VETERINARY MICROBIOLOGY
·
2024
·
IF 2.4
Guangbin Bao,Shinuo Fan,Chunyan Hu,Chen Li,Fei Ma,Guijun Wang,Hongjie Fan,Qing Wang
Duck Tembusu virus (DTMUV) is a newly emerging pathogen that causes massive economic losses to the poultry industry in China and neighbouring countries. Vimentin, an intermediate filament protein, has been demonstrated to be involved in viral replication during infection. However, the specific role of vimentin in DTMUV replication has not been determined. In this study, we found that overexpression of vimentin in BHK-21 cells can inhibit DTMUV replication. Moreover, DTMUV replication was enhanced after vimentin expression was reduced in BHK-21 cells via small interfering RNA (siRNA). Further research indicated that DTMUV infection had no effect on the transcription or expression of vimentin. However, we found that DTMUV infection induced vimentin rearrangement, and the rearrangement of vimentin was subsequently confirmed to negatively modulate viral replication through the use of a vimentin network disrupting agent. Vimentin rearrangement is closely associated with its phosphorylation. Our experiments revealed that the phosphorylation of vimentin at Ser56 was promoted in the early stage of DTMUV infection. In addition, by inhibiting the phosphorylation of vimentin at Ser56 with a CDK5 inhibitor, vimentin rearrangement was suppressed, and DTMUV replication was significantly enhanced. These results indicated that DTMUV infection induced vimentin phosphorylation and rearrangement through CDK5, resulting in the inhibition of DTMUV replication. In summary, our study reveals a role for vimentin as a negative factor in the process of DTMUV replication, which helps to elucidate the function of cellular proteins in regulating DTMUV replication.
研究领域:
病毒学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Hongbo Xie,Haixia Wen,Denan Zhang,Lei Liu,Bo Liu,Qiuqi Liu,Qing Jin,Kehui Ke,Ming Hu,Xiujie Chen
Alzheimer's disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer's disease remain limited. The multifactorial nature of Alzheimer's disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease. In this study, using a molecular docking method to screen a virtual library, we discovered molecules that can simultaneously inhibit Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 as lead compounds for the treatment of Alzheimer's disease. The docking results revealed the key residues in the substrate binding sites of both Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5. A receiver operating characteristic curve indicated that the docking model consistently and selectively scored the majority of active compounds above decoys. The pre-treatment of cells with screened compounds protected them against A β 25-35 - induced cell death by up to 80%. Collectively, these findings suggest that some compounds have potential to be promising multifunctional agents for Alzheimer's disease treatment.
研究领域:
药理学
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神经科学
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计算生物学
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DOI
PubMed
高影响因子
Research
·
2023
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IF 11
Chu Tong,Peng-Xiang Min,Qian Zhang,Ru-Xin Gu,Yao-Hai Wen,Yi Shi,Yu-Huan Bao,Xiang Chen,Yi-Xuan Zhang,Xing-Feng Mao,Hao-Yang Yuan,Xiu-Xiu Liu,Takuya Sasaki,Li Zhang,Feng Han,Ying-Mei Lu
Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors. However, the molecular mechanisms underlying this disturbance remain elusive. Here, we showed that cyclin-dependent kinase 5 (Cdk5) was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis. Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms. Moreover, Cdk5 deficiency in cholinergic neurons triggered paw tremors, abnormal motor coordination, and motor balance deficits in mice. These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+ channels (BK channels). Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice. Furthermore, CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908. Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice. Together, these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuron-mediated motor function, providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.
研究领域:
神经科学
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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
Translational Neurodegeneration
·
2022
·Vol. 11
·期 1
·1-19
·
IF 9.883
Chen Dongmei,Lan Guihua,Li Ruomeng,Mei Yingxue,Shui Xindong,Gu Xi,Wang Long,Zhang Tao,Gan Chen-Ling,Xia Yongfang,Hu Li,Tian Yuan,Zhang Mi,Lee Tae Ho
Background Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease (AD). Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models. However, the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.Methods Immunofluorescence, immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice, in which nonmutated human tau is overexpressed on a mouse tau knockout background. High-throughput microRNA (miRNA) sequencing, quantitative RT-PCR, luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.Results We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD. Moreover, melatonin significantly reduced the number of neurofibrillary tangles (NFTs) and attenuated neuronal loss in the cortex and hippocampus. Furthermore, using miRNA microarray analysis, we found that miR-504-3p expression was upregulated by melatonin in the hTau mice. The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39, an activator of the well-known tau kinase cyclin-dependent kinase 5 (CDK5). Compared with miR-504-3p mimics alone, co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.Conclusion sOur results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.
研究领域:
神经科学
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分子生物学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
PSYCHOPHARMACOLOGY
·
2022
·Vol. 239
·期 11
·3579-3593
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IF 4.415
Mou Chen-Ye,Xie Yan-Fei,Wei Jia-Xin,Wang Qi-Yao,Le Jing-Yang,Bao Yong-Jie,Zhang Pan-Pan,Mao Yue-Chun,Huang Xing-Han,Pan Han-Bo,Naman C. Benjamin,Liu Lin,Liang Hong-Ze,Wu Xiang,Xu Jia,Cui Wei
Rationale
Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer’s disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila . However, it was unknown if RB could produce anti-AD effects in rodents. Objectives The research aimed to investigate if and how RB could prevent β-amyloid (Aβ) oligomers-induced tau hyperphosphorylation in rodents. Methods and results RB was tested in vitro (0.3–1 μM) and prevented Aβ oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10–30 mg/kg, i.p. ) effectively attenuated cognitive impairments induced by Aβ oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3β (GSK3β) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3β and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation. Conclusions RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3β and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.
研究领域:
神经科学
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药理学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2017
·Vol. 41
·期 2
·1138-1146
·
IF 2.341
Xiu‑Yin Shen,Tao Luo,Sheng Li,Ou‑Yang Ting,Feng He,Jie Xu,Hua‑Qiao Wang
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA‑induced tau protein hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin‑dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+‑calpain‑p25‑CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative tauopathies.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cancer & Metabolism
·
2025
·
IF 5.3
Wu Qilong,Zhu Xiaotong,Wan Xinxin,Lu Xinjie,Chen Jiayan,Ying Zhe,Li Yan,Hu Xing,Lu Jiahai,Lou Yongliang,Li Xiang
Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production—collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.
研究领域:
肿瘤学
·
癌症代谢
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分子生物学
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表观遗传学
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
APOPTOSIS
·
2026
·Vol. 31
·期 6
·156
·
IF 9
Lv Feng,Li Xiao-huan,Li Si-qi,Deng Hao-wei,Wei Hao-tang,Li Ke-zhi,Xie Ming-zhi,Xie Li-ye,Ning Shu-fang,Hu Bang-li
This study aimed to determine the effect of Artesunate (ART) on oxaliplatin-resistance of colorectal cancer (CRC) and the underlying mechanism. CRC parent and oxaliplatin-resistance cells were induced ferroptosis by ART, overexpression or silence of CDK5 and Nrf2 was conducted on CRC cells, and the function of cells were tested. The protein location, binding effect, protein–protein interaction, ART–CDK5 interaction were determined. Mice model was used to validated the effect of ART on CRC cells. ART induces ferroptosis and inhibits oxaliplatin-resistance of CRC cells. CDK5 promoted the viability, invasive, migration of CRC cells, but did not lead to increases cell apoptosis. CDK5 was associated with ferroptosis and oxaliplatin-resistance of CRC cells, and ART binding and inhibited the expression of CDK5. CDK5 inhibit CRC cells ferroptosis and promote oxaliplatin-resistance; CDK5 binding to Nrf2, increased stability and promote translocation of Nrf2 from cytosol to nuclear. By combination of overexpression of CDK5 and the overexpression or silence of Nrf2 in CRC cells, we found that CDK5 inhibited ferroptosis of CRC cells and enhance resistance to oxaliplatin via Nrf2/GPX4 pathway. The in vivo experiments exhibited that combination of ART and sh-CDK5 reduce the growth of tumors with low toxicity in xenograft models, and reduced Nrf2 and GPX4 expression. ART induced ferroptosis thereby overcomes oxaliplatin-resistance of CRC cells, this effect was via modulating the CDK5/Nrf2/GPX4 pathway. These findings highlight CDK5 as a critical regulator of redox homeostasis in CRC and the therapeutic potential of ART in treating chemoresistant tumors. Graphical abstract The alternative text for this image may have been generated using AI. The present study demonstrate that ART was able to induce ferroptosis via binding and regulation of CDK5, and CDK5 modulates the expression of Nrf2, thereby inhibited biological function of CRC cells and attenuates oxaliplatin-resistance of the cells, this effect was via orchestrating the Nrf2/GPX4 pathway.
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2020
·
IF 4.902
Yao Qi,Lin Guo,Yibing Jiang,Yijie Shi,Haijuan Sui,Liang Zhao
It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer’s disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.
研究领域:
神经科学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2018
·
IF 4.936
Pan Liu,Xiao Chen,Haizhe Zhou,Liqun Wang,Zaijun Zhang,Xiaohu Ren,Feiqi Zhu,Yi Guo,Xinfeng Huang,Jianjun Liu,Peter S. Spencer,Xifei Yang
Alzheimer’s disease (AD), the most common neurodegenerative disease, has no effective treatment. Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, reportedly has neuroprotective effects in cerebral ischemia. Here, we investigated the effects of DAU on N2a cells stably transfected with Swedish mutant amyloid precursor protein (N2a/APP), an AD-like cell model. ELISA and Western blot analysis revealed that DAU inhibited APP processing and reduced Aβ accumulation. In addition, DAU ameliorated tau hyperphosphorylation via PP2A, p35/25, and CDK5 pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by DAU was also validated in HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis revealed 85 differentially expressed proteins in the lysates between the wild-type N2a cells (N2a/WT) and the N2a/APP cells in the presence or absence of DAU; these were classified into 6 main categories according to their functions: endoplasmic reticulum (ER) stress-associated proteins, oxidative stress-associated proteins, cytoskeleton proteins, molecular chaperones, mitochondrial respiration and metabolism-related proteins, and signaling proteins. Taken together, we demonstrated that DAU treatment reduces AD-like pathology, thereby suggesting that DAU has potential therapeutic utility in AD.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
蛋白质组学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）