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| Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress | |
Niu,Zhenpeng; Tang,Guihua ; Wang,Xuenan; Yang,Xu; Zhao,Yueqin; Wang,Yinyuan; Liu,Qin; Zhang,Fan; Zhao,Yuhan; Ding,Xiao; Hao,Xiaojiang
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| 2023 | |
| Source Publication | PHYTOMEDICINE
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| ISSN | 1618-095X |
| Volume | 112Pages:154720 |
| Abstract | Background: Macroautophagy (henceforth autophagy) is the major form of autophagy, which delivers intracel-lular cargo to lysosomes for degradation. Considerable research has revealed that the impairment of lysosomal biogenesis and autophagic flux exacerbates the development of autophagy-related diseases. Therefore, reparative medicines restoring lysosomal biogenesis and autophagic flux in cells may have therapeutic potential against the increasing prevalence of these diseases. Purpose: The aim of the present study was thus to explore the effect of trigonochinene E (TE), an aromatic tet-ranorditerpene isolated from Trigonostemon flavidus, on lysosomal biogenesis and autophagy and to elucidate the potential underlying mechanism. Methods: Four human cell lines, HepG2, nucleus pulposus (NP), HeLa and HEK293 cells were applied in this study. The cytotoxicity of TE was evaluated by MTT assay. Lysosomal biogenesis and autophagic flux induced by 40 mu M TE were analyzed using gene transfer techniques, western blotting, real-time PCR and confocal micro-scopy. Immunofluorescence, immunoblotting and pharmacological inhibitors/activators were applied to deter-mine the changes in the protein expression levels in mTOR, PKC, PERK, and IRE1 alpha signaling pathways. Results: Our results showed that TE promotes lysosomal biogenesis and autophagic flux by activating the tran-scription factors of lysosomes, transcription factor EB (TFEB) and transcription factor E3 (TFE3). Mechanistically, TE induces TFEB and TFE3 nuclear translocation through an mTOR/PKC/ROS-independent and endoplasmic reticulum (ER) stress-mediated pathway. The PERK and IRE1 alpha branches of ER stress are crucial for TE-induced autophagy and lysosomal biogenesis. Whereas TE activated PERK, which mediated calcineurin dephosphoryla-tion of TFEB/TFE3, IRE1 alpha was activated and led to inactivation of STAT3, which further enhanced autophagy and lysosomal biogenesis. Functionally, knockdown of TFEB or TFE3 impairs TE-induced lysosomal biogenesis and autophagic flux. Furthermore, TE-induced autophagy protects NP cells from oxidative stress to ameliorate intervertebral disc degeneration (IVDD). Conclusions: Here, our study showed that TE can induce TFEB/TFE3-dependent lysosomal biogenesis and auto-phagy via the PERK-calcineurin axis and IRE1 alpha-STAT3 axis. Unlike other agents regulating lysosomal biogenesis and autophagy, TE showed limited cytotoxicity, thereby providing a new direction for therapeutic opportunities to use TE to treat diseases with impaired autophagy-lysosomal pathways, including IVDD. |
| Keyword | Lysosomal biogenesis Autophagy TFEB TFE3 ER stress IVDD STAT3 TFE3 |
| Subject Area | Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine |
| DOI | 10.1016/j.phymed.2023.154720 |
| Indexed By | SCI |
| WOS ID | WOS:000949810100001 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.kib.ac.cn/handle/151853/75399 |
| Collection | 中国科学院昆明植物研究所 |
| Recommended Citation GB/T 7714 | Niu,Zhenpeng,Tang,Guihua,Wang,Xuenan,et al. Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress[J]. PHYTOMEDICINE,2023,112:154720. |
| APA | Niu,Zhenpeng.,Tang,Guihua.,Wang,Xuenan.,Yang,Xu.,Zhao,Yueqin.,...&Hao,Xiaojiang.(2023).Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress.PHYTOMEDICINE,112,154720. |
| MLA | Niu,Zhenpeng,et al."Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress".PHYTOMEDICINE 112(2023):154720. |
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| 1-s2.0-S094471132300（11543KB） | 期刊论文 | 出版稿 | 开放获取 | CC BY-NC-SA | View Download | |
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