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Isobavachalcone’s Alleviation of Pyroptosis Contributes to Enhanced Apoptosis in Glioblastoma: Possible Involvement of NLRP3

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Abstract

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor with high mortality rates and invariably poor prognosis due to its limited clinical treatments. There is an urgent need to develop new therapeutic drugs for GBM treatment. As a natural prenylated chalcone compound, Isobavachalcone (IBC)’s favorable pharmacological activities have been widely revealed. However, potential inhibitory effects of IBC on GBM have not been explored. In the present study, we aimed to detect the effects of IBC on GBM and clarify its anti-GBM mechanisms for the first time. It was observed that IBC could inhibit GBM cell proliferation, migration, and invasion in vitro and prevent tumor growth without any significant drug toxicity in both subcutaneous and orthotopic GBM xenograft tumor models in vivo. Mechanistically, IBC may target NOD-like receptor family pyrin domain-containing 3 (NLRP3) transcription factor estrogen receptor α (ESR1 gene) by network pharmacology and molecular docking analysis. Experimentally, IBC alleviated NLRP3 inflammasome-related pyroptosis and inflammation, arrested cell cycle at G1 phase, and induced mitochondria-dependent apoptosis in GBM cells. IBC’s inhibition on NLRP3 could be rescued by the NLRP3 antagonist CY-09 both in vitro and in vivo. These results indicate that IBC is a potential therapeutic drug against GBM and provide a new insight into GBM treatment.

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All data generated or analyzed during this study are included in this published article. Requests for material should be made to the corresponding authors.

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Acknowledgements

We thank Yu Xuanjie in the Department of Radiology, **anning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology for the MRI operation. And we also thank Yao Qing in the Medicine Research Institute & Hubei Key Laboratory of Diabetes and Angiopathy for her kind help in immunofluorescent confocal microscopy operation.

Funding

This work was supported by grants from the National Natural Science Foundation of China (no.81602649), the Natural Science Foundation of Hubei Province (2018CFB173), the Scientific Projects of Health Commission of Hubei Province (WJ2019Q022/WJ2021M089), the Foundation of the Hubei University of Science and Technology (2020TD04/2021-23GP04/2021WG02), National Training Program of Innovation and Entrepreneurship for Undergraduates (S201910927040/202110927002).

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Authors and Affiliations

  1. Research Center of Basic Medical Sciences, School of Basic Medical Sciences, **anning Medical College, Hubei University of Science and Technology, 88 **anning Avenue, **anning, 437100, Hubei, People’s Republic of China

    Yueshan Wu, **g Chang, Juanjuan Ge, Kangyan Xu, Quan Zhou, **aowen Zhang, Ni Zhu & Meichun Hu

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  1. Yueshan Wu
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  2. **g Chang
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Contributions

Yueshan Wu, Ni Zhu and Meichun Hu conceived the study. Yueshan Wu, **g Chang, Juanjuan Ge, Kangyan Xu, Quan Zhou and Meichun Hu designed, performed, and analyzed experiments. Kangyan Xu performed all animal model assays for the study. Quan Zhou and **aowen Zhang provided bioinformatics analysis and reagent preparations. Ni Zhu and Meichun Hu provided critical feedback, contributed to manuscript preparation, and oversaw the research program. All authors listed reviewed the manuscript and provided feedback with writing and revisions.

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Supplementary Figure 1

Wound healing assays of U87MG and U251 cells after IBC treatment. U87MG (a) and U251(b) cells were cultured until confluence, and a scratch was made in the cell layer. After IBC treatment for 48 h, images of both cells were taken by light microscope. (PNG 2.06 mb)

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Wu, Y., Chang, J., Ge, J. et al. Isobavachalcone’s Alleviation of Pyroptosis Contributes to Enhanced Apoptosis in Glioblastoma: Possible Involvement of NLRP3. Mol Neurobiol 59, 6934–6955 (2022). https://doi.org/10.1007/s12035-022-03010-2

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