wang, L., Tang, X., Wan, S., Huang, Q., Ran, M., Shen, H., Yang, Y., Chiampanichayakul, S., Tima, S., Anuchapreeda, S., Wu, J. (2024) Targeting CD38/cyclic ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment. Pharmacological research. 200:107068.
Abstract
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. ADP-ribosyl 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, DNA, 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/cyclic ADP-ribose-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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping