CELL BIOLOGY INTERNATIONAL
·
2024
·
IF 3.3
Meng-Wei Zhang,Xu Sun,Yi-Wen Xu,Wei Meng,Qiong Tang,Hui Gao,Ling Liu,Shao-Hui Chen
Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK-3β activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR-treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4-mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK-3β through four covalent bonds and reduced GSK-3β activity. In conclusion, our findings suggest that CUR treatment inhibits GSK-3β activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA-induced neuropathic pain.
研究领域:
药理学
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神经科学
·
炎症与免疫
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Xiaxia Fan,Dan Guo,Songtao Li,Jinmiao Tian,Chaotong Zhang,Zhuoyu Li
ABC transporter protein-mediated drug efflux is a significant contributor to induced resistance in breast cancer (BC). Novel therapies are therefore urgently needed to thwart chemoresistance. Herein, it is demonstrated that fusidic acid (FA) reduces the expression of ABC transporter proteins MRP1, P-gp, and BCRP, promotes the in vivo accumulation of agents, and exertes chemosensitizing effects. Further, DDX6 is identified as a direct target of FA by DARTS and biotin pull-down. Mechanistically, the results indicates that FA directly binds to H378 of DDX6, promotes its degradation, and downregulates its downstream p-GSK-3β, which in turn enhances the phosphorylation and ubiquitin-dependent hydrolysis of β-catenin S33/37/45/T41, blocks pro-resistance β-catenin signaling, and further prevents chemoresistance. The inhibitory effect of FA on chemoresistance is blocked following the knockout of DDX6 using CRISPR/Cas9. More importantly, FA also enhances the interaction between DDX6 and HSC70, while it facilitates DDX6 degradation via chaperone-mediated autophagy (CMA), thereby impairing the GSK-3β/β-catenin axis to enhance the efficacy of FA. Consistently, the effect of FA in combating chemoresistance by targeting DDX6 is evident in a xenograft mouse model. These findings reveal a direct protein target and molecular mechanism for FA to reverse chemoresistance, thus supporting the further development of FA as a chemosensitizing agent. Graphical FA directly binds to residue H378 of DDX6 and promotes its interaction with HSC70, leading to CMA degradation of DDX6, thereby impairing GSK-3β/β-catenin signaling, inhibiting ABC transporter proteins, and enhancing chemosensitivity.
研究领域:
癌症生物学
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药理学
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分子生物学
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生物化学
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细胞信号传导
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药物耐受
·
自噬
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产品关联
DOI
PubMed
高影响因子
ULTRASOUND IN MEDICINE AND BIOLOGY
·
2020
·
IF 2.514
Lifei Yang,Lingzi Chen,Ye Fang,Suya Ma
Accumulating evidence suggests that atherosclerosis (AS) is the underlying cause of vascular diseases, including heart disease and stroke. Ultrasound-targeted microbubble destruction (UTMD) technology provides a tolerable, efficient and effective system for drug delivery and gene transfection, which has broad application prospects in the treatment of AS. In addition, glycogen synthase kinase (GSK)-3β has been implicated as a potentially valuable therapeutic agent for AS treatment; however, the specific molecular mechanisms remain unknown. Therefore, this study was conducted to explore the effect of downregulation of GSK-3β expression via UTMD on atherosclerotic plaque stability. We established a THP-1 macrophage-derived foam cell model in vitro and an atherosclerotic plaque model in the right common carotid artery of New Zealand rabbits. We determined levels of the relevant vulnerable plaque stability elements. The results indicate that GSK-3β was upregulated in the foam cells and in atherosclerotic rabbits. Downregulation of GSK-3β expression by UTMD suppressed vulnerable plaque factors and inflammation in vitro and in vivo , changed the cytoskeleton of the foam cells in vitro , increased Young's modulus and decreased the peak intensity of atherosclerotic plaque in vivo . Moreover, GSK-3β inhibition by UTMD did not influence the viability of the foam cells. Collectively, our results indicate that GSK-3β could be a potential target for anti-atherogenic interventions and, in particular, can improve the stability of AS plaques in combination with UTMD.
研究领域:
心血管疾病
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分子生物学
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基因治疗
·
超声技术
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DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
·
2026
·
IF 2.9
Xinyao Zhang,Xu Yang,Dongpei Zhuang,Zhiyi Mu,Chuanxia Ju
Neuronal hyperexcitability is crucial to the pathogenesis of Alzheimer's disease (AD). Activating the Kv7 channel is an effective way to reduce neuronal excitability. The Kv7 channel opener retigabine (RTG) has been demonstrated to alleviate spatial memory deficits in APP/PS1 transgenic mice. However, the mechanism by which RTG reduces cognitive deficits in APP/PS1 mice remains unclear. In this study, we revealed that RTG could ameliorate learning and spatial memory deficits in APP/PS1 mice during novel object recognition and Morris water maze tests. Meanwhile, RTG increased NeuN neuronal fluorescence intensity, increased the expression of the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), improved synaptic plasticity, increased insulin-degrading enzyme (IDE) expression, decreased beta-secretase 1 (BACE1) expression, reduced Aβ 1–40 and Aβ 1–42 levels, and increased pAKT (ser473) and pGSK-3β (ser9) expression. These results indicated that RTG alleviates learning and spatial memory deficits in APP/PS1 mice, with potential mechanisms involving a reduction in neuronal loss, attenuation of synaptic damage, a decrease in β-amyloid (Aβ) deposition, and activation of the AKT/GSK-3β pathway.
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产品关联
DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
·
2026
·
IF 3.5
Awang Danzeng,La Zong,Baima Kangzhuo,Xie Hongjun,Wang Li,Liu Xinyao,Wang Yueying,Shi Yan,Zhao Yicheng,Gongga Lanzi
Hypoxia-related myocardial injury is characterized by oxidative stress, mitochondrial dysfunction, and apoptosis, ultimately resulting in impaired cardiac structure and function. Salidroside (SAL), a major bioactive component of Rhodiola, has been shown to have antioxidant and cardioprotective effects, but its role in hypoxia-related myocardial injury remains incompletely understood. In this study, we combined network pharmacology, molecular docking, and experimental validation to investigate the protective effect of SAL in CoCl 2 -induced hypoxia-mimetic models. In vitro, SAL improved cell viability, reduced ROS accumulation, restored mitochondrial membrane potential and ATP production, and attenuated apoptosis in CoCl 2 -treated H9C2 cells. In vivo, SAL alleviated electrocardiographic abnormalities, myocardial histopathological injury, cardiomyocyte hypertrophy, and associated lung and liver damage in CoCl 2 -treated rats. Mechanistically, SAL modulated the Akt/GSK-3β signaling axis under CoCl 2 -induced stress. Notably, Akt inhibition experiments revealed that SAL promotes protective GSK-3β phosphorylation and exerts its anti-apoptotic effects through a largely Akt-independent mechanism. Collectively, these findings indicate that SAL alleviates hypoxia-induced myocardial injury through the attenuation of oxidative stress, the preservation of mitochondrial function, the suppression of apoptosis, and the robust, Akt-independent regulation of GSK-3β. Graphical The alternative text for this image may have been generated using AI.
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2019
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IF 3.197
Yunbing Shen,Shengnan Yang,Xueyan Hu,Man Zhang,Xiaoyao Ma,Zhihua Wang,Yuanyuan Hou,Gang Bai
Puerarin, one of the major isoflavonoid compounds isolated from Gegen, is widely used to treat glucose and lipid disorders. Identifying the mechanism of puerarin’s action against lipid and glucose metabolism dysfunction is very important for its application and development. Based on the structure of puerarin, different chemical probes were synthesized to capture and identify puerarin’s protein target. A membrane translocation assay was conducted to identify the interaction between puerarin and target proteins. The results show that puerarin targets the PH domain of Akt1, inhibits Akt1′s transmembrane effect and activates Akt1. Activated Akt1 improves the phosphorylation or activity of downstream proteins, such as GSK-3β and PDE3, and ultimately regulates glucose and lipid metabolism. Puerarin, as a dietary supplement, could target the PH domain of Akt1 to activate the insulin pathway and improve insulin resistance, thereby assisting in the regulation of glucose and lipid metabolism disorders.
研究领域:
药理学
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代谢紊乱
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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
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Zhenghao Wu,Guqing Luo,Hongjie Li,Min Chen,Guangbo Wu,Qiang Fan,Chihao Zhang,Jiwei Yu,Jiayun Lin,Jinbo Zhao,Xiaoliang Qi,Haizhong Huo,Meng Luo,Lei Zheng
Introduction: Formononetin regulates intrahepatic fibrogenesis and macrophage polarization to improve portal pressure and liver function in rats with cirrhotic PHT through SMAD3, STAT1, STAT3 and GSK-3β signaling pathways, and modulates lymphangiogenesis through direct action and macrophage polarization-mediated indirect effects. Formononetin has the potential function of treating cirrhotic PHT.Background and aims: Formononetin (FN) has been reported to have anti-fibrotic effects in the kidneys and anti-M1 polarization effects on macrophages. Lymphangiogenesis is closely associated with macrophages, but its role in cirrhosis and portal hypertension (PHT) remains unclear. This study aims to explore the effects of FN on cirrhotic PHT and the disease-related intrahepatic lymphangiogenesis.Methods: In vivo experiments, bile duct ligation (BDL) induced PHT models were conducted in rats, followed by a 4-week FN treatment (50 mg/kg/day) administered via gavage. Hemodynamics, liver fibrosis, infiltration and polarization of intrahepatic macrophages, as well as intrahepatic lymphangiogenesis, were observed. For in vitro experiments, hepatic stellate cells, macrophages and lymphatic endothelial cells were used to observe the multiple effects of FN.Results: FN significantly ameliorated portal pressure in cirrhosis-induced PHT, improved liver function, and reduced liver fibrosis and hepatic stellate cell activation with decreased SMAD3 protein expression. The intrahepatic macrophage infiltration were markedly decreased, and M1-type macrophage polarization was suppressed by FN, accompanied by inhibition of STAT1, STAT3 and GSK-3β signaling pathways. In PHT models, FN reduced VEGF-C and VEGF-D levels in both the liver and blood, inhibiting intrahepatic lymphangiogenesis in portal area. In vitro, high-dose FN significantly inhibited lymphatic endothelial cell proliferation, while the pro-lymphangiogenic effect of conditioned medium from FN-treated M1 macrophages was diminished.Conclusions: FN significantly ameliorates cirrhotic PHT while reducing fibrosis, suppressing macrophage M1 polarization and inhibiting lymphangiogenesis. This may result from its modulation of multiple signaling pathways (SMAD3, STAT1, STAT3 and GSK-3β).
研究领域:
肝病学
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药理学
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细胞生物学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
·
2023
·Vol. 24
·期 14
·1803-1811
·
IF 2.8
Zou Min-Shu,Song Qiu-Ju,Yin Tai-Yong,Xu Hong-Tao,Nie Guo-Ming
Background: The etiology of systemic lupus erythematosus (SLE) is complex, and the disease is thus difficult to cure. In this regard, it has been established that SLE patients are characterized by differing levels of vitamin D-hydroxylation; however, the direct effects of vitamin D
(VitD) in these patients remain unknown. Objective: Therefore, we investigated the effects and mechanisms of action of VitD in the context of SLE. Methods: The effects of VitD on MRL/LPR mice were studied by synthesizing glycogen synthase kinase-3β (GSK-3β)-interfering lentiviruses
and transfecting with miR-126a-5p mimics. Changes in the body weight of mice were recorded for 6 weeks. Western blotting was performed to determine the levels of T-bet, GATA3, and GSK-3β protein expression, and qRT-PCR was performed to determine the levels of miR-126a-5p and GSK-3β
mRNA expression. ELISA was performed to determine the levels of ANA, dsDNA, and snRNP/Sm in mice serum. Results: GSK-3β and miR-126a-5p were expressed at high and low levels, respectively, in MRL/LPR mice. VitD (30 ng/kg) was found to reduce the expression of GSK-3β and increase
miR-126a-5p expression, which targets GSK-3β. T-bet and GATA3 were found to be positively regulated by miR-126a-5p and VitD and negatively regulated by GSK-3β. The body weight of mice was not altered by VitD. ANA, dsDNA, and snRNP/Sm were positively regulated by miR- 126a-5p and
VitD and negatively regulated by GSK-3β. The effects of GSK-3β were enhanced in response to the inhibition of miR-126a-5p expression. Conclusion: VitD upregulated miR-126a-5p to target GSK-3β expression, thereby alleviating the SLE in MRL/LPR mice.
研究领域:
免疫学
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分子生物学
·
药理学
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DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Yanxia Ma,Yu Liu,Linxin Teng,En Luo,Dekang Liu,Fuqiong Zhou,Kaiyuan Wang,Weiping Chen,Lei Bi
Lung cancer has become the leading cause of cancer-related death worldwide. Oxidative stress plays important roles in the pathogenesis of lung cancer. Many natural products show antioxidative activities in cancer treatment. Zi Shen decoction (ZSD) is a classic prescription for the treatment of lung disease. However, its effect on lung cancer lacks evidence-based efficacy. In this study, we investigated the anticancer effects of ZSD on lung cancer in vivo and in vitro. Our results showed that oral administration of ZSD suppressed the Lewis lung cancer (LLC) growth in a subcutaneous allograft model and promoted necrosis and inflammatory cell infiltration in the tumor tissues. Furthermore, ZSD not only inhibited tumor cell proliferation and migration but also induced cell apoptosis in lung cancer cells. PI3K/AKT signaling is well characterized in response to oxidative stress. The bioinformatics analysis and western blot assays suggested that ZSD decreased the enzyme activity of PI3K and AKT in vivo and in vitro. We also found that the AKT/GSK-3β/β-catenin pathway medicated anticancer effect of ZSD in lung cancer cells. In conclusion, we demonstrate for the first time that ZSD possesses antitumor properties, highlighting its potential use as an alternative strategy or adjuvant treatment for lung cancer therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
·
中医
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DOI
PubMed
高影响因子
Human Cell
·
2022
·Vol. 35
·期 5
·1535-1546
·
IF 4.374
Mao Dong,Zhang Xiaowei,Wang Zhaoping,Xu Guannan,Zhang Yun
Transmembrane protein 97 (TMEM97) is a conserved integral membrane protein highly expressed in various human cancers, including colorectal cancer (CRC), and it exhibits pro-tumor roles in breast cancer, gastric cancer, and glioma. However, whether TMEM97 participates in CRC progression is not fully understood. The expression of mRNA and protein was evaluated by real-time qPCR, western blotting, immunofluorescent, and immunohistochemical staining. TMEM97 functions in cell proliferation, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and transwell assays. The roles of TMEM97 in CRC cells in vivo was investigated using a subcutaneous xenograft model. The transcriptional regulation of TMEM97 was explored by luciferase reporter and ChIP assays. The silencing of TMEM97 inhibited migration and invasion of CRC cells in vitro and led to suppressed growth and enhanced apoptosis in CRC cells and xenografts, whereas overexpression of TMEM97 displayed opposite effects. Mechanistically, TMEM97 knockdown caused a reduction of the proliferating marker PCNA and an increase of pro-apoptotic proteins (cleaved caspase 8/3/7 and cleaved PARP) in CRC cells. TMEM97 also positively regulated the β-catenin signaling pathway in CRC cells and xenografts by modulating the phosphorylated-GSK-3β and active (non-phospho) β-catenin levels. Interestingly, YY1, a well-recognized oncogenic transcription factor, was identified to bind to the TMEM97 promoter and enhance its transcriptional activity, and silencing of TMEM97 abolished YY1-mediated pro-tumor effects on CRC cells. Our results suggest that TMEM97 is transcriptionally activated by YY1 and promotes CRC progression via the GSK-3β/β-catenin signaling pathway, providing that TMEM97 might be a novel therapeutic target for preventing CRC development.
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产品关联
DOI
PubMed
高影响因子
Neuroscience Bulletin
·
2025
·
IF 5.8
He Junqiu,Sun Shan,Wang Hongfeng,Ying Zheng,Tam Kin Yip
Alzheimer’s disease (AD) poses one of the most urgent medical challenges in the 21st century as it affects millions of people. Unfortunately, the etiopathogenesis of AD is not yet fully understood and the current pharmacotherapy options are somewhat limited. Here, we report a novel inhibitor, Compound 44, for targeting cholinesterases, amyloid-β (Aβ) aggregation, and glycogen synthase kinase 3β (GSK-3β) simultaneously with the aim of achieving symptomatic relief and disease modification in AD therapy. We found that Compound 44 had good inhibitory effects on all intended targets with IC 50 s of submicromolar or better, significant neuroprotective effects in cell models, and beneficial improvement of cognitive deficits in the triple transgenic AD (3 × Tg AD) mouse model. Moreover, we showed that Compound 44 acts as an autophagy regulator by inducing nuclear translocation of transcription factor EB through GSK-3β inhibition, enhancing the biogenesis of lysosomes and elevating autophagic flux, thus ameliorating the amyloid burden and tauopathy, as well as mitigating the disease phenotype. Our results suggest that triple-target inhibition via Compound 44 could be a promising strategy that may lead to the development of effective therapeutic approaches for AD.
研究领域:
神经科学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 22
·5391
·
IF 3.267
Zheng Liu,Ming Bian,Qian-Qian Ma,Zhuo Zhang,Huan-Huan Du,Cheng-Xi Wei
A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ25-35-induced PC12 cells at 5 μg/mL. We found that compound5cwas non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound5cpromoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ25-35-induced PC12 cells. In addition, our findings demonstrated that compound5cprotected PC12 cells from Aβ25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound5cshows less toxicity than donepezil in the heart and nervous system of zebrafish.Keywords:synthesis;benzo[d]oxazol;thiadiazoles;Alzheimer’s disease;β-amyloid;Akt/GSK-3β/NF-κB signaling pathway
研究领域:
神经科学
·
药理学
·
药物化学
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DOI
PubMed
高影响因子
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