NEUROSCIENCE LETTERS
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2024
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IF 2.5
Qian Sun,Li Zhang,Xiuyan Huang,Min Wang
Background Salidroside (Sal) has been found to protect against multiple impairments caused by diabetes, and we designed this study to investigate the effect of Sal on gestational hypertension (GHP)-induced impairment of offspring learning and memory. Methods We established a GHP rat model by intraperitoneal injection of NG-nitro-L-arginine methyl ester (L-NAME), and treated with Sal by daily gavage. We used Morris Water Maze test to evaluate the learning and memory ability of offspring rats. HE staining was used to measured the pathological changes in hippocampus of offspring. Immunohistochemistry, cellular immunofluorescence and western blot were used to detect the protein expression. Results The learning and memory abilities of GHP offspring rats were significantly lower than those of normal rat offspring, while Sal treatment could significantly improve the learning and memory abilities of GHP offspring rats. HE staining did not reveal pathological differences in the hippocampus of normal rats, GHP rats and Sal-treated GHP offspring rats. However, Sal treatment can significantly increase the expression of Wnt1 and Skp2 protein, and decrease the expression of P27kiwf and P21waf1 protein in the hippocampus of GHP offspring rats. In vitro, Sal significantly promoted the proliferation and differentiation on neural stem cell, while Wnt1 knockdown could reverse these promotions by Sal. In the hippocampus of GHP offspring rats, Sal treatment significantly increased the expression of Tuj1, SOX2, Ki67 and DCX protein. Conclusion Salidroside significantly improves the learning and memory impairment of offspring caused by GHP, and its mechanism may be related to the fact that Salidroside promotes the proliferation and differentiation of neural stem cells by activating the Wnt1/Skp2 signaling pathway.
CAS / MDL:
研究领域:
药理学
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神经科学
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发育生物学
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DOI
PubMed
高影响因子
MOLECULAR REPRODUCTION AND DEVELOPMENT
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2015
·Vol. 82
·期 4
·305-314
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IF 2.527
Wei-Rong Yang,Yong Wang,Yi Wang,Jiao-Jiao Zhang,Jia-Hua Zhang,Cheng Lu,Xian-Zhong Wang
SUMMARY Mammalian target of rapamycin (mTOR) is known to be involved in mammalian cell proliferation, while S-phase kinase-associated protein 2 (SKP2) plays a vital role in the cell cycle. Within the testis, estrogen also plays an important role in Sertoli cell proliferation, although it is not clear how. The present study asked if mTOR is involved in 17β-estradiol-dependent Sertoli cell proliferation. We specifically assessed if extracellular signal-regulated kinase 1/2 (ERK1/2) and/or phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) exert convergent effects toward the activation of mTOR signaling, and if this signaling regulates the expression of SKP2 through retinoblastoma (RB) and early mitotic inhibitor 1 (EMI1) protein and on CCNE1 and CCND1 mRNA levels. Treatment with 17β-estradiol for 15–90 min activated mTOR, with mTOR phosphorylation peaking after 30 min. U0126 (5 μM), a specific inhibitor of (MEK1/2), and 10-DEBC (2 μM), a selective inhibitor of AKT, both significantly reduced 17β-estradiol-induced phosphorylation of mTOR. Rapamycin suppressed 17β-estradiol-induced Sertoli cell proliferation, appearing to act by reducing the abundance of SKP2 , CCND1 , and CCNE1 mRNA as well as RB and EMI1 protein. These data indicated that 17β-estradiol enhances Sertoli cell proliferation via mTOR activation, which involves both ERK1/2 and PI3K/AKT signaling. Activated mTOR subsequently increases SKP2 mRNA and protein expression by enhancing the expression of CCND1 and CCNE1 , and inhibits SKP2 protein degradation by increasing EMI1 abundance. Mol. Reprod. Dev. 82: 305–314, 2015. © 2015 Wiley Periodicals, Inc .
研究领域:
生殖生物学
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细胞信号传导
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内分泌学
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DOI
PubMed
高影响因子
JOURNAL OF CHEMOTHERAPY
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2023
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IF 1.8
Yanzhao Jin,Jiaqing Cao,Hua Cheng,Xiaoyun Hu
This study aimed to investigate the role and mechanism of POU6F2-AS2 in the development of gastric cancer. POU6F2-AS2 expression was considerably higher in clinical stomach adenocarcinoma (STAD) tissues and gastric cancer cell lines (MKN-28 and MGC-803) than in neighbouring normal tissues and gastric mucosa epithelial cells (GES-1). POU6F2-AS2 overexpression resulted in a low overall survival probability, progression-free survival probability and post progression survival probability, as well as increased cell viability, migration and invasion of gastric cancer cells, thereby inhibiting apoptosis. Based on RNA pull-down, cycloheximide and MG132 incubation experiments, POU6F2-AS2 promoted SKP2 by stabilizing NONO expression. In addition, in vivo silencing of POU6F2-AS2 in gastric cancer cells can inhibit tumour progression and produce a synergistic antitumour effect when combined with paclitaxel. POU6F2-AS2 is overexpressed in STAD, which is attributed to a bad prognosis. In vitro and in vivo experiments have confirmed that the POU6F2-AS2/NONO/SKP2 axis promotes STAD progression, and that the silencing of POU6F2-AS2 plays a synergistic antitumour effect when combined with paclitaxel. Therefore, POU6F2-AS2 may be potentially developed as a target to inhibit STAD and reduce chemoresistance.
研究领域:
肿瘤学
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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 SCIENCE
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2021
·Vol. 112
·期 8
·3218-3232
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IF 6.716
Dan-Hua He,Yu-Fei Chen,Yi-Le Zhou,Shi-Bing Zhang,Ming Hong,Xianjun Yu,Su-Fen Wei,Xiang-Zhen Fan,Si-Yi Li,Qi Wang,Yongzhi Lu,Yong-Qiang Liu
Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome-dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant-derived Skp2 inhibitor, betulinic acid (BA), via high-throughput structure-based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non–small cell lung cancer (NSCLC) through targeting Skp2-SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H-bonds with residue Lys145, decreases its stability by disrupting Skp1-Skp2 interactions, thereby inhibiting the Skp2-SCF E3 ligase and promoting the accumulation of its substrates; that is, E-cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2-SCF E3 ligase and upregulating p27 and E-cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.
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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癌症研究
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
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2023
·
IF 5.2
Da Huang,Pei-En Wu,Zi-Jie Chen,Yan-Chun Pang,Zi-Wei Xu,Jingbo Tan,Zhi-Hua Jiang,Bing-Bing Yang,Ruoting Zhan,Hui Xu,Yong-Qiang Liu
Scope This study aims to investigate the anticancer properties of Citrus grandis ‘Tomentosa’ (CGT) in non-small cell lung cancer (NSCLC). Methods and results The ethanol extract of CGT (CGTE) is prepared by using anhydrous ethanol and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), revealing that the main chemical components in CGTE are flavonoids and coumarins, such as naringin, rhoifolin, apigenin, bergaptol, and osthole. CGTE at concentrations without inducing cell death significantly inhibits cell proliferation via inducing cell cycle G1 phase arrest by MTT, colony formation, and flow cytometry assays, implying that CGT has anticancer potential. CGTE markedly inhibits the activity of Skp2-SCF E3 ubiquitin ligase, decreases the protein level of Skp2, and promotes the accumulation of p27 by co-immunoprecipitation (co-IP) and in vivo ubiquitination assay; whereas Skp2 overexpression rescues the effects of CGTE in NSCLC cells. In subcutaneous LLC allograft and A549 xenograft mouse models, CGTE, without causing obvious side effects in mice, significantly inhibits lung tumor growth by targeting the Skp2/p27 signaling pathway. Conclusion These findings demonstrate that CGTE efficiently inhibits NSCLC proliferation both in vitro and in vivo by targeting the Skp2/p27 signaling pathway, suggesting that CGTE may serve as a therapeutic candidate for NSCLC treatment.
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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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2026
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IF 12.2
Liu Yanzhu,Yang Rui,Li Dongmei,Zeng Weiquan,Wei Yan,Huang Zhihui,Wang Ying
Tumor hypoxia/necrosis as a hallmark of glioblastoma (GBM) is strongly associated with malignant progression and poor prognosis of GBM, however, its roles and mechanisms in the behaviors of neighboring surviving GBM cells remain poorly understood. Here, we analyzed public transcriptomic datasets to characterize gene expression in hypoxic/necrotic regions in GBM, and found that the glycolytic pathway was activated in tumor cells from these regions. Furthermore, glycolysis was also elevated in GBM cells under hypoxia/necrosis-mimicking conditions in vitro. Notably, hypoxia/necrosis-mimicking cells-derived lactate promoted the viability and proliferation and migration of neighboring surviving GBM cells. Mechanistically, lactate induced the lactylation of histone H3 lysine 9 (H3K9la), activating transcription of S-phase kinase-associated protein 2 (SKP2). This transcriptional activation was associated with H3K9la enrichment at the SKP2 promoter in GBM cells. SKP2 knockdown inhibited the tumor-promoting effects induced by lactate in GBM cells. Finally, in the orthotopic murine GBM model, hypoxia/necrosis-mimicking cells promoted GBM progression via SKP2 signaling. These results identify a hypoxia/necrosis-driven metabolic-epigenetic axis in GBM, in which lactate-mediated H3K9la promotes GBM progression through SKP2 signaling, revealing SKP2 as a potential therapeutic target for disrupting hypoxia/necrosis-associated malignancy of GBM.
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DOI
高影响因子
Frontiers in Cardiovascular Medicine
·
2022
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IF 5.846
Chen Cong,Liu Shuhong,Cao Gaozhen,Hu Yang,Wang Run,Wu Min,Liu Mingya,Yiu Kai Hang
Background: This study primarily explored the role of paeonol in doxorubicin (DOX)-induced chronic heart failure (CHF), considering the cardioprotective effect of paeonol on an epirubicin-induced cardiac injury.Methods: DOX-induced CHF-modeled rats were treated with paeonol. Cardiac function and myocardial damage in rats were evaluated by using the multifunction instrument, and the histopathology, apoptosis, and the expression of miR-21-5p and S-phase kinase-associated protein 2 (SKP2) in myocardium were detected. The target gene of miR-21-5p was confirmed by a dual-luciferase reporter assay. After the required transfection or paeonol treatment, the viability, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) of the DOX-induced cardiomyocytes were determined. Reverse-transcription quantitative-PCR (RT-qPCR) and Western blot were performed to quantify the expressions of miR-21-5p, SKP2, and apoptosis-related factors.Results: Paeonol improved cardiac function and also ameliorated the cardiac damage of CHF-modeled rats, where the downregulation of abnormally elevated myocardial damage markers, including brain natriuretic peptide, lactate dehydrogenase, renin, angiotensin II, aldosterone, and endothelin 1, was observed. Paeonol alleviated the histopathological injury and suppressed the apoptosis in CHF-modeled rats, inhibited miR-21-5p expression, and upregulated SKP2 expression in vitro and in vivo. miR-21-5p targeted SKP2. Paeonol and SKP2 increased the viability and MMP, but reduced apoptosis and ROS in the DOX-induced cardiomyocytes. miR-21-5p exerted effects opposite to PAE and SKP2, and it downregulated the expression of Bcl-2 and mitochondrion-Cytochrome c (Cyt c) and upregulated the expression of Bax, C-caspase-3, and cytoplasm-Cyt c. miR-21-5p reversed the effects of paeonol, and its effects were further reversed by SKP2.Conclusion: Paeonol shows a cardioprotective effect on DOX-induced CHF via regulating the miR-21-5p/SKP2 axis.- Paeonol inhibited miR-21-5p expression in doxorubicin-induced chronic heart failure rats and in doxorubicin-induced cardiomyocytes.- SKP2 was targeted by miR-21-5p and it was down-regulated in chronic heart failure rats and doxorubicin-induced cardiomyocytes.- Paeonol showed cardioprotective effects on doxorubicin-induced chronic heart failure via regulating miR-21-5p/SKP2/PI3K/AKT axis.
研究领域:
药理学
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心脏病学
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分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
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