PLoS One
·
2016
·Vol. 11
·期 4
·e0152371
·
IF 3.057
Wei Jiang,Tao Luo,Sheng Li,Yue Zhou,Xiu-Yin Shen,Feng He,Jie Xu,Hua-Qiao Wang
Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer’s disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.
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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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Dong Wang,Xiaona Lu,Enbo Wang,Liangang Shi,Chi Ma,Xiaodong Tan
The cellular and tissue damage induced by oxidative stress (OS) contribute to a variety of human diseases, which include gastrointestinal diseases. Salvianolic acid B (Sal B), which is a natural polyphenolic acid in Salvia miltiorrhiza , exhibits prominent antioxidant properties. However, its precise function and molecular mechanisms in protecting normal intestine epithelium from OS-induced damage are still poorly defined. In this study, we tried to clarify this relationship. Here, we found Sal B addiction in the rat intestinal epithelial cell, IEC-6, prevented H 2 O 2 -induced cell viability decrease and apoptosis induction, ameliorated H 2 O 2 -induced intestinal epithelial barrier dysfunction and mitochondrial dysfunction, and suppressed H 2 O 2 -induced production of ROS to varying degrees, ranging from 10% to 30%. Moreover, by employing an ischemia reperfusion model of rats, we also discovered that Sal B treatment reversed ischemia and a reperfusion-caused decrease in villus height and crypt depth, decreased proliferation of enterocytes, and increased the apoptotic index in the jejunum and ileum. Mechanistically, Sal B treatment up-regulated the phosphorylated level of Akt and GSK3β in enterocytes in vitro and in vivo , and PI3K inhibitor LY294002 treatment abrogated the protective effects of Sal B. Meanwhile, the inactivation of GSK3β reversed the oxidative stress-induced apoptosis and mitochondrial dysfunction in IEC-6 cells. Together, our results demonstrated that the damage of intestinal epithelial cells in in vitro and in vivo models were both attenuated by Sal B treatment, and such antioxidant activity might very possibly be attributed to the activation of Akt/GSK3β signaling.
研究领域:
药理学
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胃肠病学
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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
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Han Yan-lu,Yan Teng-teng,Li Hua-xin,Chen Sha-sha,Zhang Zhen-zhen,Wang Meng-yao,Chen Mei-jie,Chen Yuan-li,Yang Xiao-xiao,Wei Ling-ling,Duan Ya-jun,Zhang Shuang
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L -NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3β, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 μM) significantly alleviated H 2 O 2 -induced oxidative stress through the MMP2/SIRT1/GSK3β pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3β, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3β signaling pathway.
研究领域:
心脏病学
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药理学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2021
·
IF 4.451
Ge Fang,Chuanjing Cheng,Manqian Zhang,Xiaoyao Ma,Shengnan Yang,Xiaotao Hou,Jiagang Deng,Yuanyuan Hou,Gang Bai
Kaempferol and quercetin, as dietary flavonoids, are beneficial to diabetes risk reduction. Clarifying the mechanism of dietary flavonoids in improving glucose metabolism may meet the functional and nutritional requirements. In this paper, PCA revealed two glucuronides, kaempferol-3-glucuronide (K-3-G) and quercetin-3-glucuronide (Q-3-G), which were the primary metabolites. Target prediction, enzymatic activity, and AKT plasma translocation assays indicated that K-3-G and Q-3-G could target the AKT PH domain. Fluorescence spectrometry was used to measure the dissociation constants of K-3-G (K D = 27.6 μM) and Q-3-G (K D = 10.8 μM). Molecular docking provided interaction insights for K-3-G and Q-3-G with the AKT PH domain. K-3-G and Q-3-G activated the AKT/GSK3β phosphorylation, thereby improving glucose consumption. Our study demonstrates that the glucuronide metabolites of flavonoids directly target the AKT PH domain and activate AKT/GSK3β signal pathway, thereby improving glucose metabolism.
研究领域:
药理学
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生物化学
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营养学
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代谢学
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产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Ya-wei Lu,Li-ya Xie,Meng-han Qi,Shen Ren,Yue-qi Wang,Jun-nan Hu,Zi Wang,Shan Tang,Jing-tian Zhang,Wei Li
Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.
研究领域:
药理学
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神经科学
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糖尿病研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACTA HISTOCHEMICA
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2021
·
IF 2.479
Xue Liu,Yumeng Shao,Xinyue Zhang,Xiang Ji,Min Xie,Huaman Liu
The precise etiology and pathogenesis of idiopathic pulmonary fibrosis are not completely understood, and no satisfactory treatment exists. This work aimed to examine the effects of calycosin (CA, an isoflavone compound) on pulmonary fibrosis (PF) and explore the underlying mechanism. In this study, we established a mice model of PF induced by 5 mg/mL bleomycin (BLM), and mice were orally administrated with 7 mg/kg or 14 mg/kg CA once a day for three weeks. In vitro , after pretreated with 80 μM CA, MLE-12 cells were stimulated with 10 ng/mL transforming growth factor-β1 (TGF-β1) for inducing epithelial-mesenchymal transition (EMT). The results showed that CA treatment ameliorated the severity of fibrosis and the lung tissue damage, as well as suppressed the secretion of inflammation factors in a dose-dependent manner of the PF mice model induced by BLM. Subsequently, CA inhibited the BLM-induced PF progression by repressing EMT, evidenced by the reverse of the downregulation of E-cadherin and the upregulation of vimentin, α-SMA, and fibronectin. Moreover, the elevated phosphorylation of AKT and GSK3β induced by BLM (or TGF-β1) was decreased by CA treatment, leading to the rescue of the high expression of β-catenin. CA prevented the translocation of β-catenin from the cytoplasm to the nucleus. The repressed effects of CA on the TGF-β1-induced EMT and the AKT/GSK3β/β-catenin axis, as well as the translocation of β-catenin were all reversed by a AKT activator SC79. Taken together, CA ameliorated PF by the EMT inhibition upon suppressing the AKT/GSK3β/β-catenin signaling pathway.
研究领域:
药理学
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肺科学
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细胞生物学
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信号传导
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Wenxin Zhang,Hongbo Teng,Tianyi Zhao,Roberts I. Eglitis,Xv Wang,Zhengxuan Yu,Shurong Qu,Haijing Wang,Yaru Zhao,Bowen Fan,Shuangli Liu,Yan Zhao
Introduction: Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.Methods: In this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.Results: It was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.Discussion: These findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.
研究领域:
药理学
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肿瘤学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2024
·Vol. 30
·期 1
·1-16
·
IF 6
Fang Lini,Tao Yang,Che Guoying,Yun Yongzi,Ren Min,Liu Yujie
Background Reperfusion is the most effective strategy for myocardial infarct, but induces additional injury. WD repeat and SOCS box containing protein 1 (WSB1) plays a protective role in ischemic cells. This study aims to investigate the effects of WSB1 on myocardial ischemia–reperfusion (IR) injury.Methods The myocardial IR was induced by left anterior descending (LAD) ligation for 45 min and subsequent reperfusion. The overexpression of WSB1 was mediated by tail vein injection of AAV9 loaded with WSB1 encoding sequence two weeks before IR surgery. H9c2 myocardial cells underwent oxygen-sugar deprivation/reperfusion (OGD/R) to mimic IR, and transfected with WSB1 overexpression or silencing plasmid to alter the expression of WSB1.Results WSB1 was found highly expressed in penumbra of myocardial IR rats, and the WSB1 overexpression relieved IR-induced cardio dysfunction, myocardial infarct and pathological damage, and cardiomyocyte death in penumbra. The ectopic expression of WSB1 in H9c2 myocardial cells mitigated OGD/R-caused apoptosis, and silencing of WSB1 exacerbated the apoptosis. In addition, WSB1 activated β-catenin signaling, which was deactivated under the ischemic condition. The co-immunoprecipitation results revealed that WSB1 mediated ubiquitination and degradation of glycogen synthase kinase 3 beta (GSK3β) as an E3 ligase in myocardial cells. The effects of WSB1 on myocardial cells under ischemic conditions were abolished by an inhibitor of β-catenin signaling.Conclusion WSB1 activated β-catenin pathway by promoting the ubiquitination of GSK3β, and restrained IR-induced myocardial injury. These findings might provide novel insights for clinical treatment of myocardial ischemic patients.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2024
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IF 4.2
Guoqiang Fan,Lingling Huang,Mengxuan Wang,Haoran Kuang,Yanfei Li,Xiaojing Yang
The development of nonalcoholic fatty liver disease (NAFLD) may worsen due to chronic stress or prolonged use of glucocorticoids . Glycerol-3-phosphate acyltransferase 3 (GPAT3), has a function in obesity and serves as a key rate-limiting enzyme that regulates triglyceride synthesis. However, the precise impact of GPAT3 on corticosterone (CORT)-induced NAFLD and its underlying molecular mechanism remain unclear. For our in vivo experiments, we utilized male and female mice that were GPAT3 −/− and wild type (WT) and treated them with CORT for a duration of 4 weeks. In our in vitro experiments, we transfected AML12 cells with GPAT3 siRNA and subsequently treated them with CORT. Under CORT-treated conditions, the absence of GPAT3 greatly improved obesity and hepatic steatosis while enhancing the expression of genes involved in fatty acid oxidation , as evidenced by our findings. In addition, the deletion of GPAT3 significantly inhibited the production of reactive oxygen species (ROS), increased the expression of antioxidant genes, and recovered the mitochondrial membrane potential in AML12 cells treated with CORT. In terms of mechanism, the absence of GPAT3 encouraged the activation of the glycogen synthase kinase 3β (GSK3β)/nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway, which served as a defense mechanism against liver fat accumulation and oxidative stress . Furthermore, GPAT3 expression was directly controlled at the transcriptional level by the glucocorticoid receptor (GR). Collectively, our findings suggest that GPAT3 deletion significantly alleviated hepatic steatosis and oxidative stress through promoting GSK3β/Nrf2 signaling pathways .
研究领域:
肝病学
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分子生物学
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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
Frontiers in Pharmacology
·
2024
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IF 4.4
Huang Yuechang,Zhang Xingmin,Li Qian,Zheng Wende,Wu Panpan,Wu Rihui,Chen Wen-Hua,Li Chen
Type 2 diabetes mellitus is regarded as a chronic metabolic disease characterized by hyperglycemia. Long-term hyperglycemia may result in oxidative stress, damage pancreatic β-cell function and induce insulin resistance. Herein we explored the anti-hypoglycemic effects and mechanisms of action of N-p-coumaroyloctopamine (N-p-CO) in vitro and in vivo. N-p-CO exhibited high antioxidant activity, as indicated by the increased activity of SOD, GSH and GSH-Px in HL-7702 cells induced by both high glucose (HG) and palmitic acid (PA). N-p-CO treatment significantly augmented glucose uptake and glycogen synthesis in HG/PA-treated HL-7702 cells. Moreover, administration of N-p-CO in diabetic mice induced by both high-fat diet (HFD) and streptozotocin (STZ) not only significantly increased the antioxidant levels of GSH-PX, SOD and GSH, but also dramatically alleviated hyperglycemia and hepatic glucose metabolism in a dose-dependent manner. More importantly, N-p-CO upregulated the expressions of PI3K, AKT and GSK3β proteins in both HG/PA-induced HL-7702 cells and HFD/STZ-induced mice. These findings clearly suggest that N-p-CO exerts anti-hypoglycemic and anti-oxidant effects, most probably via the regulation of a PI3K/AKT/GSK3β signaling pathway. Thus, N-p-CO may have high potentials as a new candidate for the prevention and treatment of diabetes.
研究领域:
药理学
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内分泌学
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代谢性疾病
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产品关联
DOI
PubMed
高影响因子
Genes & Diseases
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2023
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IF 6.8
Yanran Bi,Ruiling Zheng,Jiahao Hu,Ruiqing Shi,Junfeng Shi,Yutao Wang,Peng Wang,Wenyi Jiang,Gyudong Kim,Zhiguo Liu,Xiaokun Li,Li Lin
Glioblastoma (GBM) is a malignant brain tumor that grows quickly, spreads widely, and is resistant to treatment. Fibroblast growth factor receptor (FGFR)1 is a receptor tyrosine kinase that regulates cellular processes, including proliferation, survival, migration, and differentiation. FGFR1 was predominantly expressed in GBM tissues, and FGFR1 expression was negatively correlated with overall survival. We rationally designed a novel small molecule CYY292, which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro . CYY292 also exerted an effect on the conserved Ser 777 residue of FGFR1 . CYY292 dose-dependently inhibited cell proliferation, epithelial–mesenchymal transition, stemness, invasion, and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells, and this effect was prevented by pharmacological inhibitors and critical gene knockdown. In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547. CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models. This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292, which targets FGFR1, on downstream signaling pathways directly reducing GBM cell growth, invasion, and metastasis and thus impairing the recruitment, activation, and function of immune cells.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
细胞生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Siyu Zhao,Yue Li,Lin Dai,Bo Cheng
The development of artificial biomaterials that simulate the extracellular matrix of bone tissue is a promising strategy for bone regeneration. Hydrogel has become a feasible alternative, yet its lack of biological activity still needs to be improved. Herein, a piezoelectric composite hydrogel (TBP) based on tripolyglycerol monostearate (TM) and loaded with barium titanate (BTO) nanoparticles through hydrogen bonding provided by polydopamine has been developed to promote osteogenesis. In vitro , TBP exhibits excellent injectability, shape adaptability and biodegradability, ensuring the feasibility of its biological applications. Moreover, by virtue of the piezoelectric conversion capability of BTO, TBP has the response ability to low-intensity pulsed ultrasound (LIPUS) and can generate local electrical signals. Meanwhile, TBP performs outstandingly in promoting the proliferation, migration, adhesion and osteogenic differentiation of MC-3 T3-E1 cells. More importantly, TBP combined with LIPUS stimulation can regulate mitochondrial oxidative phosphorylation (OXPHOS) through the AKT/GSK3β/β-catenin signaling cascade, thereby accelerating osteogenesis. In vivo , the application of TBP hydrogel to the bone defect site of rats, combined with LIPUS stimulation, shows satisfactory effects in promoting bone regeneration. To sum up, this piezoelectric composite hydrogel is expected to become a promising candidate for bone tissue engineering.
研究领域:
生物材料
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组织工程
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生物医学工程
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纳米技术
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细胞生物学
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再生医学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）