ANTI-CANCER DRUGS
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2021
·Vol. 32
·期 7
·727
·
IF 2.248
Zhang Zuo-yan,Dong Shu-min,Liu Ye-han,Zhang Man-man,Zhang Jian-kang,Zhu Hua-jian,Shao Jia-an,Liu Hua-qing,Li Yang-ling,Zhang Chong,Zeng Ling-hui
Vinpocetine is widely used to treat cerebrovascular diseases. However, the effect of vinpocetine to treat hepatocellular carcinoma (HCC) has not been investigated. In this study, we revealed that vinpocetine was associated with antiproliferative activity in HCC cells, but induced cytoprotective autophagy, which restricted its antitumor activity. Autophagy inhibitors improved the antiproliferative activity of vinpocetine in HCC cells. Sorafenib is effective to treat advanced HCC, but the effect of autophagy induced by sorafenib is indistinct. We demonstrated vinpocetine plus sorafenib suppressed the cytoprotective autophagy activated by vinpocetine in HCC cells and significantly induced apoptosis and suppressed cell proliferation in HCC cells. In addition, vinpocetine plus sorafenib activates glycogen synthase kinase 3β (GSK-3β) and subsequently inhibits cytoprotective autophagy induced by vinpocetine in HCC cells. Meanwhile, overexpression of GSK-3β was efficient to increase the apoptosis induced by vinpocetine plus sorafenib in HCC cells. Our study revealed that vinpocetine plus sorafenib could suppress the cytoprotective autophagy induced by vinpocetine and subsequently show synergistically anti-HCC activity via activating GSK-3β and the combination of vinpocetine and sorafenib might reverse sorafenib resistance via the PI3K/protein kinase B/GSK-3β signaling axis. Thus, vinpocetine may be a potential candidate for sorafenib sensitization and HCC treatment, and our results may help to elucidate more effective therapeutic options for HCC patients with sorafenib resistance.
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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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR BIOCHEMISTRY
·
2017
·Vol. 119
·期 4
·3510-3518
·
IF 3.085
Denan Zhang,Lei Liu,Lin Pang,Qing Jin,Kehui Ke,Ming Hu,Jingbo Yang,Weifang Ma,Hongbo Xie,Xiujie Chen
Glycogen synthase kinase-3 beta (GSK-3 β ) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3 β activity have been implicated in diabetes, heart disease, Parkinson disease, and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3 β were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Twenty selected compounds were tested, which led to the discovery of two hits. Compound 14 (IC 50 = 8.48 µM) and compound 19 (IC 50 = 2.19 µM) were identified with high affinity. Molecular dynamics (MD) simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the binding modes and energetics of GSK-3 β inhibitors. The detailed analysis of molecular dynamics results shows that Ile62, Val70, Tyr134, and Leu188 in GSK-3 β are key residues responsible to the binding of compound 14 and compound 19 . Importantly, our results also validated this combined virtual screening and biophysical technique approach to discovery kinase inhibitors, which may be applied for future inhibitor discovery work for GSK-3 β .
研究领域:
生物信息学
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药理学
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结构生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Shanhui Zhang,Fuhui Zhao,Changluan Pan,Yajing Wang,Zhangxiang Yang,Jing Yang,Yunniao Meng,Shaofang Lv,Jiayu Huang,Li Dong,Lei Li,Yongxi Dong
Type 2 diabetes (T2DM), which is characterized by insulin resistance and diminished sensitivity, accounts for more than 90 % of the incidence rate of diabetes. At present, the drugs used to treat T2DM in clinic are restricted due to their poor compliance or serious adverse reactions. The abnormally elevated activity of GSK-3β plays an important regulatory role in the occurrence and development of T2DM. Herein, we report the therapeutic effect of a GSK-3β covalent inhibitor N -(3-(4-benzyl-3,5-dioxo-1,2,4-thiadiazol-2-yl) phenyl) acrylamide ( GL10a ), which was discovered by our group with excellent inhibitory activity and homologous kinase selectivity. Further research had confirmed that GL10a could inhibit the activity of GSK-3β, thereby increasing the hepatic glycogen synthesis, restoring glucose homeostasis, regulating insulin signaling pathways, and improving pancreatic β-cell function with consequent increase in insulin secretion. Additionally, our findings revealed that GL10a exerted beneficial effects on gut microbiota dysbiosis in T2DM, which may contribute to its therapeutic efficacy and facilitate disease recovery. These comprehensive pharmacological properties positioned GL10a as a promising candidate, potentially offering novel therapeutic strategies and clinical options for T2DM management.
研究领域:
药理学
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代谢疾病
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分子生物学
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药物开发
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转化医学
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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
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xue-na Gong,Yan-xin Zhou,Chen-yu Wang,Tian-tian Wang,Zi-yao Gao,Wen-cai Long,Rong Li,Li Cai
The GSK-3β/β-catenin signaling axis is critically involved in the pathogenesis of depression. Targeted inhibition of GSK-3β to activate β-catenin signaling may provide a promising depression therapy. The novel GSK-3β inhibitor compound 47 (CPD47) has exhibited therapeutic promise in neurodegenerative disorders such as Alzheimer's disease, but its potential antidepressant effects and underlying mechanisms remain to be elucidated. This study assessed CPD47's protective effects against PC12 cell injury induced by corticosterone (CORT) and its antidepressant-like activity in rats exposed to chronic unpredictable mild stress (CUMS), with a special focus on the mechanisms involving the regulation of the GSK-3β/β-catenin signaling pathway. In this research, CPD47 treatment attenuated CORT-induced neurotoxicity in PC12 cells, as indicated by increased viability, decreased apoptosis, reduced oxidative stress, and suppressed inflammatory responses. In vivo, administration of CPD47 substantially alleviated depressive-like behaviors in CUMS rats, as indicated by behavioral improvements in sucrose preference, forced swim, sucrose splash, and open field tests. Additionally, CPD47 ameliorated hippocampal pathological damage and promoted hippocampal neurogenesis in CUMS rats. Notably, CPD47 markedly mitigated neuroinflammation in the hippocampus of CUMS rats. Mechanistically, CPD47 significantly inhibited GSK-3β activity and activated β-catenin signaling both in vitro and in vivo, with upregulated p-GSK-3β (Ser9) and β-catenin expression and decreased p-β-catenin. Importantly, GSK-3β overexpression abolished CPD47's benefits in CORT-stimulated PC12 cells, providing further evidence that GSK-3β is its crucial molecular target. Collectively, our findings indicate that CPD47 produces potent antidepressant-like effects through modulation of the GSK-3β/β-catenin axis, highlighting its promise as a candidate for depression therapy.
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Shengli Quan,Jinhua Li,Shuxian Ding,Xingjie Zhuo,Yuanxiao Yang,Qin Li
Background Parkinson's disease is a progressive neurodegenerative disorder of the brain, that commonly leads to motor dysfunction and dementia. Artemether is a semi - synthetic derivative of artemisinin, which is extracted from the traditional Chinese herb Artemisia annua. And it is widely used in the treatment of malaria. Recent studies have shown that it exhibits significant neuroprotective effects and holds potential for the treatment of neurodegenerative diseases. However, its effects and mechanisms in the context of Parkinson 's disease remain unclear. Objective To explore Artemether's neuroprotective effects and mechanisms in 6-OHDA-induced PD models. Methods Network pharmacology and molecular docking were used to predict potential pathways and targets of Artemether against Parkinson's disease. PD models were established using 6-OHDA-induced PC12 cells and C57BL/6 mice to assess Artemether's effects and mechanisms. Results Through network pharmacological analysis and molecular docking verification, it was found that Artemether against Parkinson 's disease was related to apoptosis-related signaling pathways, and Artemether had good spontaneous binding activity with key targets PI3K, Akt, GSK-3β, and Bcl-2. Furthermore, the related experimental results showed that Artemether could increase the cell viability of PC12 cells induced by 6-OHDA, reduce intracellular ROS level, increase mitochondrial membrane potential and decrease apoptosis. In addition, Artemether improved motor dysfunction and cognitive dysfunction in Parkinson 's disease mice, and increased the expression of dopamine neurons in both the Substantia Nigra and Striatum. Conclusion Artemether exerted neuroprotective effects in Parkinson 's disease models in vitro and in vivo induced by 6-OHDA through the PI3K/Akt/GSK-3β signaling pathway.
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
CELL TRANSPLANTATION
·
2021
·
IF 4.064
Xiao-Yu Chen,Sheng-Yong Yang,Xiao-Jie Ruan,Hong-Yue Ding,Ning-Xi Wang,Fang Liu,Jia-Chu Li,Yi Li
Methionine sulfoxide reductase B1 (MsrB1) can catalyze both free and protein-bound R-methionine sulfoxides (R-MetO) to methionine (Met). It has been reported that MsrB1 plays an important role in the development of HCC and human bone osteosarcoma. However, little is known about the functions of MsrB1 in human colorectal cancer (CRC). Herein, we detected MsrB1 expression level in CRC tissue and cell lines, and investigated the effect of MsrB1 knockdown on CRC phenotypes and possible mechanisms involved in. The results showed that MsrB1 was highly expressed in both CRC tissues and cell lines, and that cell proliferation, migration and invasion were significantly inhibited, but apoptosis was increased after MsrB1 knockdown in colorectal cancer HCT116 and RKO cell lines, compared to control siRNA group. In addition, E-cadherin protein level was increased, vimentin and Snail protein were greatly decreased after knockdown of MsrB1 in cells. Furthermore, pGSK-3β (Ser9) and β-catenin protein levels were reduced, the promoter activity of TCF/LEF construction was inhibited after MsrB1 knockdown in cells, suggesting that GSK-3β/β-catenin signaling axis was involved in the tumorigenesis of CRC. In conclusion, the oncogenic role and related mechanisms of MsrB1 in CRC discovered in our work determined the potential role of MsrB1 as a biomarker and may provide a new target for clinical therapy of CRC.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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信号转导
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2020
·
IF 2.985
Gen Liu,Bo-fang Zhang,Qi Hu,Xiao-pei Liu,Jing Chen
Syringic acid is an abundant phenolic acid compound that possesses anti-oxidant, anti-microbial, anti-inflammatory, and anti-endotoxic properties. However, the research of pretreatment with syringic acid against myocardial ischemia reperfusion is still limited. Thus, our research revealed the protective effect of syringic acid in the rat model with myocardial ischemia reperfusion injury. Histological analysis was performed by hematoxylin and eosin (H&E). The myocardial systolic function was detected by echocardiographic. Myocardial infarct size was measured by Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining. The apoptosis index was recorded by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining (TUNEL). The contents of creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were determined by a commercial kit. The expression of the PI3K/Akt/GSK-3β signaling pathway-related molecules and apoptosis-associated indicators was detected by western blotting or real-time PCR. We found that pretreatment with syringic acid obviously increased the myocardial systolic function (LVEF and LVFS) and decreased the infarct size, the apoptosis index as well as the serum level of CK-MB and LDH. Meanwhile, syringic acid also remarkably augmented the contents of p-PI3K, p-Akt, p-GSK-3β, Bcl-2 and mitochondria cytochrome c . However, the expression of caspase-3, -9 and Bax significantly reduced. Interestingly, co-treatment with PI3K inhibitor of LY294002 counteracted those effects induced by syringic acid. In conclusion, pretreatment with syringic acid can mitigate myocardial ischemia reperfusion injury by inhibiting mitochondria-induced apoptosis which is regulated by the PI3K/Akt/GSK-3β signaling pathway .
研究领域:
药理学
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心脏病学
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分子生物学
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PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2022
·Vol. 396
·期 4
·683-692
·
IF 3.195
Huang Hui,Xue Jie,Xie Tao,Xie Mei-Lin
Osthole is a natural coumarin substance that has an inhibitory effect on hepatic cancer, but its radiosensitization effect on hepatoma cells has not been reported. This study aimed to investigate the effect of osthole. Human HCC-LM3 and SK-Hep-1 hepatoma cells were used and treated with or without osthole, irradiation, or their combination; the cell survival, migration, colony formation, DNA damage repair, intracellular lactic acid content, and glycolysis-related glycogen synthase kinase-3β (GSK-3β), p-GSK-3β, AMP-activated protein kinase (AMPK), p-AMPK, mammalian target of rapamycin (mTOR), p-mTOR, glucose transporter-1 (GLUT-1), GLUT-3, and pyruvate kinase isozyme type M2 (PKM2) protein expressions were determined. Compared with the irradiation group, the osthole plus irradiation group could further decrease the survival rate, migration, colony formation, and DNA damage repair of both hepatoma cells, indicating a synergistic effect of the combination treatment. Moreover, the combination of osthole and irradiation could decrease the content of intracellular lactic acid, ratios of intracellular p-GSK-3β/GSK-3β and p-mTOR/mTOR proteins, and expressions of intracellular GLUT-1/3 and PKM2 proteins, and increase the ratio of intracellular p-AMPK/AMPK proteins. Osthole can increase the radiosensitivity of hepatoma cells, and its radiosensitization mechanisms may be related to glycolytic inhibition by attenuating the GSK-3β/AMPK/mTOR pathway.
研究领域:
癌症生物学
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分子生物学
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药理学
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放射生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Yanwen Wang,Miao Cai,Yue Lou,Siran Zhang,Xiaoli Liu
To elucidate the potential molecular mechanisms of ZBTB20-AS1 on ZBTB20 and GSK-3β/Tau signaling pathway in the pathogenesis of Alzheimer's disease (AD), SH-SY5Y cells were obtained for in vitro experiments and AD models were constructed using β-Amyloid 1–42. CCK8 assay was implemented for determining cell viability . Flow cytometry was used for cell apoptosis detection. Dual-luciferase reporter and RNA-RNA pull down assay was employed for elucidating molecular interactions . Immunohistochemistry, RT-qPCR and western blotting were performed for measuring gene expression. The results showed that expression of LncRNA ZBTB20-AS1 was significantly upregulated, while ZBTB20 was downregulated in SH-SY5Y-AD cells. ZBTB20 was the target gene of LncRNA ZBTB20-AS1. Overexpression of ZBTB20 or knockdown of LncRNA ZBTB20-AS1 inhibited SH-SY5Y-AD cells apoptosis and suppressed GSK3β/Tau pathway, and knockdown of ZBTB20-AS1 increased cell viability and decreased apoptosis. In conclusion, overexpression of ZBTB20-AS1 inhibited ZBTB20 expression and promoted GSK-3β expression and Tau phosphorylation, contributing to the development of AD.
研究领域:
神经科学
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分子生物学
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Tianyang Wang,Jian Zhang,Haokai Wei,Xi Wang,Minjuan Xie,Yinjie Jiang,Jie Zhou
Introduction Matrine (MT), an ingredient extracted from the Chinese herb Sophora flavescens , can result in nephrotoxicity because of long-term exposure. However, the underlying mechanism by which MT leads to kidney injury remains unclear. This study aimed to investigate the roles of oxidative stress and mitochondria in MT-induced kidney toxicity both in vitro and in vivo . Methods Mice were exposed to MT for 20 days, and NRK-52E cells were exposed to MT with or without LiCl (a GSK-3β inhibitor), tert-Butylhydroquinone (t-BHQ, an Nrf2 activator), or small interfering RNA . Results The results showed that MT caused nephrotoxicity accompanied by an increase in reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Meanwhile, MT significantly upregulated glycogen synthase kinase-3β (GSK-3β) activity, released cytochrome c (Cyt C) and cleaved caspase-3, decreased the activity of nuclear factor-erythroid 2-related Factor 2 (Nrf2), and reduced the expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), which led to the inactivation of antioxidant enzymes and the activation of apoptosis . In addition, GSK-3β inhibition by LiCl or small interfering RNA pretreatment or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of MT in NRK-52E cells. Conclusions Taken together, these results revealed that MT-induced apoptosis triggered kidney toxicity and that GSK-3β or Nrf2 might serve as a promising nephroprotective target for MT-induced kidney injury.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2021
·Vol. 47
·期 2
·264-278
·
IF 3.996
Gao Tianyu,Gao Ce,Liu Zhidong,Wang Yun,Jia Xiaoxia,Tian Hao,Lu Qian,Guo Lin
Further understanding the mechanism for microglia activation is necessary for developing novel anti-inflammatory strategies. Our previous study found that the activation of sigma-1 receptor can effectively inhibit the neuroinflammation, independent of the canonical mechanisms, such as NF-κB, JNK and ERK inflammatory pathways. Thus, it is reasonable that an un-identified, non-canonical pathway contributes to the activation of microglia. In the present study, we found that a sigma-1 receptor agonist of 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) suppressed lipopolysaccharide (LPS) elevated nitric oxide (NO) content in BV-2 microglia culture supernatant and LPS-raised mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) in BV-2 microglia. Moreover, PRE-084 alleviated LPS-increased Ser 9 de-phosphorylation of glycogen synthase kinase-3 beta (GSK-3β), LPS-elevated catalytic activity of calcineurin, and LPS-raised percent and frequency of Ca 2+ oscillatory BV-2 cells. We further found that the inhibitory effect of PRE-084 was reversed by a calcineurin activator of chlorogenic acid and a GSK-3β activator of pyrvinium. Moreover, an IP 3 receptor inhibitor of 2-aminoethoxydiphenyl borate mimicked the anti-inflammatory activity of PRE-084. Thus, we identified a noncanonical pro-neuroinflammary pathway of Ca 2+ oscillation/Calcineurin/GSK-3β and the inhibition of this pathway is necessary for the anti-inflammatory activity of sigma-1 receptor activation.
研究领域:
神经科学
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药理学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）