Journal of the American Heart Association
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2026
·Vol. 15
·期 3
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IF 5.3
Zhu‐chen Zhou,Meng‐ting Liu,Yi‐jia Fangma,Bing‐jie Wan,Jing Zhou,Xiao‐lan Zhang,Yu‐ting Yan,Shu‐hui Deng,Yan Zhang,Yuan‐jie Zhang,Wen‐lu Li,Zhong Chen,Yan‐rong Zheng
BackgroundInflammasome hyperactivation drives neuroinflammation following cerebral ischemia, yet pharmacological strategies inducing their selective clearance remain largely unexplored. Selective autophagy holds particular promise as a therapeutic strategy by eliminating detrimental substrates while avoiding the side effects of excessive autophagy. However, few compounds are currently available to achieve this selective regulation.MethodsTransient middle cerebral artery occlusion was used to screen the active compounds from Fritillaria, combined with TTC staining and neurological scores. Postischemic apoptosis, inflammation, and autophagy were evaluated via immunofluorescence and immunoblotting. RNA sequencing of the ischemic penumbra revealed transcriptomic changes. Cell‐specific effects were confirmed using cell coculture and glial‐deficient transgenic mice. Compound‐inflammasome interactions were studied by biolayer interferometry and molecular dynamics.ResultsPeiminine demonstrates robust neuroprotection after cerebral ischemia. RNA sequencing and immunoblotting analyses revealed that peiminine markedly suppresses postischemic inflammation. Correspondingly, peiminine exerts its neuroprotective effect primarily through actions on microglia but not astrocytes, indicated by neuron–glia cocultures and transgenic mice models with targeted cell‐type depletion. Biolayer interferometry and molecular dynamics simulations indicated that peiminine selectively binds to AIM2, showing no interaction with NLRP1 (NLR family pyrin domain containing 1) and approximately 100‐fold higher affinity compared with NLRP3. Notably, peiminine specifically activates the selective autophagic clearance of AIM2 inflammasomes within microglia without increasing overall autophagic flux or affecting other inflammasomes. Selective blockage of autophagy in microglia abolished the neuroprotective effect of peiminine.ConclusionsPeiminine exhibited robust neuroprotection against cerebral ischemia by selectively promoting the autophagic clearance of AIM2 inflammasomes to mitigate neuroinflammation.
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高影响因子
COMPOSITES PART B-ENGINEERING
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2024
·
IF 12.7
Guoyang Zhang,Dingyi Shi,Yiyao Wei,Mingqi Wang,Haohan Wang,Zhiqi Lin,Haihan Gao,Weixuan Lin,Hanyi Wang,Yonglin Guo,Yingyu Ge,Yi Lin,Yiwen Jiang,Xiaoyu Yan,Yuhao Kang,Liren Wang,Jinzhong Zhao,Weiyang Ying
Natural small-molecule drugs have promising potential to promote tissue regeneration in various fields. Therefore, maximizing drug efficiency while minimizing potential side effects is imperative. Peiminine, a natural product extracted from natural Fritillaria , is one of small-molecule drugs in the field of bone regeneration due to its good bone-promoting and anti-inflammatory abilities. However, its application is limited by a lack of biological activity, poor biocompatibility at high concentrations, and difficulty in achieving long-term slow-release and therapeutic effects. Extracellular vesicles (EVs) produced by preconditioned cells are considered to have special biological functions, and their potential to further retain, buffer, and transmit drug effects and expand the therapeutic effect has been widely studied. Thus, our study provides a drug-free bioengineering strategy by preconditioning bone marrow mesenchymal stem cells (BMSC) with Peiminine, then EVs, secreted as Peim-EVs, were extracted and combined with a decellularized extracellular matrix (dECM). The final EVs-dECM system with a spatiotemporally controlled release system was formed. In vitro studies demonstrated that Peim-EVs solved the problem of Peiminine biocompatibility and exhibited osteogenic and anti-inflammatory effects, which may be related to PI3K/AKT, MAPK/NF-κB, and Hippo signaling pathways. An in vivo model of rotator cuff injury in rats also showed that EVs-dECM had a good effect on rotator cuff repair. Combined with engineering strategy, this study provides verification and scenario expansion for drug application, especially for drug-free strategies that retain the biological effects of drugs, and has broad significance.
研究领域:
再生医学
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细胞生物学
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生物工程
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BIOMEDICINE & PHARMACOTHERAPY
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2024
·
IF 6.9
Jiajin Xu,Zeyi Zhang,Hongtao Hu,Yaqin Yang,Chenghong Xiao,Luyi Xi,Jiahui Lu,Shasha Tian,Huajun Zhao
Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the most potent chemotherapeutic agents for breast cancer (BC). This study was designed to investigate the efficacy and underlying mechanisms of Peiminine combined with Doxorubicin in treating BC. Our results demonstrated that the combination of Peiminine and 1 mg/kg Doxorubicin exhibited more significant suppression of tumor growth compared with the monotherapy in MDA-MB-231 xenograft nude mice model, which is comparable to the effect of 3 mg/kg Doxorubicin in vivo. Notably, the 3 mg/kg Doxorubicin monotherapy resulted in organ toxicity, specifically in the liver and heart, whereas no toxicity was observed in the combination group. In vitro , this combined treatment exhibited a synergistic reduction on the viability of BC cells. Peiminine enhanced the cell cycle arrest and DNA damage induced by Doxorubicin. Furthermore, the combination treatment effectively blocked DNA repair by inhibiting the MAPKs signaling pathways. And ZEB1 knockdown attenuated the combined effect of Peiminine and Doxorubicin on cell viability and DNA damage. In conclusion, our study found that the combination of Peiminine and Doxorubicin showed synergistic inhibitory effects on BC both in vivo and in vitro through enhancing Doxorubicin-induced DNA damage. These findings support that their combination is a novel and promising therapeutic strategy for treating BC .
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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高影响因子
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
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2018
·Vol. 51
·期 4
·1566-1583
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IF 5.5
Zhao Boxian,Shen Chen,Zheng Zhixing,Wang Xiaoxiong,Zhao Wenyang,Chen Xin,Peng Fei,Xue Linmeng,Shu Mengting,Hou Xu,Wang Kaikai,Zhong Chen,Sun Jingxian,Wan Jinzhao,Zhao Shiguang
Background/Aims: Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumour in adults, with poor survival rate and high mortality rates. Existing treatments do not provide substantial benefits to patients; therefore, novel treatment strategies are required. Peiminine, a natural bioactive compound extracted from the traditional Chinese medicine Fritillaria thunbergii, has many pharmacological effects, especially anticancer activities. However, its anticancer effects on GBM and the underlying mechanism have not been demonstrated. This study was conducted to investigate the potential antitumour effects of peiminine in human GBM cells and to explore the related molecular signalling mechanisms in vitro and in vivo Methods: Cell viability and proliferation were detected with MTT and colony formation assays. Morphological changes associated with autophagy were assessed by transmission electron microscopy (TEM). The cell cycle rate was measured by flow cytometry. To detect changes in related genes and signalling pathways in vitro and in vivo, RNA-seq, Western blotting and immunohistochemical analyses were employed. Results: Peiminine significantly inhibited the proliferation and colony formation of GBM cells and resulted in changes in many tumour-related genes and transcriptional products. The potential anti-GBM role of peiminine might involve cell cycle arrest and autophagic flux blocking via changes in expression of the cyclin D1/CDK network, p62 and LC3. Changes in Changes in flow cytometry results and TEM findings were also observed. Molecular alterations included downregulation of the expression of not only phospho-Akt and phospho-GSK3β but also phospho-AMPK and phospho-ULK1. Furthermore, overexpression of AKT and inhibition of AKT reversed and augmented peiminine-induced cell cycle arrest in GBM cells, respectively. The cellular activation of AMPK reversed the changes in the levels of protein markers of autophagic flux. These results demonstrated that peiminine mediates cell cycle arrest by suppressing AktGSk3β signalling and blocks autophagic flux by depressing AMPK-ULK1 signalling in GBM cells. Finally, peiminine inhibited the growth of U251 gliomas in vivo. Conclusion: Peiminine inhibits glioblastoma in vitro and in vivo via arresting the cell cycle and blocking autophagic flux, suggesting new avenues for GBM therapy
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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高影响因子
Frontiers in Pharmacology
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2019
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IF 3.845
Ma Xiaoyao,Liu Aina,Liu Wenjuan,Wang Zhihua,Chang Nianwei,Li Suyun,Li Jiansheng,Hou Yuanyuan,Bai Gang
Chronic obstructive pulmonary disease (COPD) has been a major public health problem and is still a formidable challenge for clinicians. It is urgent to find new compounds for minimizing the risk of disease progression and exacerbation especially in the early phase of COPD. A traditional Chinese medicine (TCM) formula, Chuan Bei Pi Pa dropping pills (CBPP), was tested in this study to investigate its potential mechanisms in preventing the exacerbation of COPD. Phosphoproteomics analysis for a smog stimulated early stage COPD mice model was employed to detect the underlying molecular mechanisms of CBPP. In addition, protein–protein interaction (PPI) and bioinformatics analyses were included to analyze the key proteins and predict the key bioactive compounds. The results indicated that peiminine (PEI) target epidermal growth factor receptor (EGFR) prevented the exacerbation of COPD by inhibiting the EGFR signaling pathway, and ursolic acid (UA) can alleviate inflammation disorders via inhibition of CASP3 on mitogen-activated protein kinase (MAPK) signaling pathway. After in vivo and in vitro evaluations, we revealed that PEI from CBPP, as a lead compound, can improve lung function and alleviate pulmonary fibrosis by acting on the EGFR and MLC2 signaling pathways. Furthermore, the approach described here is an effective way to analyze and identify the bioactive ingredients from a mixture by functional proteomics analysis.
研究领域:
药理学
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呼吸病学
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蛋白质组学
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传统中药
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高影响因子
危险品化学品经营许可证（带存储）