INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 12
·6468
·
IF 4.9
Yuying Li,Wei Yan,Yu Qin,Liwei Zhang,Sheng Xiao
Chemotherapy resistance in cancer is an essential factor leading to high mortality rates. Tumor multidrug resistance arises as a result of the autophagy process. Our previous study found that compound 1-nitro-2 acyl anthraquinone-leucine (C2) exhibited excellent anti-colorectal cancer (CRC) activity involving autophagy and apoptosis-related proteins, whereas its underlying mechanism remains unclear. A notable aspect of this study is how C2 overcomes the multidrug susceptibility of HCT116/L-OHP, a colon cancer cell line that is resistant to both in vitro and in vivo oxaliplatin (trans-/-diaminocyclohexane oxalatoplatinum; L-OHP). In a xenograft tumor mouse model, we discovered that the mixture of C2 and L-OHP reversed the resistance of HCT116/L-OHP cells to L-OHP and inhibited tumor growth; furthermore, C2 down-regulated the gene expression levels ofP-gpandBCRPand decreasedP-gp’sdrug efflux activity. It is important to note that while C2 re-sensitized the HCT116/L-OHP cells to L-OHP for apoptosis, it also triggered a protective autophagic pathway. The expression levels of cleaved caspase-3 and Beclin 1 steadily rose. Expression of PI3K, phosphorylated AKT, and mTOR were decreased, while p53 increased. We demonstrated that the anthraquinone derivative C2 acts as an L-OHP sensitizer and reverses resistance to L-OHP in HCT116/L-OHP cells. It suggests that C2 can induce autophagy in HCT116/L-OHP cells by mediating p53 and the PI3K/AKT/mTOR signaling pathway.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-15
·
IF 5.2
Zhang Wen,Cai Shuhui,Qin Lihong,Feng Yaru,Ding Menglei,Luo Zichen,Shan Jinjun,Di Liuqing
Aconiti Lateralis Radix Praeparata ( Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2023
·Vol. 9
·期 7
·e18046
·
IF 4
Weijie Zhang,Lei Shi,Wei Zhou,Xin Liu,Yuan Xi,Xinyin Wang,Ya Li,Xia Xu,Youcai Tang
Breast cancer is one of the most common cancers. Oridonin, a traditional Chinese medicine, is believed to inhibit tumor growth, but its particular effects on breast cancer remain unknown. In this study, we examined oridonin's effects on 4T1, MCF-7, and MDAMB-231 cellular activity using CCK8. Scratch assays were used to detect oridonin's effects on cellular migration. Oridonin's effects on the breast cancer cell cycle were studied using flow cytometry, and expression of cell cycle related proteins p53, CDK2, and p21 was detected using Western blot assays. Metabolomics assays were used to detect changes in small molecule metabolites and metabolic pathways in breast cancer cells after treatment with oridonin. Oridonin's effects on breast cancer growth were also studied using xenograft mice. Metabolomics assays were used to detect changes in metabolites and metabolic pathways in xenograft mouse plasma in a control group, model group, and drug administration group. Experimental results showed that oridonin could significantly inhibit breast cancer growth both in vivo and in vitro. Scratch experiments showed that oridonin could inhibit breast cancer cell migration. Oridonin was also able to arrest cells in S phase by affecting several cell cycle-related proteins, including p53, CDK2, and p21. Metabolomic analysis of 4T1 cells identified a total of 33 differential metabolites, including multiple amino acids (such as l-Glutamic acid, l-Asparagine, l-Histidine, l-Valine, and l-Isoleucine). KEGG pathway enrichment analysis showed significant changes in aminoacyl-tRNA biosynthesis, and in multiple amino acid metabolic pathways. Plasma metabolomic analyses of xenograft mice revealed 28 differentially-expressed metabolites between the different animal model groups, including multiple amino acids. KEGG pathway analysis showed significant alterations in multiple amino acid metabolic pathways in oridonin-treated mice. Additionally, changes in the expression of PI3K, AKT and mTOR proteins, as well as in branched amino acids, suggest that oridonin affects the PI3K/AKT/mTOR signaling pathway by inhibiting the biosynthesis of valine, leucine and isoleucine. Taken together, our results suggest that oridonin has strong anti-tumor activity in vitro and in vivo, and has potential as an adjuvant to breast cancer treatment regimens.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
代谢组学
✓ 已验证
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2019
·
IF 3.208
Xiaohong Xu,Vinothkumar Rajamanickam,Sheng Shu,Zhoudi Liu,Tao Yan,Jinxin He,Zhiguo Liu,Guilong Guo,Guang Liang,Yi Wang
Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. Methods Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. Results Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. Conclusion Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Fang Yuwei,Shi Kangpei,Lu Haining,Lu Lin,Qiu Bo
Objective: To investigate the effect of Mingmu Xiaomeng tablets (MMXM) on the expression of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)-related proteins in a diabetic rat model.Methods: Thirty-two male Sprague Dawley rats were randomly divided into four groups: normal control (NC), diabetic model (DM) control, MMXM, and calcium dobesilate (CD) Rats injected with streptozotocin (STZ) were used as an experimental diabetes model. After 14 weeks, autophagy and PI3K/Akt/mTOR signaling pathway proteins were detected by western blot. Glial fibrillary acidic protein (GFAP) expression in Müller cells was examined by immunohistochemistry. Retinal function was evaluated with electroretinography, and retinal ultrastructure was observed by transmission electron microscopy. Serum cytokine levels were detected with protein chip technology.Results: MMXM restored autophagy by decreasing the protein expression of LC3-II and p62 and reducing the phosphorylation of PI3K, Akt, and mTOR, thus promoting autophagy. MMXM decreased GFAP expression in retinal Müller cells; restored electrophysiology indexes and retinal ultrastructures; and reduced serum levels of interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor.Conclusion: MMXM may protect the diabetic retina by inhibiting PI3K/Akt/mTOR signaling and enhancing autophagy.
研究领域:
药理学
·
糖尿病
·
眼科学
·
细胞信号传导
·
动物模型
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2020
·
IF 4.099
Xueli Lv,Yaolu Zhu,Yingguang Deng,Shichang Zhang,Qing Zhang,Boxin Zhao,Guofeng Li
Doxorubicin (DOX) is one of the most effective and irreplaceable chemotherapeutic agents but its clinical use is limited due to its cardiotoxicity. Glycyrrhizin(GL) has been applied to liver disorders for long. However, little is known that if GL could be meaningful in attenuating cardiotoxicity. The aim of this study is to investigate the cardioprotective effects of GL in DOX-induced cardiotoxicity (DIC) and the underlying mechanism. Here, H9c2 cardiomyoblasts, Neonatal rat cardiomyocytes (NRCMs), and Rats were introduced as test models. A single dose of 20 mg/kg DOX (i.p.) was applied to induce acute cardiotoxicity in vivo, as reflected by growth inhibition, increased levels of AST and CK-MB, and reduction of SOD activity, while GL (25 or 50 mg/kg/d, 14 d, i.p.) could counteract these effects. Moreover, pre-incubation with GL (0.8 mM for 12 h) in H9c2 cells protected against DOX-induced cytotoxicity, oxidative stress and depolarization of mitochondrial membrane potential (MMP). Besides, Western blot analysis showed that DOX upregulated the expression of LC3 II and p62 whereas GL reversed that both in vitro and in vivo and improved the obstructed autophagy flux in DOX-treated H9c2 cells with an autophagy inhibitor Bafilomycin A1 (Baf A1, 50 nM, 2 h). It has been previously documented that High-mobility group box 1 (HMGB1) was involved in DIC. In our work, knockdown of HMGB1 significantly increased cell viability and LC3 II level in H9c2, suggesting HMGB1 was crucial in DOX-induced autophagy-triggering cell death. Intriguingly, GL is a direct inhibitor of HMGB1. We found that GL downregulated Akt/mTOR autophagy signaling pathway in DOX-treated H9c2 cells. More importantly, in non-silencing H9c2 cells (transfected with negative control siRNA) cells, the expression of phospho-Akt, phospho-mTOR, p62, and LC3 II was significantly decreased with GL pretreament compared to DOX alone. However, in H9c2/HMGB1 － (transfected with HMGB1 siRNA) cells exposed to DOX, the expression of p-Akt, p-mTOR, p62, LC3 II had no statistical difference with or without GL, revealing that HMGB1 mediated the cardioprotective action of GL in DIC. Taken together, our findings demonstrate that improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway might contribute to attenuate DIC and go a novel insight into the underlying mechanisms of GL’s cardioprotective action. GL could be a potential candidate for the prevention of DIC.
研究领域:
药理学
·
心脏病学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ANIMAL SCIENCE
·
2024
·
IF 2.7
Ma Zifeng,Li Qiao,Xu Hongmei,Li Yueyue,Wang Shujin,Xiong Yan,Lan Daoliang,Li Jian,Xiong Xianrong,Fu Wei
Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 μM and 20 μM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.
研究领域:
兽医学
·
毒理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Mengxiang Chen,Yi Peng,Rongtao Zhu,Xiaoting Luo,Xuemin Yang,Jiazhi Chen,Haiyan Chen,Wei Zhou,Zhiyun Du
Psoriasis is a chronic inflammatory skin disease with significant impacts on quality of life. Current treatments face challenges like high costs and side effects. This study explores the therapeutic potential of Rosa rugosa polysaccharide (RRPS) and its nanofiber membrane in psoriasis treatment. RRPS was extracted using a yeast fermentation enzyme-assisted method and characterized. In vitro studies on RAW264.7 macrophages showed that RRPS significantly reduced nitric oxide (NO) production, indicating anti-inflammatory effects. The nanofiber membrane, fabricated via electrospinning, has high porosity and sustained-release properties, enhancing drug delivery and skin barrier repair. In vivo studies using an imiquimod-induced psoriasis mouse model demonstrated that both RRPS and its nanofiber membrane improved psoriasis symptoms, reduced transepidermal water loss (TEWL), and inhibited pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A). Mechanistically, they suppressed the PI3K-AKT/mTOR pathway. The nanofiber membrane showed superior efficacy compared to RRPS alone, highlighting the benefits of electrospinning. This study suggests that Rosa rugosa polysaccharide and its nanofiber membrane could be a novel, effective, and safe alternative for psoriasis treatment by targeting the PI3K-AKT/mTOR pathway.
研究领域:
皮肤病学
·
药理学
·
纳米技术
·
免疫学
·
生物技术
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2024
·Vol. 104
·期 4
·e70003
·
IF 3.2
Xiang Yu,Di Zhang,Chengming Hu,Zejun Yu,Yang Li,Cheng Fang,Yinsheng Qiu,Zhinan Mei,Lingyun Xu
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignant tumor. Hepatocellular carcinogenesis is closely linked to apoptosis, autophagy, and inflammation. Diosmetin and chrysin, are two flavonoid compounds, exhibit anti-inflammatory and anticancer properties. In this study, the TCGA database was utilized to identify differentially expressed genes between normal subjects and HCC patients. Molecular docking and molecular dynamics analyses were employed to assess the binding affinity of chrysin and diosmetin to key proteins in the PI3K/AKT/mTOR/NF-κB signaling pathway. Western blotting and RT-qPCR were used to measure the protein and gene expression within this pathway. The results indicated that HCC patients had elevated levels of PI3K, AKT, mTOR, and P65 proteins compared to normal subjects, which adversely affected patient survival. Molecular docking and dynamics studies demonstrated that diosmetin and chrysin are effectively bound to these four proteins. In vitro experiments revealed that the combination of diosmetin and chrysin could induce apoptosis, enhance autophagy, reduce inflammatory mediator production, and improve the tumor cell microenvironment by inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. Notably, the synergy score for the combination of diosmetin (25 μM) and chrysin (10 μM) was 16. Thus, the diosmetin–chrysin combination shows promise as an effective therapeutic approach for hepatocellular carcinoma due to its strong synergistic effect.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging and Disease
·
2023
·
IF 7.4
Guoxiang Liu,Xiaoxia Li,Fanghao Yang,Jingyu Qi,Lipeng Shang,Huhu Zhang,Shuang Li,Fenghua Xu,Lingne Li,Huaxin Yu,Yang Li,Xiaolei Dong,Qinghang Song,Feng Zhu,Guang Chen,Can Cao,Liangqian Jiang,Junzhe Su,Lina Yang,Xiaohui Xu,Zhe Zhang,Robert Chunhua Zhao,Bing Li
The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.
研究领域:
干细胞生物学
·
衰老研究
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2024
·
IF 3.7
Hong Duan,Han Li,Tianyi Liu,Yuan Chen,Mengmeng Luo,Ying Shi,Jing Zhou,Marwan M. A. Rashed,Kefeng Zhai,Lili Li,Zhaojun Wei
Atherosclerosis (AS) is a common cardiovascular disease that poses a major threat to health. Schisandra chinensis is a medicinal and edible plant that is commonly used to treat cardiovascular diseases. In this paper, HPLC was used to detect and analyze 5 different components in Schisandra chinensis. Network pharmacological predictions highlight the PI3K/AKT/mTOR pathway as an important pharmacological pathway. The effective ingredient Schisandrin C was screened by the molecular docking technique. ox-LDL-induced HUVECs were used to construct the atherosclerosis model for further experimental verification. The results showed that Schisandrin C interfered with the PI3K/AKT/mTOR autophagy pathway. This study lays a foundation for the further application of Schisandrin C in the prevention and treatment of atherosclerosis in the future.
研究领域:
心血管疾病
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
·
2025
·
IF 4.3
Qingyan Wang,Yunjie Su,Qian Yang,Trust Beta,Fei Shen,Qin Liu
Bisphenol A (BPA) is a typical endocrine disrupting chemical widely distributed in the environment and in food systems. The adverse effects of BPA on reproductive health have posed major concerns worldwide. The aim of this study was to determine the potential of epigallocatechin gallate (EGCG) to protect against BPA-induced male reproductive toxicity and investigate the underlying protective mechanism. The protective effects of EGCG on BPA-induced reproductive toxicity were investigated using male zebrafish model. The results showed that EGCG alleviated BPA-induced developmental toxicity of F1 generation of zebrafish, reversed testis disorder and combated the blood-testis barrier (BTB) damage caused by BPA in zebrafish. In order to unravel the underlying mechanism, TM4 cell - constructed BTB model was used for further study. The results indicated that EGCG counteracted the damage induced by BPA on the integrity of BTB model and reduced the autophagy caused by BPA. Furthermore, EGCG effectively inhibited the BPA-induced upregulation of the expression level of AMPK (p-AMPKα/AMPKα), significantly restored the BPA-mediated downregulation of the expression levels o。f p-mTOR/mTOR, p-AKT/AKT and Raptor. The results suggested that EGCG mitigated the BPA-induced male reproductive toxicity through maintaining the integrity of BTB by inhibiting the autophagy mediated by AMPK/AKT/mTOR signaling pathway. This study provided a strategy for combating the BPA-induced reproductive toxicity using a well-known bioactive component as a potential therapeutic approach.
研究领域:
毒理学
·
生殖生物学
·
环境健康
·
分子生物学
·
药理学
✓ 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）