EXPERIMENTAL CELL RESEARCH
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2023
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IF 3.7
Hanqing Zhu,Hongliang Zhang,Jiahui Guo,Chao Zhang,Quanwu Zhang,Fenghou Gao
Mdm2 promotes the ubiquitination and degradation of p53, while Mdm2-p60 can bind to p53 and reduce the Mdm2-induced p53 ubiquitination to improve its stability. USP2a can deubiquitinate and stabilize Mdm2, whether USP2a can regulate Mdm2-p60 needs to be further confirmed and elucidated. We found that oxidative stress can up-regulate USP2a at the post-transcriptional level and induce USP2a to be oxidized by forming inter-subunit disulfide bonds . The oxidized USP2a is closely related with cell apoptosis. In apoptotic cells, oxidized USP2a has enhanced protein stability and further stabilizes Mdm2-p60 through deubiquitination , and the USP2a-Mdm2-p60-p53 axis plays a role in cell apoptosis. Altogether USP2a is oxygen sensitive, oxidized USP2a exerts apoptotic effects through the Mdm2-p60-p53 axis, which provides an experimental basis for regulating p53 apoptotic signaling by targeting USP2a.
研究领域:
细胞生物学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
Cancer Medicine
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2019
·Vol. 8
·期 11
·5313-5326
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IF 3.357
Han-Qing Zhu,Chao Zhang,Zhu-Ying Guo,Jun-Mei Yang,Jia-Hui Guo,Chen Chen,Qiang-Hua Yao,Feng Liu,Quan-Wu Zhang,Feng-Hou Gao
Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis- and cell cycle arrest-related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53-induced Mdm2 (E3 ubiquitin-protein ligase Mdm2) to generate Mdm2-p60. The generation of Mdm2-p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2-p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
GLIA
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2025
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IF 5.1
Xinrui Ma,Jingmin Liu,Jiale Cai,Huqian Zheng,Ye He,Shuyi Xu,Haowen Zhang,Jinkun Wen,Xianghai Wang,Jiasong Guo
RhoA is well known as a key molecular switch for cytoskeleton remodeling, and previous studies reveal RhoA plays a pivotal role in Schwann cell myelination which is highly dependent on the dynamics regulation of the actin and microtubule cytoskeleton. Existing evidence indicates RhoA modulates myelination and other biofunctions by targeting actin filament turnover; however, the role of RhoA in microtubule dynamics remains unknown. Herein, Bulk mRNA sequencing and bioinformatic analysis enriched microtubule dynamics-related ontology terms in RhoA knockout Schwann cells, and identified that microtubules contribute to RhoA deficiency-caused hypomyelination. Both in vivo and in vitro experiments demonstrated that genetic ablation or pharmacological inhibition of RhoA attenuates microtubule dynamics in Schwann cells, whereas activated RhoA overexpression or RhoA agonist enhances the microtubule dynamics. RhoA conditional knockout (cKO) in Schwann cells led to hypomyelination, dysmyelination and nerve functional deficits in mice. Mechanistically, the present study identified CDK2 as a crucial mediating molecule for RhoA regulating microtubule dynamics. CDK2 overexpression could reverse the reduced microtubule dynamics, hypomyelination and motor deficits in RhoA cKO mice. Furthermore, RhoA modulating CDK2 is dependent on YAP/TEAD signaling, and the ASPM/p60-Katanin axis mediates the role of CDK2 in controlling microtubule dynamics. Collectively, this study uncovered a novel RhoA/YAP1/TEAD3/CDK2/ASPM/p60-Katanin axis in regulating microtubule dynamics during Schwann cell myelination, which indicates that this pathway may be utilized as new targets for repairing congenital hypomyelination/dysmyelination neuropathy or peripheral nerve injury.
研究领域:
神经科学
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细胞生物学
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分子生物学
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周围神经系统疾病
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信号转导
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DOI
PubMed
高影响因子
Cureus Journal of Medical Science
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2024
·
IF 1
Ye-Ran Mao,Ling-Yi Zhu,Ruo-Fei Du,Xiao-Yu Liu,Zhidan Liu,Li Li
Background and objectives: In ancient China, bee venom was widely used to treat various diseases. Although using bee venom is not currently a mainstream medical method, some have applied it to treat certain conditions, including idiopathic facial paralysis (IFP). Recently, melittin (Mel), the main active component of bee venom, has been shown strong anti-inflammatory and analgesic effects. However, how bee venom improves neurological dysfunction in facial paralysis remains unknown. This study aimed to investigate the anti-neurotraumatic effect of Mel on Schwann cells (SCs), the main cells of the neuron sheath, injured by oxidative stress. Methods: A model of hypoxic SCs was established, and CCK-8 assay, siRNA transfection, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, immunofluorescence, and cell ultrastructure analyses were conducted to investigate the mitigation of hypoxia-induced damage to SCs in vitro, revealing the effects of Mel on oxidative stress injury in SCs. Results: The overexpression of HIF-1α in CoCl 2 -induced SCs (p < 0.05) indicated the establishment of an SCs hypoxia model. The proliferation and regeneration process of the hypoxic SCs enhanced in the Mel-treated group compared to the CoCl 2 group has been proven through the CCK-8 experiment (p < 0.0001) and S-100 mRNA expression detection (p < 0.0001). The increased level of reactive oxygen species (ROS) (p < 0.001) and decreased superoxide dismutase (SOD) levels (p < 0.05) in the CoCl 2 -induced SCs indicated that Mel can alleviate the oxidative stress damage to SCs induced by CoCl 2 . Mel alleviated oxidative stress and inflammation in hypoxic SCs by reducing pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001). In addition, Mel augmented cellular vitality and regulated indicators related to oxygen metabolism, cell repair, neurometabolism, and vascular endothelial formation after hypoxia, such as C-JUN (p < 0.05), glial cell line-derived neurotrophic factor (GDNF; p < 0.001), vascular endothelial growth factor (VEGF; p < 0.05), hypoxia-inducible factor 1-alpha (HIF-1α; p < 0.05), interleukin-1 receptor type 1 (IL-1R1; p < 0.05), enolase1 (ENO1; p < 0.05), aldose reductase (AR; p < 0.01), SOD (p < 0.05), nerve growth factor (NGF; p < 0.05), and inducible nitric oxide synthase (iNOS; p < 0.05). In terms of its mechanism, Mel inhibited the expression of proteins associated with the NF-κB pathway such as IKK (p < 0.01), p65 (p < 0.05), p60 (p < 0.001), IRAK1 (p < 0.05), and increased IKB-α (p < 0.0001). Moreover, knocking out of IL-1R1 in the si-IL-1R1 group enhanced the therapeutic effect of Mel compared to the Mel-treated group (all of which p < 0.05). Conclusion: This research provided evidence of the substantial involvement of IL-1R1 in oxidative stress damage caused by hypoxia in SCs and proved that Mel alleviated oxidative stress injury in SCs by targeting IL-1R1 to downregulate the NF-κB-mediated inflammatory response. Mel could potentially serve as an innovative therapeutic approach for the treatment of IFP.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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炎症
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氧化应激
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面瘫
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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）