Molecular Medicine Reports
·
2025
·Vol. 32
·期 3
·1-12
·
IF 3.5
Kaixiang Zhao,Shaochen Wang,Dandan Feng,Dongwei Wang,Guang Yang,Fangfang Lang
The specific mechanisms of doxorubicin (Dox)‑induced cardiotoxicity (DIC) remain unclear. In the present study, H9c2 cardiomyocytes were treated with Dox, and it was revealed that DEAD‑box RNA helicase 3 X‑linked (DDX3X), mitochondrial antiviral signaling (MAVS) and stress granules (SGs) were present at lower levels in the treated H9c2 cardiomyocytes compared with those in the control cells. The present study further investigated the mechanisms through which DIC occurs. Pretreatment with arsenite, which pharmacologically accelerates SGs, alleviated the myocardial injury caused by Dox. By contrast, anisomycin, an SG inhibitor, increased cardiomyocyte apoptosis induced by Dox. In addition, both DDX3X knockdown and pretreatment with RK‑33 (a DDX3X pharmacological inhibitor) decreased SG expression, whereas DDX3X overexpression promoted SG generation. These results indicated that DDX3X mitigated DIC through the regulation of SGs. In addition, MAVS knockdown inhibited SG assembly and reduced the expression of the anti‑apoptotic inhibitor Bcl2, and MAVS was influenced by DDX3X, thereby serving as a connector between DDX3X and SGs. The results from western blotting, reverse transcription‑quantitative PCR, immunofluorescence and flow cytometry analysis demonstrated that DDX3X, MAVS, and SGs may serve as key protective factors in DIC.
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PHARMACOLOGICAL RESEARCH
·
2026
·
IF 12.2
Minglv Fang,Ying Liu,Yongli Han,Yashi Xu,Jing Yu,Yingxuan Yan,Zhigang Jin,Xiaojun Wu,Cheng Huang,Shengjie Fan
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with limited therapeutic options. Stress granules (SGs), membraneless organelles formed via liquid-liquid phase separation (LLPS) in response to cellular stress, function as a cytoprotective mechanism against stress induced apoptosis and pyroptosis. SGs can counteract NLRP3 inflammasome by sequestering dead-box helicase 3 X-linked (DDX3X), thereby promoting the survival of pyroptotic cells. Here, we identified that plumbagin (PL), a natural naphthoquinone with antioxidant and anti-inflammatory properties, as a novel SG inducer. In microglia, PL induced SGs that suppressed NLRP3-mediated pyroptosis and subsequent mitochondrial dysfunction, with DDX3X as a potential target. Furthermore, PL alleviated neuroinflammation and demyelination and suppressed oxidative stress in the CNS of both the cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) mouse models. Our findings reveal that PL can mitigate neuroinflammation and myelin damage by modulating the DDX3X-SG axis, supporting a novel therapeutic strategy for MS.
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CELL DEATH AND DIFFERENTIATION
·
2024
·
IF 13.7
Cai Jiangxue,Li Chenxuan,Liu Suyuan,Tan Meiling,Sun Yiran,Sun Xiaoxiao,Yang Miaoxin,He Bin
The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5′-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5′-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5′-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.
研究领域:
免疫学
·
分子生物学
·
炎症
·
代谢紊乱
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CELL BIOLOGY AND TOXICOLOGY
·
2026
·Vol. 42
·期 1
·68
·
IF 5.7
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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