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Targeting CD38/ ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment.
Liu, Yuanzhi; Zhang, Linwei; Wang, Long; Tang, Xiaoqin; Wan, Shengli; Huang, Qianqian; Ran, Mei; Shen, Hongping; Yang, Yan; Chiampanichayakul, Sawitree; Tima, Singkome; Anuchapreeda, Songyot; Wu, Jianming.
Afiliação
  • Liu Y; Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China; School of Basic Medical Sciences
  • Zhang L; State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
  • Wang L; School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, Si
  • Tang X; School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, Si
  • Wan S; Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China; School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • Huang Q; School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, Si
  • Ran M; School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, Si
  • Shen H; The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • Yang Y; Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • Chiampanichayakul S; Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand.
  • Tima S; Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand.
  • Anuchapreeda S; Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: songyot.anuch@cm
  • Wu J; School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China; Laboratory for Drug Discovery and Druggability Evaluation of Sichuan Province, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical Universi
Pharmacol Res ; 200: 107068, 2024 Feb.
Article em En | MEDLINE | ID: mdl-38232908
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, 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antígenos CD / Leucopenia Tipo de estudo: Diagnostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antígenos CD / Leucopenia Tipo de estudo: Diagnostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article