Biochemistry and Cell Biology
·
2025
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IF 2.1
Hongyu Wang,Liyang Liang,Yanfei Wang,Xuan Zhong,Chao Zhang,Zhipeng Liu,Jinzhong Liu,Wanning Hu
WD repeat domain 4 (WDR4) has been reported to promote tumor metastasis in various cancers. However, its precise function in colorectal cancer (CRC) has not been reported yet. Herein, the expression pattern of WDR4 in CRC was determined by analyzing Gene Expression Omnibus datasets (GSE110225, GSE127069, GSE156355, and GSE184093) and GEPIA online dataset. In vitro and in vivo experiments, including CCK-8, colony formation, flow cytometry, wound healing, transwell assays, and xenograft mouse models, were used to investigate the role of WDR4 in CRC. Firstly, data from Kaplan–Meier database showed that high expression of WDR4 was associated with the poor prognosis of CRC patients. Then, upregulation of WDR4 was confirmed in clinical CRC tissues. In vitro functional experiments suggested that overexpression of WDR4 promoted cell proliferation, migration, and invasion, while knockdown of WDR4 has the opposite effects. Also, the oncogenic role of WDR4 was also verified in in vivo experiments. CO-IP-LC/MS analysis uncovered that glycogen synthase kinase 3β (GSK3β) is the central protein that binds to WDR4. Mechanistically, WDR4 activated the β-catenin pathway by promoting GSK3β phosphorylation. This study demonstrates that WDR4 promotes CRC progression through activating GSK3β/β-catenin pathway, indicating that WDR4 might be a potential therapeutic target for CRC treatment.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2025
·
IF 3.1
Li Yue,Li Hailan,Sun Minhui,Chen Hong,Xiao Yao,Wang Jieman,Zhang Yuanyuan,Fang Shuhua,Kou Junping
Silibinin (Sil) is a major bioactive component of silymarin, extracted from the fruit and seeds of Silybum marianum . Silibinin meglumine (SM) is a water-soluble derivative of silibinin that has shown significant potential in liver fibrosis. However, the potential effects and underlying mechanisms of SM on acute liver failure (ALF) are still not fully understood. This study aims to find the likely mechanism. An ALF mouse model and a cell model were established with GalN/LPS. SM was administered to mice via the tail vein or to a hepatocyte line (alpha mouse liver 12, AML12). The results showed that SM particularly lowered the mortality and improved liver pathological lesions in ALF mice. Meanwhile, SM improved the levels of GSH, SOD, TNF-α, IL-6, IL-1β, and IL-10 in the liver tissues and serum. Additionally, SM enhanced cell viability and reduced oxidative stress in vitro. In the AKT/GSK3β/Nrf2/GPX4 pathway, the subpathway of AKT/GSK3β was inhibited, and the subpathway of Nrf2/GPX4 was activated by SM both in vivo and in vitro. In addition, ferrostatin-1, a ferroptosis inhibitor, and the silencing of AKT using siRNA weakened the protective effect of SM, indicating that this process is mediated in an AKT-dependent manner. All the results suggested that SM inhibits inflammation and oxidative stress by modulating the AKT/GSK3β/Nrf2/GPX4 pathway.
研究领域:
药理学
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肝脏病学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2015
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IF 2.297
Jintao Wu,Dexiao Zhu,Jing Zhang,Guibao Li,Zengxun Liu,Jinhao Sun
Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro . Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathway in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro , while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway.
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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DOI
PubMed
高影响因子
FEBS LETTERS
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2018
·Vol. 593
·期 2
·175-186
·
IF 2.999
Shengnan Yang,Yuan Zhang,Fukui Shen,Xiaoyao Ma,Man Zhang,Yuanyuan Hou,Gang Bai
Baicalin is one of the main flavonoids of the dried root of Scutellaria baicalensis Georgi and is reported to exert beneficial effects on the regulation of glucose/lipid metabolism. However, understanding its specific target and unique mechanism for improving glucose utilization is a challenge. In this paper, target fishing with a baicalin probe reveals that baicalin interacts with AKT. An immunofluorescence assay further demonstrates the colocalization of baicalin with AKT in the cytoplasm. A competitive test and virtual docking show that baicalin might bind to the pleckstrin homology domain of AKT. This specific binding hampers AKT membrane translocation, activates the phosphorylation of AKT on Ser473, induces the downstream glycogen synthase kinase 3β activation, and affects glycogen synthesis.
研究领域:
药理学
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分子生物学
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代谢
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2017
·
IF 4.581
Jinhua Hu,Zhao Mao,Shuangcheng He,Yuanran Zhan,Rui Ning,Wei Liu,Bingfang Yan,Jian Yang
Osteoporosis is a serious public health concern worldwide. Herba epimedii has been used for centuries and even thousands of years to treat osteoporotic conditions. Icariin , a flavonol glycoside , is one of the major active ingredients. In this study, we have shown that icariin protected against glucocorticoid-induced osteoporotic changes in SaoS-2 cells and mice. We have also shown that dexamethasone (a glucocorticoid) suppressed and icariin induced DEC1, a structurally distinct helix-loop-helix protein. DEC1 overexpression promoted whereas DEC1 knockdown decreased osteogenic activity. Likewise, DEC1 overexpression and knockdown inversely regulated the expression of β-catenin and PIK3CA, an essential player in the Wnt/β-catenin and PI3K/Akt signaling pathways, respectively. Interestingly, DKK1, an inhibitor of Wnt/β-catenin signaling inhibitor, and LY294002 , an inhibitor of PI3K/Akt signaling, abolished the induction of DEC1 by icariin. It is established that these two pathways are interconnected by the phosphorylation status of GSK3β. Dexamethasone decreased but icariin increased GSK3β phosphorylation. Finally, DEC1 deficient mice developed osteoporotic phenotypes. Taken together, it is concluded that DEC1 likely supports the action of icariin against glucocorticoid induced osteoporosis with an involvement of the PI3K/Akt/GSK3β/β-catenin integrated signaling pathway.
研究领域:
药理学
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分子生物学
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细胞生物学
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内分泌学
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骨生物学
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DOI
PubMed
高影响因子
WORLD JOURNAL OF GASTROENTEROLOGY
·
2015
·
IF 2.369
Gui-Li Huang,Dong-Yan Shen,Cheng-Fu Cai,Qiu-Yan Zhang,Hong-Yue Ren,Qing-Xi Chen
AIM: To develop a safe and effective agent for cholangiocarcinoma (CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in combination with chemotherapy on CCA cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells (QBC939, Sk-ChA-1, and MZ-ChA-1). Immunocytochemistry was used to detect the expression of P-glycoprotein (P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, pS9-GSK3β, pT216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting. RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil (5-FU) cells to 5-FU, vincristine sulfate (VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone ( P < 0.05). In addition, the combination of β-escin (20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the mRNA and protein expression of P-gp was down-regulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3a resulted in up-regulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner. CONCLUSION: β-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.
研究领域:
肿瘤学
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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
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2020
·Vol. 473
·期 1
·217-228
·
IF 2.795
Wu Xinghan,Liu Chuanliang,Li Zihaoran,Gai Chengcheng,Ding Dejun,Chen Weijuan,Hao Fengyun,Li Wentong
Ferroptosis is a newly discovered form of regulated cell death and characterized by an iron-dependent accumulation of lethal lipid reactive oxygen species (ROS), ferroptosis may exhibit a novel spectrum of clinical activity for cancer therapy. However, the significance of ferroptosis in the context of carcinoma biology is still emerging. Glycogen synthase kinase-3β (GSK-3β) has been found to be a fundamental element in weaking antioxidant cell defense by adjusting the nuclear factor erythroid 2-related factor 2 (Nrf2). In our study, decreased expression of GSK-3β was observed in the cancer tissues of breast cancer patients, results of immunohistochemistry indicated that Nrf2 was highly expressed in low-GSK-3β-expressed breast cancer tissues. The contributions of aberrant expression of GSK-3β and Nrf2 to the erastin-induced ferroptosis in breast cancer were further assessed, silence of GSK-3β blocked erastin-induced ferroptosis with less production of ROS and malondialdehyde (MDA) via upregulation of GPX4 and downregulation of arachidonate 15-lipoxygenase (Alox15), overexpression of GSK-3β enhanced erastin-triggered ferroptosis with elevated ROS and MDA. Enhanced erastin-induced ferroptosis by overexpression of GSK-3β was blocked by activating Nrf2. We further confirmed that overexpression of GSK-3β strengthened erastin-induced tumor growth inhibition in breast cancer xenograft models in vivo. In summary, our findings conclude that modulation the balance between GSK-3β/Nrf2 is a promising therapeutic approach and probably will be important targets to enhance the effect of erastin-induced ferroptosis in breast cancer.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症治疗
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PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chen Bo,Li Xiaoli,Wu Lihong,Zhou Duanfang,Song Yi,Zhang Limei,Wu Qiuya,He Qichen,Wang Gang,Liu Xu,Hu Hui,Zhou Weiying
High invasiveness is a biological and clinical characteristic of glioblastoma and predicts poor prognosis of patients. Quercetin, a natural flavonoid compound, exhibits anticancer activity. However, we have a limited understanding of the possible underlying mechanism of quercetin in glioblastoma. In this study, we investigated the anticancer effect of quercetin in human glioblastoma cells. Our results showed that quercetin markedly suppressed the viability of glioblastoma cells in vitro and in vivo, and significantly inhibited glioblastoma cell migration and invasion. Moreover, quercetin reversed EMT-like mesenchymal phenotype and reduced the expression levels of EMT-related markers. Furthermore, we found that quercetin suppressed GSK-3β/β-catenin/ZEB1 signaling in glioblastoma. Taken together, our results demonstrate that quercetin inhibited migration and invasion of human glioma cells by suppressing GSK3β/β-catenin/ZEB1 signaling. Our study provides evidence that quercetin is a promising therapeutic natural compound to treat glioblastoma.
研究领域:
肿瘤学
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药理学
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细胞生物学
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PubMed
高影响因子
Environment & Health
·
2023
·
IF 0
Wei Wei,Bingwei Yang,Xiangyu Zhu,Xuting Liu,Erqun Song,Yang Song
When nanoparticles (NPs) enter a physiological environment, they tend to adsorb proteins to form a so-called corona. A comprehensive understanding of the effect of protein corona on NPs’ toxicity is required. Our previous study indicated that silica nanoparticles (SiO2 NPs) exposure with different routes resulted in distinct brain damage; however, an exact molecular mechanism of protein corona on the regulation of SiO2 NPs-induced damages needs further investigation. SiO2 NPs exposure via intravenous injection may encounter a protein-rich bio-matrix, which drives the adsorption of serum protein on their surface to form a stable SiO2 NPs@serum complex. On the contrary, SiO2 NPs exposure via intranasal instillation remained their original feature, due to a protein infertile environment of cerebrospinal fluid. Apparently, surface adsorption of proteinaceous substances altered inherent toxic behavior of SiO2 NPs. In addition, glycogen synthase kinase 3 beta (GSK3β) phosphorylate was found at different residues, which play an essential role in orchestrating apoptosis and autophagy threshold. Route-dependent corona formation determined GSK3β phosphorylation status and ultimately the toxic behavior of SiO2 NPs. This work presented the evidence of bio-corona on the regulation of SiO2 NPs-induced toxicity, which can be used to guide risk assessment of environmental NPs.
研究领域:
纳米毒理学
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神经毒理学
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环境卫生
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生物化学
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分子生物学
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DOI
Nutrients
·
2018
·Vol. 10
·期 10
·1366
·
IF 4.196
Jie Gao,Xin He,Yuejiao Ma,Xuezhi Zhao,Xiaotao Hou,Erwei Hao,Jiagang Deng,Gang Bai
Chlorogenic acid (CGA), a bioactive component in the human diet, is reported to exert beneficial effects on the regulation of glucose metabolism. This study was designed to investigate the specific target of CGA, and explore its underlying mechanisms. Beneficial effects of CGA in glucose metabolism were confirmed in insulin-treated human hepatocarcinoma HepG2 cells. Protein fishing, via CGA-modified functionalized magnetic microspheres, demonstrated the binding of CGA with protein kinase B (AKT). Immunofluorescence using a CGA molecular probe further demonstrated the co-localization of CGA with AKT. A competitive combination test and hampering of AKT membrane translocation showed that CGA might bind to the pleckstrin homology (PH) domain of AKT. The specific binding did not lead to the membrane translocation to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), but directly activated the phosphorylation of AKT on Ser-473, induced the phosphorylation of the downstream molecules, glycogen synthase kinase 3β (GSK3β) and forkhead box O1 (FOXO1), and improved glucose metabolism. Collectively, our data demonstrate that CGA exerts regulatory effects on glucose metabolism via direct targeting the PH domain of AKT. This study clarifies the mechanism of the potential benefits of nutrients containing CGA in the complementary therapy of glucose metabolism disorders.Keywords:chlorogenic acid;glucose metabolism;protein kinase B (AKT);pleckstrin homology (PH) domain;glycogen synthase kinase 3β (GSK3β);forkhead box O1 (FOXO1)
研究领域:
药理学
·
细胞生物学
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代谢
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DOI
PubMed
高影响因子
Aging-US
·
2019
·
IF 5.515
Chao Guo,Junrong Zhu,Jingwen Wang,Jialin Duan,Shanbo Ma,Ying Yin,Wei Quan,Wei Zhang,Yue Guan,Yi Ding,Aidong Wen,Yingdong Zhang
Mitochondrial dysfunction and oxidative damage are closely related to the pathogenesis of Parkinson's disease (PD). The pharmacological mechanism of protocatechuic aldehyde (PCA) for PD treatment have retained unclear. The purposes of the present study were to clarify the neuroprotective effects of post-treatment of PCA for PD treatment by mitigating mitochondrial dysfunction and oxidative damage, and to further determine whether its effects were mediated by the polo-like kinase 2/phosphorylated glycogen synthase kinase 3 β/nuclear factor erythroid-2-related factor 2 (PLK2/p-GSK3β/Nrf2) pathways. We found that PCA improved 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic cell loss. Moreover, PCA increased the expressions of PLK2, p-GSK3β and Nrf2, following the decrease of α-synuclein (α-Syn) in MPTP-intoxicated mice. Cell viability was increased and the apoptosis rate was reduced by PCA in 1-methyl-4-phenylpyridinium iodide (MPP + )-incubated cells. Mitochondrial membrane potential (MMP), mitochondrial complex I activity and reactive oxygen species (ROS) levels in MPP + -incubated cells were also ameliorated by treatment with PCA. The neuroprotective effects of PCA were abolished by inhibition or knockdown of PLK2, whereas overexpression of PLK2 strengthened the protection of PCA. Furthermore, GSK3β and Nrf2 were involved in PCA-induced protection. These results indicated that PCA has therapeutic effects on PD by the PLK2/p-GSK3β/Nrf2 pathway.
研究领域:
神经科学
·
药理学
·
分子生物学
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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Zhigang Nie,Sen Chen,Shuang Deng,Linsheng Long,Puji Peng,Mingyong Gao,Shile Cheng,Jiarui Cao,Hao Peng
Objective Glucocorticoids (GCs)-induced osteoblast apoptosis has been identified as an important cause of GCs related osteonecrosis of the femoral head (ONFH). Glycogen synthase kinase 3β (GSK3β) has been proved to mediate dexamethasone (Dex)-induced osteoblast apoptosis. This study aimed to investigate the underlying mechanism of GSK3β in Dex-induced osteoblast apoptosis. Methods Osteoblast cells were transfected with lentivirus expressing GSK3β-shRNA, and a DNA microarray was performed to analyze gene expression after Dex treatment with or without GSK3β-shRNA. Some differentially expressed genes were further validated by quantitative real-time-PCR (qRT-PCR). Results 460 genes were up-regulated (at least 2-fold) with Dex treatment but down-regulated (at least 2-fold) with GSK3β-shRNA treatment. In addition, 315 genes were down-regulated (at least 2-fold) with Dex treatment but up-regulated (at least 2-fold) with GSK3β-shRNA treatment. Among these genes, the apoptosis-related genes Hoxb8 , Kif18a , Dock8, Dlk1, Tnfsf14 , Casq2 , Bcl2l14 and mechanosensation-related gene Piezo2 were selected for further qRT-PCR analysis. 7 of 8 genes (Piezo2, Hoxb8, Kif18a, Dlk1, Tnfsf14, Casq2, Bcl2l14) showed the same tendency between gene chip results and qRT-PCR results. The microarray data also showed that apoptotic pathway, MAPK pathway, TGFβ pathway and Wnt pathway might be related to the mechanism of GSK3β in Dex-induced osteoblast apoptosis. Conclusion Our findings indicate that GSK3β-shRNA treatment can alter various genes expression levels and change diverse signaling pathways involved in Dex-induced osteoblast apoptosis. Furthermore, Piezo2, Hoxb8, Kif18a, Dlk1, Tnfsf14, Casq2 and Bcl2l14 genes may play an important role in the GSK3β-mediated osteoblast apoptosis process.
研究领域:
药理学
·
细胞生物学
·
分子生物学
·
基因组学
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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）