TY - JOUR
T1 - Notch Inhibitors from Calotropis gigantea That Induce Neuronal Differentiation of Neural Stem Cells
AU - Yoneyama, Tatsuro
AU - Arai, Midori A.
AU - Akamine, Ryuta
AU - Koryudzu, Kazune
AU - Tsuchiya, Anna
AU - Sadhu, Samir K.
AU - Ahmed, Firoj
AU - Itoh, Motoyuki
AU - Okamoto, Ryuichi
AU - Ishibashi, Masami
N1 - Funding Information:
This study was supported by KAKENHI grant numbers 26305001, 26293022, 25670045, and 15H04650 from JSPS and 23102008 from MEXT (a Grant-in-Aid for Scientific Research on Innovative Areas in “Chemical Biology of Natural Products”). The study was supported also by a Workshop on Chirality at Chiba University (WCCU). We also thank Prof. T. Tomita of the University of Tokyo for assaying test compound γ-secretase inhibition and for helpful discussions. This work was inspired by the international and interdisciplinary environments of the JSPS Core-to-Core Program “Asian Chemical Biology Initiative”.
Publisher Copyright:
© 2017 The American Chemical Society and American Society of Pharmacognosy.
PY - 2017/9/22
Y1 - 2017/9/22
N2 - Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease occur due to loss of the structure and function of neurons. For the potential treatment of neurodegenerative diseases, accelerators of neuronal differentiation of neural stem cells (NSCs) have been focused on and a cell-based assay system for measuring Notch signaling pathway activity was constructed. Using this assay system, eight compounds isolated from Calotropis gigantea were identified as inhibitors of the Notch signaling pathway. Hes1 and Hes5 are target genes of the Notch signaling pathway, and compound 1, called uscharin, decreased the protein levels of Hes1 and Hes5 in assay cells and MEB5 cells (mouse NSCs). Furthermore, uscharin (1) enhanced the differentiation of MEB5 cells into neurons. The mechanism of uscharin (1) for the Notch signaling inhibitory activity would be acceleration of the degradation of the Notch intracellular domain (NICD) in the MEB5 cells.
AB - Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease occur due to loss of the structure and function of neurons. For the potential treatment of neurodegenerative diseases, accelerators of neuronal differentiation of neural stem cells (NSCs) have been focused on and a cell-based assay system for measuring Notch signaling pathway activity was constructed. Using this assay system, eight compounds isolated from Calotropis gigantea were identified as inhibitors of the Notch signaling pathway. Hes1 and Hes5 are target genes of the Notch signaling pathway, and compound 1, called uscharin, decreased the protein levels of Hes1 and Hes5 in assay cells and MEB5 cells (mouse NSCs). Furthermore, uscharin (1) enhanced the differentiation of MEB5 cells into neurons. The mechanism of uscharin (1) for the Notch signaling inhibitory activity would be acceleration of the degradation of the Notch intracellular domain (NICD) in the MEB5 cells.
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U2 - 10.1021/acs.jnatprod.7b00282
DO - 10.1021/acs.jnatprod.7b00282
M3 - Article
C2 - 28817274
AN - SCOPUS:85029737555
SN - 0163-3864
VL - 80
SP - 2453
EP - 2461
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 9
ER -