PHYTOTHERAPY RESEARCH
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2025
·
IF 6.3
Ning Han,Liu-Gen Li,Mei-Yi Liu,Tao Ren,Yao-Hua Lu,Xing-Chun Peng,Cunqing Kong,Fan Leng,Lei Zhang,Jun Hu,Lei Wang,Tong-Fei Li,Mei-Fang Wang,Xiao Chen
Harringtonine (HT) is an alkaloid extracted from the botanical cephalotaxus fortunei Hook.f ., which has potent anti-tumor activity. Nevertheless, the target and mechanism of HT in cancer have not been reported. The present work aims to explore the crucial target of HT in triggering ferroptosis and elucidate its mechanism. Lewis lung cancer cells and tumor-bearing mice models prepared thereof were used in this study. Network pharmacology and RNA sequencing were utilized to screen the pivotal target and information. Flow cytometry, Western blots, qRT-PCR, and immunoprecipitation were exploited to elucidate the mechanism. The affinity experiments were employed to analyze the interaction of HT and FASN. Reduced cell viability and increased apoptosis were observed in HT-treated lung cancer cells and the 3-D cell model. Consistently, HT exhibited pronounced anti-cancer effects in in vivo experiments. The interaction molecules of HT and lung cancer were enriched in ferroptosis, which was validated by the accumulation of ferrous ions etc. Blockage of ferroptosis mitigated HT-mediated efficacy. Further investigation showed alternations in fatty acid metabolism when adding HT, especially fatty acid synthase (FASN). HT was demonstrated to bind to FASN, thereby dampening SYVN1-mediated ubiquitination. Finally, the silence of FASN dampened the ferroptosis and anti-cancer efficacy introduced by HT. Collectively, HT could bind to FASN and thereby enhance the activity by reducing ubiquitination, resulting in increased fatty acid synthesis and infiltrating into the membrane, which leads to ferroptosis. The present work identifies the critical target for phytomedicine HT-driven ferroptosis and provides a foundation for cancer 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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天然产物研究
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Zhao-Lei Ding,Yi-Chen Ma,Chuan-Mei Liu,Xiu Lu,Rong-Rong Wang,Min-Min Tang,Dong-Xu Hua,Ling Zheng,Hui Zhao,Lin Fu
Background 1-Nitropyrene (1-NP) is harmful to the respiratory system and can evoke acute lung injury (ALI). Pyroptosis and apoptosis, two important types of programmed cell death, are involved in the pathological process of ALI. However, the roles and mechanisms of pyroptosis and apoptosis on 1-NP-incurred ALI remain unclear. Methods All the mice were exposed to a single dose of 1-NP (20 μg/mouse, dissolved in saline) or normal saline via intratracheal instillation. At different times after 1-NP exposure, the mice were sacrificed. Mouse lung epithelial (MLE-12) cells were incubated with 1-NP (5 μM), the indicators of pyroptosis and apoptosis were detected. Results Pulmonary pathological injury and inflammatory cell infiltration was observed in 1-NP-exposed mice. Additionally, the indicators of apoptosis, Bcl-2 was downregulated, Bad and Caspase-3, and apoptotic cells were increased in 1-NP-exposed mouse lungs and mouse lung epithelial (MLE-12) cells. Meanwhile, the proteins of GSDMD and Pro- and Cleaved Caspase-11 and the mRNAs of Il-1β and Il-18 , which are markers of pyroptosis, were increased after 1-NP treatment. Moreover, pretreatment with wedelolactone (WED), an antagonist of Caspase-11, alleviated 1-NP-induced ALI. As expected, pharmacological inhibition or genetic deletion of Caspase-11 abolished 1-NP-induced apoptosis and pyroptosis. Interestingly, 1-NP attenuated Caspase-11 proteasome degradation. Mechanistically, 1-NP downregulated the expression of SYVN1, an E3 ubiquitin ligase of Caspase-11. 1-NP promoted the interaction between SYVN1 and Caspase-11 and inhibited Caspase-11 ubiquitination and subsequent proteasome degradation. Transfection with SYVN1 overexpression plasmids abolished 1-NP-mediated the reduction of Caspase-11 ubiquitination-dependent degradation, apoptosis, and pyroptosis. Conclusions These results revealed that acute 1-NP may induce ALI via Caspase-11-mediated apoptosis and pyroptosis by downregulating SYVN1.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Yongyan Chen,Xu Han,Yuxuan Hao,Xu Wang,Fupeng Wu,Sheng Tan,Huijing Ye,Yang Hong,Xiaoyan Shen
Background Vascular calcification is a major cause of death in chronic kidney disease (CKD), with osteoblastic transdifferentiation of vascular smooth muscle cells (VSMCs) considered to be the crucial pathologic process. However, there remains a significant deficiency in effective prevention and treatment strategies. Purpose In an in vitro calcification screening model, we observed an inhibitory activity of Emodin on osteoblastic transdifferentiation of VSMCs. In the present study, we therefore aimed to evaluate its efficacy in CKD-induced medial vascular calcification in vitro and in vivo, and to further explore the underlying mechanisms. Study design A7R5 and MOVAS cells were treated with sodium phosphate to induce osteogenic transdifferentiation as in vitro models, while mice were fed with adenine and a high-phosphorus diet, and additionally received an intraperitoneal injection of 10,000 IU Vitamin D3 to induce chronic kidney disease (CKD) as an in vivo model. Vitamin K2 served as a positive control. Methods Alizarin Red S staining and VON-KOSSA staining were used to evaluate the effects of Emodin on osteogenic transdifferentiation. Western blotting, RT-qPCR and Von-Kossa staining were used to detect the effects of Emodin on aortic calcification in CKD mice in vivo. Chemical biology techniques including ITC, fluorescence titration, dual fluorescein reporter genes, CETSA, and DARTS, were used to detect the binding activity of Emodin to ERα and SYVN1. Immunoprecipitation, immunostaining, etc. were used to explore the mechanisms, and small molecule inhibitors and small RNA interference were used to verify the target of Emodin. Results Emodin could effectively inhibit the osteogenic transdifferentiation of A7R5 and MOVAS cells in vitro, and alleviate aortic calcification in CKD mice in vivo. Mechanism study revealed that Emodin could act as a molecular glue that binds directly to ERα and SYVN1 and enhances their interaction, thereby accelerating the ubiquitination degradation process of ERα. The decrease in ERα diminished the inhibition of ERα on the deacetylation of HIF-1α by SIRT6, thereby inhibiting VSMC osteogenic transdifferentiation and relieving the vascular cells calcification. Conclusion Our study demonstrates that ERα has a non-genomic effect to inhibit the deacetylation of HIF-1α by SIRT6, which can be abrogated by Emodin through SYVN1-mediated ERα degradation. These results provide evidences for Emodin to serve as a candidate drug for controlling clinical vascular calcification in CKD.
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DOI
PubMed
高影响因子
BIOLOGICAL RESEARCH
·
2023
·Vol. 56
·期 1
·1-14
·
IF 6.7
Dai Bing,Liu Si,Shen Wenxin,Chen Li,Zhou Qianlan,Han Lina,Zhang Qinzhen,Shan Lishen
Background Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and degradation. However, the role of SYVN1 in the pathogenesis of asthma is unclear. Results In the present study, an ovalbumin (OVA)-induced murine model was used to evaluate the effect of SYVN1 on asthma. An increase in SYVN1 expression was observed in the lungs of mice after OVA induction. Overexpression of SYVN1 attenuated airway inflammation, goblet cell hyperplasia and collagen deposition induced by OVA. The increased ER stress-related proteins and altered epithelial-mesenchymal transition (EMT) markers were also inhibited by SYVN1 in vivo. Next, TGF-β1-induced bronchial epithelial cells (BEAS-2B) were used to induce EMT process in vitro. Results showed that TGF-β1 stimulation downregulated the expression of SYVN1, and SYVN1 overexpression prevented ER stress response and EMT process in TGF-β1-induced cells. In addition, we identified that SYVN1 bound to SIRT2 and promoted its ubiquitination and degradation. SIRT2 overexpression abrogated the protection of SYVN1 on ER stress and EMT in vitro. Conclusions These data suggest that SYVN1 suppresses ER stress through the ubiquitination and degradation of SIRT2 to block EMT process, thereby protecting against airway remodeling in asthma.
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Lijiao He,Xiao Zhang,Shengwei Zhang,Yi Wang,Weichao Hu,Jie Li,Yunyi Liu,Yu Liao,Xue Peng,Jianjun Li,Haiyan Zhao,Liting Wang,Yang-Fan Lv,Chang-Jiang Hu,Shi-Ming Yang
Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA -positive H. pylori . Tert knockout significantly ameliorated H. pylori -induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
研究领域:
胃肠病学
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分子生物学
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肿瘤学
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病理学
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DOI
PubMed
高影响因子
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