EXPERIMENTAL CELL RESEARCH
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2018
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IF 3.309
Yanting Zhu,Fangwei Li,Wenhua Shi,Cui Zhai,Jian Wang,Xin Yan,Qingting Wang,Qianqian Zhang,Lan Yang,Li Gao,Manxiang Li
Up-regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor β-transduction repeat-containing protein (β-TrCP) have been shown to be associated with cancer cells proliferation . However, it is unclear whether CSN6 and β-TrCP are also involved in PDGF-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up-regulated CSN6 protein expression , this was accompanied with β-TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF-induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF-induced β-TrCP down-regulation, Cdc25A up-regulation and cell proliferation. Furthermore, pre-treatment of cells with MG-132 also abolished PDGF-induced β-TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre-depletion of Cdc25A by siRNA transfection suppressed PDGF-induced PASMCs proliferation. Taken together, our study indicates that up-regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases β-TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF-induced PASMCs proliferation.
研究领域:
细胞生物学
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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
JOURNAL OF IMMUNOLOGY
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2025
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IF 3.4
Huang Wenji,Wang Yafang,Ji Ning,Xiao Hehe,Chen Kangyong,Guo Jiahong,Feng Jianhua,Mustafa Nageen,Wang Junya,Feng Hao,Zou Jun
A balanced IFN response, tightly regulated at multiple levels, is essential for host defense against viral infection. Tripartite motif-containing (TRIM) proteins are a large group of E3 ubiquitin ligases, and have been shown to be involved in the regulation of IFN response. However, the regulatory functions of individual TRIM proteins remain controversial. Here, we show that a virus-inducible TRIM2 homolog acts as a negative regulator for IFN production in zebrafish. Zebrafish Trim2a was upregulated in response to spring viremia of carp virus (SVCV) infection, and knockout of Trim2a significantly increased the expression of antiviral genes, leading to enhanced resistance to SVCV. Overexpression of Trim2a resulted in pronounced ubiquitination of IFN regulatory factor 3 (IRF3) via K11, K27, K29, and K48, promoting IRF3 degradation and stability of SVCV phosphoprotein to favor viral replication. Moreover, TRIM2a induced ubiquitination of autophagic cargo receptor p62, which then interacted with IRF3, instigating IRF3 degradation. Further, the inhibitory effects of TRIM2a on IFN production were also observed in human HEK293 cells, suggesting that the regulatory functions of TRIM2 are likely to be conserved during evolution. Collectively, our findings demonstrate that TRIM2a is a negative regulator of IFN production, and could serve as a potential target to dampen exacerbated IFN response triggered by aberrant activation of retinoic acid-inducible gene 1 (RIG-I)-like receptors. Our study provides insights into a previously uncharacterized role of TRIM2 in the regulation of IFN signaling.
研究领域:
免疫学
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病毒学
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分子生物学
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DOI
PubMed
高影响因子
Microorganisms
·
2025
·Vol. 13
·期 8
·1865
·
IF 4.2
Chenchen Zhao,Yan Qin,Haixin Huang,Yuying Li,Xinyu Zhang,Lin Zhou,Lulu Xie,Yimin Zhou,Yanqing Hu,Wei Chen,Tian Lan,Wen-Chao Sun
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a recently discovered enteric coronavirus that has caused considerable economic losses in the pig industry. SADS-CoV was first reported in 2017 in Guangdong Province, China, and subsequently in Fujian, Guangxi, Henan and Jiangxi Provinces. Bone marrow stromal cell antigen 2 (BST-2), also known as tetherin, acts as an antiviral protein to limit the release of a wide range of enveloped viruses. However, the relationship between BST-2 and SADS-CoV has rarely been studied. Here, we showed that endogenous BST-2 expression is downregulated by SADS-CoV infection in Vero-E6 and ST cells by 2- to 3-fold. The overexpression of BST-2 inhibited SADS-CoV replication, whereas the knockdown of the BST-2 gene in Vero cells restored SADS-CoV replication. Further study revealed that BST-2 targets the SADS-CoV nucleocapsid protein (N) and decreases N protein expression, and that the BST-2 transmembrane (TM) domain is essential for this activity. Moreover, the degradation of the SADS-CoV N protein promoted by BST-2 is mediated by the membrane-associated ring-CH-type finger 8 (MARCHF8)/calcium binding and coiled-coil domain 2 (NDP52) autophagosome pathway. Overall, we found that BST-2 suppresses viral proliferation by inducing the breakdown of the SADS-CoV N protein via the MARCHF8/NDP52 pathway.
研究领域:
病毒学
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分子生物学
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免疫学
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细胞生物学
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微生物学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Liyun Zheng,Zhongwei Zhao,Li Chen,Wenjing Yang,Giorgio Ercolani,Pan Qin,Bin Lin,Mengzhu Han,Qiaoyou Weng,Yeyu Zhang,Bin Wu,Minjiang Chen,Zouying Yao,Shiji Fang,Jiansong Ji
Astragalin (ASG), a natural flavonoid glycoside, is known for its multiple pharmacological effects. In this study, we explored the antitumor effects of ASG and its underlying mechanism. Specifically, the growth inhibitory effects of ASG were assessed. Apoptosis rate, reactive oxygen species (ROS) accumulation, mitochondrial damage, and the activation of the endoplasmic reticulum stress induced by ASG were assessed. The potential target of ASG was identified and validated. The effects of ASG on immunogenic cell death (ICD) were determined. Furthermore, ASG’s growth inhibition was validated in vivo , and its potential synergistic effects with anti-PD-L1 antibody were examined. Our findings demonstrate that ASG effectively inhibits growth in liver cancer cell lines. ASG treatment induces apoptosis by promoting mitochondrial membrane potential disruption and ROS accumulation. Additionally, ASG directly bounds to quinone oxidoreductase 2 (NQO2), leading to a reduction in NQO2 protein levels and subsequent upregulation of key ER stress markers, including p-PERK, p-eIF2α, GRP78, and CHOP. Moreover, ASG induces hallmark features of ICD, including calreticulin exposure, nuclear high mobility group box 1 reduction, and adenosine triphosphate release. ASG-treated liver cancer cells effectively enhance dendritic cell maturation in a coculture system. In vivo , the tumor growth is synergistically inhibited by ASG combined with anti-PD-L1 antibody in Hepa1-6 tumor-bearing mice. This synergy is associated with increased dendritic cell maturation, enhanced CD8 + T cell infiltration, and a reduction in regulatory T cells. In conclusion, ASG can be served as a potential anticancer agent for liver cancer and enhance the antitumor efficacy of immunotherapy by activating the ROS-mediated endoplasmic reticulum stress and ICD pathways.
研究领域:
肿瘤学
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药理学
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生物化学
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免疫学
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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
ARCHIV DER PHARMAZIE
·
2025
·Vol. 358
·期 9
·e70089
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IF 3.6
Leyao Chen,Xinluan Lv,Xiaoyu Chang,Ruiyong Wang
The SARS-CoV-2 pandemic has spurred global efforts to develop therapeutic approaches. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and a key target for therapeutic development. In this study, 22 thiosemicarbazone derivatives were synthesized. Enzyme activity assays showed compound 3c exhibited obvious inhibition of Mpro, with an IC 50 value of 3.89 μM. The interaction mechanisms between thiosemicarbazone derivatives and Mpro were investigated using synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectroscopy. The fluorescence results indicate that static quenching is predominant. The equilibrium dissociation constant ( K d ) of 2.3 μM between 3c and Mpro was obtained by microscale thermophoresis. This K d value demonstrates the binding affinity of 3c for Mpro, consistent with the spectral results. Meanwhile, the binding modes and stability of thiosemicarbazone derivatives with Mpro were evaluated through molecular docking and molecular dynamics simulations, which also confirmed the stable binding between compound 3c and Mpro. This study provides valuable insights into the interaction mechanism between thiosemicarbazone derivatives and Mpro and provides clues for the design of Mpro inhibitors.
研究领域:
病毒学
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药物化学
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结构生物学
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分子药理学
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抗病毒治疗
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生物物理化学
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计算生物学
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DOI
PubMed
高影响因子
Veterinary Sciences
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2025
·Vol. 12
·期 3
·257
·
IF 2.3
Chenchen Zhao,Yan Qin,Haixin Huang,Wei Chen,Yanqing Hu,Xinyu Zhang,Yuying Li,Tian Lan,Wenchao Sun
Simple SummarySADS-CoV is a newly emerging coronavirus affecting the swine industry worldwide. However, our understanding of its pathogenic pathways remains limited. In this study, the researchers aimed to determine the role of the host factor, poly(A)-binding protein 4 (PABPC4), in SADS-CoV infection. This study found that PABPC4 inhibits SADS-CoV replication by degrading the nucleocapsid protein through selective autophagy. This discovery could potentially contribute to developing novel antiviral strategies to prevent and control SADS-CoV infections, protecting the pig industry from significant economic losses.Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important mechanism of host defense against virus invasion. However, the mechanism through which SADS-CoV-mediated selective autophagy mediates the innate immune response remains unknown. Here, we report that the host protein PABPC4 can inhibit SADS-CoV replication through targeting and degrading its N protein. Furthermore, we demonstrate that PABPC4 recruits MARCHF8 (an E3 ubiquitin ligase), which ubiquitinates the N protein and is degraded via NDP52/CALCOCO2 (a selective autophagy cargo receptor). Taken together, these findings reveal a new mechanism by which PABPC4 inhibits virus replication, and reveal a new target for antiviral drug development.
研究领域:
病毒学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Runyu Dong,Yao Fei,Yiren He,Peng Gao,Bo Zhang,Menglin Zhu,Zhixiong Wang,Longfei Wu,Shuai Wu,Xiaoming Wang,Juan Cai,Zhiqiang Chen,Xueliang Zuo
Drug resistance remains a major hurdle for the therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, the underlying mechanisms remain largely undetermined. Unbiased proteomic screening is performed to identify the potential regulators of lenvatinib resistance in HCC. Patient-derived organoids, patient-derived xenograft mouse models, and DEN/CCl 4 induced HCC models are constructed to evaluate the effects of HECTD2 both in vitro and in vivo. HECTD2 is found to be highly expressed in lenvatinib-resistant HCC cell lines, patient tissues, and patient-derived organoids and xenografts. In vitro and in vivo experiments demonstrated that overexpression of HECTD2 limits the response of HCC to lenvatinib treatment. Mechanistically, HECTD2 functions as an E3 ubiquitin ligase of KEAP1, which contributes to the degradation of KEAP1 protein. Subsequently, the KEAP1/NRF2 signaling pathway initiates the antioxidative response of HCC cells. Lactylation of histone 3 on lysine residue 18 facilitates the transcription of HECTD2. Notably, a PLGA-PEG nanoparticle-based drug delivery system is synthesized, effectively targeting HECTD2 in vivo. The NPs achieved tumor-targeting, controlled-release, and biocompatibility, making them a promising therapeutic strategy for mitigating lenvatinib resistance. This study identifies HECTD2 as a nanotherapeutic target for overcoming lenvatinib resistance, providing a theoretical basis and translational application for HCC treatment.
研究领域:
肿瘤学
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分子生物学
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药物研发
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纳米医学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Xingkang Diao,GuoHua Qi,Xinli Li,Yu Tian,Jing Li,Yongdong Jin
Cell cycle analysis is crucial for disease diagnosis and treatment, especially for investigating cell heterogeneity and regulating cell behaviors. Exosomes are highly appealing as noninvasive biomarkers for monitoring real-time changes in the cell cycle due to their abundant molecular information inherited from their metrocyte cells and reflecting the state of these cells to some extent. However, to our knowledge, the relationship between exosomes and the cell cycle has not been reported. Herein, we successfully monitored the variation of exosomal surface-enhanced Raman spectroscopy (SERS) spectra to discriminate different cell cycle stages (G0/G1, S, and G2/M phases) based on label-free surface-enhanced Raman spectroscopy (SERS) combined with the machine learning method of linear discriminant analysis (LDA). An average accuracy of 85% based on the trained SERS spectra of exosomes from different cell cycle stages confirmed the high reliability of the support vector machine (SVM) algorithm for analyzing dynamic changes in the cell cycle at different time points. Importantly, the related molecular mechanisms among mitotic processes (prometaphase, metaphase, and anaphase/telophase) and unique biomolecular events between cancerous (HeLa) and normal (H8) cells were also revealed by the present label-free SERS detection platform. Based on SERS analysis, the content of phenylalanine (Phe) within HeLa cells increased, and some structures of proteins containing Phe and tryptophan (Trp) residues may be transformed during the mitotic process. Notably, the α-helix and β-sheet of proteins coexisted in HeLa cells; meanwhile, the α-helix of the proteins was more dominant in H8 cells than in HeLa cells. The strategy is effective for discriminating cell cycle stages and elucidating the associated molecular events during the cell mitotic process and will provide potential application value for guiding the cell cycle treatment strategies of cancer in the future.
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2023
·
IF 7.4
Daohui Gong,Xueping Liu,Pengfei Wu,Yue Chen,Yuhang Xu,Zhan Gao,Hang Qian,Guansong Wang,Binfeng He
Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1 . During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis . Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS , MDA , and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.
研究领域:
免疫学
·
细胞生物学
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传染病学
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产品关联
DOI
PubMed
高影响因子
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