FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Xin Xie,Yan Zhu,Huimin Cheng,Haili Li,Yadi Zhang,Rong Wang,Wenyong Li,Fengrui Wu
Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo . The results showed that BPA (10 μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10 μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo ; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.
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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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2022
·
IF 4.145
Feng Chi,Long Chen,Xiaoming Jin,Guijin He,Zhen Liu,Sijia Han
Cytoskeleton-associated protein 2-like (CKAP2L) is a mitotic spindle protein and its high expression is reported to be associated with the poor prognosis of cancer patients. Interestingly, TNMplot website analysis indicated that CKAP2L expression was significantly higher in breast cancer (BC) tissues than in normal breast tissues ( P < 0.001). Thus, this study was conducted to investigate the role of CKAP2L in breast carcinogenesis and its underlying molecular mechanisms. The mRNA and protein expression levels of CKAP2L in 40 paired fresh BC and para-carcinoma specimens were first analyzed, and the results confirmed the high expression of CKAP2L in BC tissues. Functional studies revealed that CKAP2L silencing dramatically suppressed the proliferation, migration, and invasion, induced cell cycle arrest and apoptosis of BC cells in vitro , and inhibited the growth of xenografted tumors in vivo . However, CKAP2L overexpression produced the opposite results. Mechanically, CKAP2L could activate the AKT/mTOR signaling pathway in BC cells accompanied by increased phosphorylation levels of AKT, mTOR , and p70S6K in CKAP2L-overexpressed cells. Forkhead box protein P3 (FOXP3), a transcription factor with tumor-suppressive properties, was proved to negatively regulate CKAP2L expression in BC cells through binding to the promoter of CKAP2L and inhibiting its transcription. In summary, the present study demonstrates that CKAP2L, transcriptionally regulated by FOXP3 , activates the AKT/mTOR signaling pathway and promotes breast carcinogenesis. CKAP2L may serve as a promising target of therapeutic intervention for BC.
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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DOI
PubMed
高影响因子
EXPERIMENTAL PHYSIOLOGY
·
2020
·Vol. 105
·期 11
·1918-1927
·
IF 2.431
Manfeng Wang,Xiaowei Wu,Lu Gan,Zongyan Teng,Haijin Zhang,Yina Zhang
New Findings What is the central question of this study? Does Dnmt3a play a crucial role in regulating diabetic muscle atrophy? What is the main finding and its importance? Muscle atrophy is one of the major long-term complications of diabetes mellitus. However, little is known about the molecular mechanism involved. In this paper, we demonstrated that Dnmt3a overexpression effectively improves the diabetic muscle health in mice and documented the underlying mechanisms. DNMT3A might become a promising target to prevent muscle atrophy in patients with diabetes. Muscle atrophy is one of the major long-term complications of diabetes mellitus, which greatly affects the mobility of patients. Epigenetic processes mediated by DNA methyltransferases (DNMTs) play crucial roles in the locomotor system, but little is known about the functions of DNMTs in diabetic muscle atrophy. Here, we investigated the function of Dnmt3a in diabetic muscle atrophy and explored the mechanisms involved. Adeno-associated virus AAV2 overexpressing Dnmt3a or its vector control was injected into the tibialis anterior muscle of streptozotocin-induced diabetic mice. Muscle mass and muscle cross-sectional area were used to evaluate muscle atrophy. In vitro , adeno-associated virus AAV2 overexpressing Dnmt3a or its vector control was transfected into C2C12 myoblasts. Horse serum was used to induce differentiation and palmitate to stimulate the C2C12 myoblasts. The expressions of myogenic regulatory factors were examined by real-time PCR and western blot analysis. Overexpression of Dnmt3a attenuated muscle atrophy in diabetic mice and promoted myotube formation of C2C12 myoblasts. Overexpression of Dnmt3a restored the expressions of myogenic regulatory factors atrogin-1, MuRF1, Pax7, Myod1 and myogenin, both in vivo and in vitro . Moreover, overexpression of Dnmt3a activated the phosphorylation of Akt by inhibiting the activation of Pten. This study demonstrates that overexpression of Dnmt3a prevents diabetic muscle atrophy by modulating the Pten/Akt pathway.
研究领域:
分子生物学
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糖尿病
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肌肉生理学
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表观遗传学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Yue Wang,Ying Li,Liang Wang,Buze Chen,Miaolin Zhu,Chunyi Ma,Chunyan Mu,Aibin Tao,Shibao Li,Lan Luo,Ping Ma,Shuai Ji,Ting Lan
Ovarian cancer is one of the most common gynecological malignancies in women worldwide with a poor survival rate. Cinnamaldehyde (CA), a bioactive substance isolated from cinnamon bark, is a natural drug and has shown that it can inhibit the progression of other tumors. However, the role of CA in ovarian cancer and its mechanism is poorly understood. In this study, wound healing assays, plate cloning, CCK-8, and transwell assays were used to determine cell proliferation and invasion. Western blot and flow cytometry were used to detect apoptosis levels. Western blot and immunofluorescence were used to detect changes in cellular EMT levels. The Western blot was used to detect levels of the PI3K/AKT signaling pathway. In vivo , we established a subcutaneous transplantation tumor model in nude mice to verify the role of CA in the progression and metastasis of ovarian cancer. Our data showed that in vitro CA was able to inhibit the cell viability of ovarian cancer. The results of scratch assay and transwell assay also showed that CA inhibited the proliferation and invasion ability of A2780 and SKOV3 cells. In addition, CA promoted apoptosis by increasing the expression of cleaved-PARP and cleaved-caspase 3 in ovarian cancer cells. Mechanistically, we found that CA inhibited the EGF-induced PI3K/AKT signaling pathway and reduced the phosphorylation levels of mTOR, PI3K, and AKT. The EGF-induced EMT process was also abolished by CA. The EMT process induced by AKT-specific activator SC79 was also suppressed by CA. Furthermore, in in vivo , CA significantly repressed the progression of ovarian cancer as well as liver metastasis. In all, our results suggest that CA inhibits ovarian cancer progression and metastasis in vivo and in vitro and inhibits EGF-induced EMT processes through the PI3K/AKT signaling pathway.
研究领域:
肿瘤学
·
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
BIOLOGICAL PROCEDURES ONLINE
·
2024
·Vol. 26
·期 1
·1-15
·
IF 3.7
Wang Huizhi,Min Jingyu,Ding Yuntao,Yu Zhengyue,Zhou Yujing,Wang Shunyu,Gong Aihua,Xu Min
Background Gastric cancer (GC) is a common malignancy and a leading cause of cancer-related death with high morbidity and mortality. Methyl-CpG binding domain protein 3 (MBD3), a key epigenetic regulator, is abnormally expressed in several cancers, participating in progression and metastasis. However, the role of MBD3 in GC remains unknown. Methods MBD3 expression was assessed via public databases and validated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The prognosis of MBD3 was analysed via bioinformatics based on the TCGA dataset. The migration, invasion and proliferation of GC cells were examined by transwell, wound healing, cell counting kit (CCK)-8, colony-formation and xenograft mouse models. Epithelial-mesenchymal transition (EMT) and phosphatidylinositide 3-kinases/ protein Kinase B (PI3K/AKT) pathway markers were evaluated by Western blotting. RNA sequencing was used to identify the target of MBD3. Results MBD3 expression was higher in GC tissues and cells than in normal tissues and cells. Additionally, high MBD3 levels were associated with poor prognosis in GC patients. Subsequently, we proved that MBD3 enhanced the migration, invasion and proliferation abilities of GC cells. Moreover, western blot results showed that MBD3 promoted EMT and activated the PI3K/AKT pathway. RNA sequencing analysis showed that MBD3 may increase actin γ1 (ACTG1) expression to promote migration and proliferation in GC cells. Conclusion MBD3 promoted migration, invasion, proliferation and EMT by upregulating ACTG1 via PI3K/AKT signaling activation in GC cells and may be a potential diagnostic and prognostic target.
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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癌症生物学
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DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2021
·
IF 6.576
Wei Wei,Fan Xiao-Man,Jia Shao-Hui,Zhang Xi-Ping,Zhang Zhao,Zhang Xue-Jun,Zhang Jiu-Xun,Zhang Ye-Wang
Sea cucumbers are one of many marine echinoderm animals that contain valuable nutrients and medicinal compounds. The bioactive substances in sea cucumbers make them have promising biological and pharmacological properties, including antioxidant, anti-bacterial, and anti-tumor effects. In this study, sea cucumber intestinal peptide (SCIP) is a small molecular oligopeptide (<1,000 Da) extracted from sea cucumber intestines hydrolyzed by alkaline protease. The analysis of amino acid composition showed that hydrophobic amino acids and branched-chain amino acids were rich in SCIP. Nowadays, although increasing studies have revealed the biological functions of the sea cucumber active substances, there are few studies on the function of SCIP. Furthermore, due to the anti-cancer activity being an essential characteristic of sea cucumber active substances, we also investigated the anti-cancer potential and the underlying mechanism of SCIP in vivo and in vitro. The results indicate that SCIP inhibits the growth of MCF-7 tumor cells in zebrafish and increases the apoptosis of human breast cancer MCF-7 cells. Further mechanism studies confirm that SCIP promotes the expression of apoptosis-related proteins and thus promotes the breast cancer cells (MCF-7) apoptosis via inhibition of PI3K/AKT signal transduction pathway.
研究领域:
海洋生物学
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药理学
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肿瘤学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Jue Bai,Si-Yuan Yang,Shao-Mei Yu,Ying Cao,Chang-Han Ma,Xuan-Yi Hu,Xiong Chen,Ying-Nan Song,Hong-Jin Chen
Background: Myocardial ischemia/reperfusion injury (MIRI) is a critical problem in cardiovascular medicine, often occurring after coronary revascularization procedures or cardiopulmonary bypass. The characters of MIRI are both energy metabolism disturbances and severe myocardium insulin resistance (IR), which exacerbated myocardial damage and cell death. Isoliquiritigenin (ISL), a flavonoid derived from licorice roots (Glycyrrhiza spp.), has demonstrated protective effects on MIRI. However, the potential cardio-protective effects and mechanism of ISL in MIRI remain unclear.Propose: In this study, we aimed to investigate ISL’s therapeutic effects on MIRI. Moreover, we elucidate the underlying mechanisms of ISL regulated myocardium insulin resistance in vivo and in vitro.Methods: In vivo, SD rats underwent left anterior descending coronary artery ligation/reperfusion to induce MIRI. Chest echocardiography was performed to monitor cardiac function post-reperfusion, followed by measurement of myocardial injury and IR markers. In vitro, H9C2 cardiomyocytes subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Markers associated with myocardial injury and IR were assessed. Then, we identified potential therapeutic targets IGFBP5 for MIRI by network pharmacology and molecular docking analysis. Finally, lentivirus were used to silence or over-express IGFBP5 to elucidate the role of IGFBP5 in regulating the therapeutic effects of ISL on IR in MIRI.Results: In the present study, In vivo experiments demonstrated that ISL attenuated myocardial infarct size, decreased serum markers of myocardial injury, improved left ventricular systolic function, and enhanced insulin sensitivity. In vitro data revealed that ISL ameliorated glucose uptake and cell survival rate. Furthermore, ISL increased AKT phosphorylation and upregulated membrane-bound GLUT4 (M-GLUT4) protein expression levels. These effects of ISL are mediated by the induction of IGFBP5, as demonstrated using gene-specific shRNA or overexpression for IGFBP5.Conclusion: Our results reveal that ISL protects against myocardial damage caused by MIRI through the regulation of IR via the IGFBP5/AKT/GLUT4 pathway.
研究领域:
心血管医学
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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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 8
·3914
·
IF 4.9
Ruxi Gao,Fanyi Wang,Xiang Liu,Chu Yuan,Guoshun Shan
This study investigated the therapeutic mechanism of Rehmanniae Radix Praeparata (RRP) in treating blood deficiency syndrome (BDS) through integrated chemical analysis and pharmacological validation. UPLC-Q-TOF-MS identified chemical components of Rehmanniae Radix (RR) and RRP, with network pharmacology analysis suggesting AKT1 and NOS3 in the PI3K-AKT pathway as potential therapeutic targets. Pharmacodynamic evaluations using ELISA, hematological analysis, histopathology, and immunohistochemistry demonstrated RRP’s efficacy in improving hematological parameters, energy metabolism, and organ pathology in BDS mice. Experimental validation via RT-qPCR and Western blot confirmed significant upregulation of AKT1 and NOS3 mRNA and protein expression following RRP treatment. The findings indicate that RRP alleviates BDS by activating the PI3K-Akt signaling pathway to modulate AKT1 and NOS3 expression, providing mechanistic insights into its therapeutic actions.
研究领域:
中药学
·
分子生物学
·
网络药理学
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病理学
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产品关联
DOI
PubMed
高影响因子
Biomolecules
·
2019
·Vol. 9
·期 6
·219
·
IF 4.694
Stoyan Dirimanov,Petra Högger
Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18%), quercetin (36 ± 8%), urolithin A (35 ± 12%), apigenin, fisetin, and resveratrol; (p< 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478,p= 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds’ antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level.Keywords:Akt/PKB;endothelium;diabetes;polyphenols;in vitro;structure-activity relationships;screening
研究领域:
药理学
·
细胞生物学
·
糖尿病研究
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营养科学
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产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-21
·
IF 6.1
Guo Qinglong,Wang Yi,Yu Liangchen,Guan Liao,Ji Xuefei,Li Xiaohui,Pang Gang,Ren Zhenhua,Ye Lei,Cheng Hongwei
Background Olfactory dysfunction occurs frequently in Parkinson’s disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice.Methods MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R−) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines.Results Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R− HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis.Conclusion sThis study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.
研究领域:
神经科学
·
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
Journal of Orthopaedic Surgery and Research
·
2023
·Vol. 18
·期 1
·1-13
·
IF 2.6
Zhang Yang,Liu Wenguang,Liu Zhonghao,Liu Yi
Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.
Materials and methods The cytotoxicity of H 2 O 2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot. Results Our results indicated that H 2 O 2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H 2 O 2 . Western blot and immunofluorescence analyses showed that DAS decreased the H 2 O 2 -induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H 2 O 2 -induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13. Conclusion Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H 2 O 2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.
研究领域:
药理学
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细胞生物学
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风湿病学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2024
·
IF 2.7
Qianqian Wang,Yaqian Yang,Pengfei Li,Ruoyun Dong,Chenhao Sun,Guanling Song,Yan Wang
Titanium dioxide nanoparticles (TiO 2 NPs) can cause apoptosis in TM4 cells; however, the underlying mechanism has not been entirely elucidated. The purpose of this study was to investigate the effects of TiO 2 NPs on ROS, Ca 2+ level, p38/AKT/mTOR pathway, and apoptosis in TM4 cells and to evaluate the role of Ca 2+ in p38/AKT/mTOR pathway and apoptosis. After exposure to different concentrations (0, 50, 100, 150, and 200 μg/mL) of TiO 2 NPs for 24 h, cell viability, ROS, Ca 2+ level, Ca 2+ -ATPase activity, p38/AKT/mTOR pathway-related proteins, apoptosis rate, and apoptosis-related proteins (Bax, Bcl-2, Caspase 3, Caspase 9, and p53) were detected. The ROS scavenger NAC was used to determine the effect of ROS on Ca 2+ level. The Ca 2+ chelator BAPTA-AM was used to evaluate the role of Ca 2+ in p38/AKT/mTOR pathway and apoptosis. TiO 2 NPs significantly inhibited cell viability, increased ROS level, and elevated Ca 2+ level while suppressing Ca 2+ -ATPase activity. TiO 2 NPs regulated the p38/AKT/mTOR pathway via increasing p-p38 level and decreasing p-AKT and p-mTOR levels. TiO 2 NPs significantly enhanced the apoptosis. NAC attenuated Ca 2+ overload and reduction in Ca 2+ -ATPase activity caused by TiO 2 NPs. BAPTA-AM alleviated TiO 2 NPs-induced abnormal expression of p38/AKT/mTOR pathway-related proteins. BAPTA-AM assuaged the apoptosis caused by TiO 2 NPs. Altogether, this study revealed that TiO 2 NPs elevated intracellular Ca 2+ level through ROS accumulation. Subsequently, the heightened intracellular Ca 2+ level was observed to exert regulation over the p38/AKT/mTOR pathway, ultimately culminating in apoptosis. These results provides a complementary understanding to the mechanism of TiO 2 NPs-induced apoptosis in TM4 cells.
研究领域:
纳米技术
·
细胞生物学
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毒理学
✓ 已验证
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）