BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Tianfeng Yang,Suyu Zhang,Kun Nie,Xiuhong Peng,Jian Huo,Xiao Fu,Yanmin Zhang
Although ferroptosis as an emerging way exhibits tremendous promising in the therapy of hepatocellular carcinoma (HCC), the novel therapeutic agents targeting ferroptosis are still scarce. In our previous study, we found that the natural products toosendanin (TSN) possessed significant anti-proliferative efficacy by regulating WW domain-containing oxidoreductase (WWOX) in HCC. However, there is very limited understanding about TSN-induced ferroptosis, and the role of WWOX in ferroptosis has not been studied. In present study, we investigated the effect and underlying molecular mechanisms of TSN in WWOX-mediated ferroptosis in HCC. We found that TSN induced ferroptosis in HCC cells and its effect was dependent on WWOX. RNA-seq and RT-qPCR assay identified that TSN significantly increased spermidine/spermine N1-acetyltransferase 1 (SAT1) expression while decreased solute carrier family 40 member 1 (SLC40A1) expression, which play vital roles in ferrous ion transport. Further dual-luciferase reporter assay and Co-IP assay revealed that TSN-induced WWOX activation controlled the transcriptional activity of p53 and NF-E2-related factor 2 (NRF2) by regulating their interaction. Meanwhile, IF assay and WB assay confirmed that TSN increased the nuclear distribution of p-WWOX and p-p53 dimers, but impeded the nuclear translocation of NRF2 by inducing its ubiquitination degradation, ultimately regulating the transcription of their downstream target genes. In addition, the results from cell viability assay and the tumor xenograft model verified that co-treatment of TSN, ML385 (NRF2 inhibitor), and MIRA-1 (p53 activator) could effectively inhibit HCC cells growth in the presence of Fer-1 (ferroptosis inhibitor) in vitro and in vivo. Overall, our study contributes to the necessary understanding of the molecular mechanisms of WWOX-mediated ferroptosis regulation, and identifies TSN as a potential therapeutic agent targeting ferroptosis for HCC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
GENE
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2023
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IF 3.5
Benshui Shu,Yanzheng Lin,Yuting Huang,Luyang Liu,Xueming Cai,Jintian Lin,Jingjing Zhang
The fall armyworm, Spodoptera frugiperda , is a destructive agricultural pest that seriously threatens global food security. Insecticide resistance of this pest has gradually formed in recent years due to improper usage, and alternative methods are badly needed. Toosendanin (TSN) is a botanical compound with broad-spectrum insecticidal activities against many pests. However, the effects of TSN on S. frugiperda are still unclear. In this study, the growth inhibition phenomenon, including weight loss and prolonged developmental duration, in the larvae with TSN exposure was clearly observed. Compared to the control group, a total of 450 and 3314 differentially expressed genes (DEGs) were identified by RNA-Seq in the larvae groups treated with 10 and 20 mg/kg TSN, respectively. Furthermore, the DEGs involved in the juvenile hormone and ecdysone signal pathways and downstream processes, including detoxifying enzyme genes, chitin synthesis and metabolism genes, and cuticular protein genes, were found. Our findings suggest that TSN regulates the expression of key genes in juvenile hormone and ecdysone signal pathways and a series of downstream processes to alter the hormone balance and cuticle formation and eventually inhibit larval growth, which laid the foundation for the molecular toxicological mechanism research of TSN on S. frugiperda larvae.
研究领域:
昆虫学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2023
·
IF 4.7
Yanzheng Lin,Yuting Huang,Jiafu Liu,Luyang Liu,Xueming Cai,Jintian Lin,Benshui Shu
The fall armyworm, Spodoptera frugiperda , is a polyphagous pest worldwide and feeds on many grain and cash crops, which threatens the safety of agriculture and forestry production. Toosendanin (TSN) is a commercial insecticidal active ingredient used to manage various pests in the field and showed adverse effects against S. frugiperda , while the effects of TSN on the larval midguts are not yet known. In this study, the effects of 10 and 20 mg/kg TSN exposures on the larval midguts were analyzed. The structural changes of the larval midgut induced by TSN treatments were also determined by hematoxylin-eosin staining. Besides, TSN treatments also changed the enzyme activities of three digestive enzymes (α-amylase, lipase, and trypsin) and two detoxification enzymes (CarE and GST). A total of 2868 differentially expressed genes (DEGs) were identified by RNA-Seq in the larval midguts with 20 mg/kg TSN treatment, and the DEGs responsible for food digestion and detoxification were further examined. Our findings revealed the preliminary modes of action of TSN on the larval midguts of S. frugiperda , which provide a preliminary rationale for controlling S. frugiperda with TSN in the field.
研究领域:
昆虫学
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分子生物学
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害虫管理
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毒理学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 8
·4567-4578
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IF 5.882
Tianfeng Yang,Jian Huo,Rui Xu,Yanmin Zhang
Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β-catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.
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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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2025
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IF 6.3
Qian Hu,Mengyao Wang,Meng Chen,Jinjin Wang,Ting Niu
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma, with two-thirds of patients relapsing or resisting existing therapies, highlighting the urgent need for effective treatments. Toosendanin (TSN), a triterpenoid from Meliae Cortex, exhibits significant anti-cancer activity by modulating cell survival and proliferation. This study investigates the anti-lymphoma effects and underlying mechanisms of TSN, proposing it as a potential therapeutic agent to address the challenges of DLBCL. Network pharmacology, molecular docking, and transcriptome sequencing were employed to predict TSN's anti-DLBCL potential. Findings were validated through in vitro and in vivo experiments, including cell viability assays, flow cytometry, quantitative PCR, Western blotting, reverse experiments with small-molecule inhibitors or genetic editing, and a cell-derived xenograft (CDX) model. Bioinformatics analyses revealed TSN's strong binding affinity to PI3Kα/β and Polo-like kinase 1 (PLK1). Experiments showed that TSN downregulated the PI3K/Akt signaling pathway and reduced PLK1 mRNA and protein levels, inducing apoptosis, cell cycle arrest, and cell death in DLBCL cells. RNA sequencing and metabolic assays indicated TSN upregulated cholesterol biosynthesis in DLBCL cells. Co-treatment with a statin enhanced TSN's anti-DLBCL effects while mitigating hepatic and pulmonary toxicity. This study identifies TSN as a dual inhibitor of PI3K and PLK1 with significant therapeutic potential for DLBCL. It also proposes a lipid-modulating strategy to enhance TSN's cytotoxicity while reducing adverse effects, offering a promising approach to improve DLBCL treatment outcomes.
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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生物信息学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2025
·
IF 2.5
Shaobin Xu,Jiaxuan He,Genqiang Chen,Xiaobo Huang,Yuee Tian,Zhiping Che
18β-Glycyrrhetinic acid (GA) is a pentacyclic triterpenoid compound mainly extracted from the roots of the leguminous plant licorice. To discover botanical pesticides, twelve 3β-acyloxy-18β-glycyrrhetinic acid derivatives ( 3a – l ) were synthesized, and their structures were characterized by 1 H NMR, 13 C NMR, and HR–MS. In addition, we assessed the bioactivities of these title compounds as anti-oomycete and insecticidal agents against two serious agricultural pests, Phytophthora capsici and Mythimna separata . Amongst all tested target compounds, (1) Six compounds 3d , 3e , 3h , 3i , 3j , and 3k indicated promising anti-oomycete activity against P. capsici , with EC 50 values of 28.27, 29.36, 23.88, 20.03, 23.07, and 25.93 mg/L, respectively. (2) Six compounds showed significant insecticidal activity, the final mortality rates of 3b , 3c , 3f , 3g , 3i , and 3l were 66.7%, 55.6%, 63.0%, 60.7%, 51.9%, and 75.6%, respectively. The anti-oomycete and insecticidal activities of the title compounds were closely related to R, which has a significant impact on its activity. Graphical
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产品关联
DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
·
2022
·Vol. 78
·期 8
·3442-3455
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IF 4.462
Zhiping Che,Xiaolong Guo,Yuanhao Li,Song Zhang,Lina Zhu,Jiaxuan He,Di Sun,Yihao Guo,Yibo Liu,Ruxue Wei,Xiaobo Huang,Shengming Liu,Genqiang Chen,Yuee Tian
Background Paeonol is extracted and isolated as a rich and sustainable natural bioresource from the root bark of Paeonia suffruticosa , the derivatives of which exhibit numerous biological activities. It is well known that ester compounds play a very important role in pest control, such as organophosphorus, carbamate and pyrethroid pesticides. Results To discover biorational natural product-based pesticides, three series of (60) paeonol ester derivatives ( 7a–t , 8g , p , 9g , p , 10g–j , n–u , 11g , u , 12g , u , 13a–p , 14b , c , and 15b , c ) were prepared by structural modification of paeonol, and their structures were well characterized by proton nuclear magnetic resonance ( 1 H-NMR), carbon-13 nuclear magnetic resonance ( 13 C-NMR), high-resolution mass spectrometry (HRMS), and melting point. Furthermore, we assessed the compounds as insecticidal, nematicidal, and anti-oomycete agents against three serious agricultural pests, Mythimna separata , Heterodera glycines , and Phytophthora capsici . Among all tested compounds: (i) compound 8p showed more significant insecticidal activity than toosendanin, and the final mortality rates of 8p and toosendanin against M. separata (1 mg mL −1 ) were 70.4%, and 51.9%, respectively; (ii) compound 7a exhibited more promising nematicidal activity than paeonol, and the median lethal concentration (LC 50 ) values of 7a and 1 against H. glycines were 15.47 and 50.80 mg L −1 , respectively; (iii) compounds 7n and 13m displayed more significant anti-oomycete activity compared to zoxamide against Phytophthora capsici , and the median effective concentration (EC 50 ) values of 7n , 13m , and zoxamide were 23.72, 24.51, and 26.87 mg L −1 , respectively; and the protective effect of the compounds against Phytophthora capsici in vivo further confirmed the effectiveness of the agents. Conclusion This study suggested that the introduction of a nitro at the C5 or C3 position of paeonol could improve its bioactivity against M. separata , H. glycines , and Phytophthora capsici . © 2022 Society of Chemical Industry.
研究领域:
植物化学
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农药科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）