Li Ting,Feng Mengxiao,Wang Ping,Jiang Miao,Cui Jaiyu,Jin Mengxia,Song Congying,Lin Liying,Lu Yuan-Qiang
Baicalein, a naturally occurring flavonoid with well-documented anti-inflammatory and neuroprotective effects, has shown therapeutic promise in multiple models of neurological disorders. However, whether baicalein can counteract diquat-induced neurotoxicity remains uncertain. This study reveals that baicalein alleviates diquat-induced neuroinflammation and microglial pyroptosis in mice in a gut microbiota (GM)-dependent manner. In the in vivo experiments, multi-omics analyses demonstrated that baicalein elevates the GM-derived metabolite indole-3-propionic acid (IPA), which was sufficient to suppress pyroptosis. In parallel, IPA was identified as a critical mediator of baicalein's neuroprotective effects, as exogenous IPA administration recapitulated baicalein's protection, and baicalein treatment significantly elevated IPA levels. Mechanistically, through inhibiting the DEAD-box helicase 3 X-linked / GTPase-activating protein (SH3 domain) binding protein 1 pathway by in vitro experiments. Our study demonstrated that baicalein mitigates diquat-induced neuroinflammation, underscoring the therapeutic potential of targeting the GM to counteract herbicide-related neurotoxicity. Graphical
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Xiaoxian Hu,Peiye Wu,Yu Zhao,Yun Wang,Zhongrui Li,Chao Han
Photodynamic therapy (PDT) is a minimally invasive treatment technique that combines photosensitizers and light and can selectively exert cytotoxic effects on malignant tumor cells and prevent their metastasis. However, while PDT is effective, it also triggers a tumor cell integrated stress response (ISR) to produce cytoprotective stress granules (SGs), decreasing its therapeutic efficacy. In this study, we designed a nanodrug delivery system capable of inhibiting the ISR to enhance the antitumor effect of PDT. Specifically, the low-toxicity photosensitizer hypericin (HY) and the highly effective SGs inhibitor imatinib (IM) were encapsulated in the HY and IM nanoparticles (HINPs). HY converts oxygen into reactive oxygen species under light conditions, inducing the apoptosis of tumor cells but simultaneously induces the formation of SGs through the eukaryotic initiation factor-2α-dependent pathway, reducing tumor sensitivity to PDT. IM tightly binds to the SGs core protein Ras-GAP SH3 domain binding protein 1 (G3BP1), preventing G3BP1 from forming a complex with ubiquitin-associated protein 2-like protein to inhibit SGs formation; it also inhibits the ATF3/CHOP/GADD34/PP1 negative feedback regulatory signaling axis of ISR, further disrupting tumor cell ISR and enhancing the efficacy of HY PDT. Both in vivo and in vitro experiments confirmed that HINPs have potent antitumor activity, providing a way to improve the antitumor efficacy of PDT.
Yang Fan,Li Lin,Mu Zhenzhen,Liu Pengyue,Wang Ying,Zhang Yue,Han Xiuping
The nuclear import receptor karyopherin β1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.
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