JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yongping He,Qianxue Yu,Xiaoyu Ma,Diya Lv,Hui Wang,Weian Qiu,Xiao fei Chen,Yang Jiao,Yue Liu
Ethnopharmacological relevance Tanacetum parthenium (L.) Schultz-Bip, commonly known as feverfew, has been traditionally used to treat fever, migraines, rheumatoid arthritis, and cancer. Parthenolide (PTL), the main bioactive ingredient isolated from the shoots of feverfew, is a sesquiterpene lactone with anti-inflammatory and antitumor properties. Previous studies showed that PTL exerts anticancer activity in various cancers, including hepatoma, cholangiocarcinoma, acute myeloid leukemia, breast, prostate, and colorectal cancer. However, the metabolic mechanism underlying the anticancer effect of PTL remains poorly understood. Aim of the study To explore the anticancer activity and underlying mechanism of PTL in human cholangiocarcinoma cells. Material and methods In this investigation, the effects and mechanisms of PTL on human cholangiocarcinoma cells were investigated via a liquid chromatography/mass spectrometry (LC/MS)-based metabolomics approach. First, cell proliferation and apoptosis were evaluated using cell counting kit-8 (CCK-8), flow cytometry analysis, and western blotting. Then, LC/MS-based metabolic profiling along with orthogonal partial least-squares discriminant analysis (OPLS-DA) has been constructed to distinguish the metabolic changes between the negative control group and the PTL-treated group in TFK1 cells. Next, enzyme-linked immunosorbent assay (ELISA) was applied to investigate the changes of metabolic enzymes associated with significantly alerted metabolites. Finally, the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established using MetaboAnalyst 5.0 and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. Results PTL treatment could induce the proliferation inhibition and apoptosis of TFK1 in a concentration-dependent manner. Forty-three potential biomarkers associated with the antitumor effect of PTL were identified, which primarily related to glutamine and glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, nicotinate and nicotinamide metabolism, pyrimidine metabolism, fatty acid metabolism, phospholipid catabolism, and sphingolipid metabolism. Pathway analysis of upstream and downstream metabolites, we found three key metabolic enzymes, including glutaminase (GLS), γ-glutamyl transpeptidase (GGT), and carnitine palmitoyltransferase 1 (CPT1), which mainly involved in glutamine and glutamate metabolism, glutathione metabolism, and fatty acid metabolism. The changes of metabolic enzymes associated with significantly alerted metabolites were consistent with the levels of metabolites, and the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established. PTL may exert its antitumor effect against cholangiocarcinoma by disturbing metabolic pathways. Furthermore, we selected two positive control agents that are considered as first-line chemotherapy standards in cholangiocarcinoma therapy to verify the reliability and accuracy of our metabolomic study on PTL. Conclusion This research enhanced our comprehension of the metabolic profiling and mechanism of PTL treatment on cholangiocarcinoma cells, which provided some references for further research into the anti-cancer mechanisms of other drugs.
研究领域:
药理学
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肿瘤学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2020
·
IF 2.87
Tian Tian,Zhiming Zhu,Yalong Ding,Guoli Li,Nan Li,Tong Shen
The first total synthesis of sanjoseolide (1), which was originally obtained from Dalea frutescens A, was achieved via an efficient route with a longest linear sequence of six steps from the commercially available 2,4-dihydroxyacetophenone in 8.6% overall yield. Meanwhile, a series of sanjoseolide representative analogues were synthesized and assessed for their antiproliferative potency against cancer cells of different origins. Compound 8e inhibited the survival of all tested cancer cell lines in a dose-dependent manner, the IC50 values of the treatment were about 12.8 μM for human cholangiocarcinoma cell lines RBE and 12.7 μM for human cholangiocarcinoma cell lines HCCC-9810, which was more active than sanjoseolide (1). Analysis of the structure–activity relationships revealed that the presence of a trifluoromethyl group may be beneficial in terms of both RBE and HCCC-9810 inhibition.
研究领域:
有机化学
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肿瘤学
·
药物化学
✓ 已验证
DOI
高影响因子
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
·
2022
·Vol. 100
·期 7
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IF 2.245
Yanzhen Han,Yan Zhou,Liyuan Zhou,Xiaoyan Jia,Xiangjun Yu,Xiaohong An,Zhe Shi
Chemotherapy is one of the most important strategies in the treatment of cancer; however, chemoresistance restricts the effect of chemotherapy. Growing reports suggest that chloride channel-3 (ClC-3) is involved in regulating the sensitivity of multiple chemotherapeutic agents in the chemotherapy of various tumours, while its role in the chemotherapy of cholangiocarcinoma (CCA) is still poorly understood. Herein, we observed that ClC-3 was highly expressed in CCA chemoresistant tissues and CCA cisplatin-resistant cells QBC939/DDP, and the sensitivities of QBC939 and QBC939/DDP cells to cisplatin were all increased after inhibition of ClC-3. Further mechanism exploration revealed that ClC-3 knockdown reduced the level of autophagy. Furthermore, in both QBC939 and QBC939/DDP cells, the autophagy agonist rapamycin eliminated the increased cisplatin sensitivity of ClC-3 knockdown without affecting ClC-3 expression. Collectively, all the findings demonstrate that ClC-3 knockdown increases cisplatin-induced cell death in CCA cells though inhibiting autophagy, regardless of the occurrence of cisplatin resistance. In addition, our results also suggest that targeted inhibition of ClC-3 may be a potential strategy for chemosensitization in CCA chemotherapy.
研究领域:
肿瘤学
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
·
2023
·
IF 5
Wei Zhao,Jing Zhao,Kun Li,Yanjiao Hu,Dongxia Yang,Bin Tan,Jian Shi
Nuclear factor of activated T cells 2 (NFATC2) is reported to contribute to the initiation and progression of various cancers; however, its expression and function in cholangiocarcinoma (CCA) remain elusive. Herein, we investigated the expression pattern, clinicopathological characteristics, cell biological functions, and potential mechanisms of NFATC2 in CCA. Real-time PCR and immunohistochemistry were performed to analyze the expression of NFATC2 in human CCA tissues. CCK-8, colony formation, flow cytometry, Western blotting and transwell assays, and in vivo xenograft and pulmonary metastasis models were used to explore the effect of NFATC2 on the proliferation and metastasis of CCA. A dual-luciferase reporter system, oligonucleotide pull down, chromatin immunoprecipitation, immunofluorescence, and coimmunoprecipitation were performed to reveal the potential mechanisms. We found that NFATC2 was upregulated in CCA tissues and cells, and its aberrantly high levels were associated with poorer differentiation pattern. Functionally, NFATC2 overexpression promoted CCA cell proliferation and metastasis, whereas knockdown of NFATC2 led to the opposite results. Mechanistically, NFATC2 could be enriched in the promoter region of neural precursor cell expressed developmentally downregulated 4 (NEDD4) to facilitate its expression. Furthermore, NEDD4 targeted fructose-1, 6-bisphosphatase 1 (FBP1), and inhibited FBP1 expression via ubiquitination. In addition, silencing NEDD4 rescued the effects of NFATC2 overexpression on CCA cells. NEDD4 was upregulated in human CCA tissues, and its expression levels were positively correlated with those of NFATC2. We thus conclude that NFATC2 promotes the progression of CCA via the NEDD4/FBP1 axis, emphasizing the oncogenic role of NFATC2 in CCA progression.
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
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2024
·
IF 3.1
Wenjun Zhang,Chuntao Dong,Zhaosheng Li,Huina Shi,Yijun Xu,Mingchen Zhu
Intrahepatic cholangiocarcinoma (iCCA) is a hepatobiliary malignancy which accounts for approximately 5–10 % of primary liver cancers and has a high mortality rate. The diagnosis of iCCA remains significant challenges owing to the lack of specific and sensitive diagnostic tests available. Hence, improved methods are needed to detect iCCA with high accuracy. In this study, we evaluated the efficacy of serum amino acid profiling combined with machine learning modeling for the diagnosis of iCCA. A comprehensive analysis of 28 circulating amino acids was conducted in a total of 140 blood samples from patients with iCCA and normal individuals. We screened out 6 differentially expressed amino acids with the criteria of |Log 2 (Fold Change, FC)| > 0.585, P-value < 0.05, variable importance in projection (VIP) > 1.0 and area under the curve (AUC) > 0.8, in which amino acids L-Asparagine and Kynurenine showed an increasing tendency as the disease progressed. Five frequently used machine learning algorithms (Logistic Regression, Random Forest, Supporting Vector Machine, Neural Network and Naïve Bayes) for diagnosis of iCCA based on the 6 circulating amino acids were established and validated with high sensitivity and good overall accuracy. The resulting models were further improved by introducing a clinical indicator, gamma-glutamyl transferase (GGT). This study introduces a new approach for identifying potential serum biomarkers for the diagnosis of iCCA with high accuracy.
研究领域:
肿瘤学
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代谢组学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2025
·
IF 3.1
Weian Qiu,Qianxue Yu,Yongping He,Yanqiu Huang,Diya Lv,Hui Wang,Yong Ye,Zhanying Hong,Yue Liu
Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis. Nitidine chloride (NitC), a bioactive alkaloid derived from Zanthoxylum nitidum (Roxb.) DC., exhibits potential anti-cancer activity against CCA. However, the metabolic mechanism underlying the anti-cancer effect of NitC remains poorly understood and requires further elucidation. This study integrated metabolomics and network pharmacology to systematically investigate the anti-cancer activity and underlying mechanisms of NitC in treating human cholangiocarcinoma cells. First, The effects of NitC on human cholangiocarcinoma cells were assessed by cell proliferation, apoptosis, and cycle. Then, potential mechanisms and targets were investigated using a combination of cell metabolomics and network pharmacology and verified by molecular docking. Finally, we measured the protein levels of potential targets in TFK1 cells using enzyme-linked immunosorbent assay (ELISA). Our results indicated that NitC treatment induced the proliferation inhibition, G2/M arrest and apoptosis of TFK1 cells in a concentration dependent manner. The metabolomics analysis identified forty differential metabolic biomarkers and five key metabolic pathways of NitC in treating CCA. Network pharmacology found 36 potential targets for NitC intervention on CCA. The integration of network pharmacology and metabolomics constructed the “compound-reaction-enzyme-gene” association and revealed that NitC exerts its efficacy on CCA through four key targets, eleven metabolic indicators, and glycine, serine and threonine metabolism, and tyrosine metabolism. Molecular docking further confirmed robust binding interactions between NitC and these key targets. Moreover, ELISA results showed that NitC treatment significantly attenuated the protein levels of PIK3CA, PTGS2, and PRKACA in TFK1 cells. This study demonstrates that combining metabolomics and network pharmacology provides a powerful strategy to elucidate the pharmacological mechanisms of natural compounds, also offering new insights into the therapeutic potential of NitC for CCA.
研究领域:
肿瘤学
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药物化学
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系统生物学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2021
·
IF 17.97
Zihao Dai,Haining Liu,Junbin Liao,Cheng Huang,Xiaoxue Ren,Wanjie Zhu,Shenghua Zhu,Baogang Peng,Shaoqiang Li,Jiaming Lai,Lijian Liang,Lixia Xu,Sui Peng,Shuibin Lin,Ming Kuang
Summary Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N 7 -methylguanosine (m 7 G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo . Mechanistically, m 7 G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m 7 G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m 7 G tRNA modification in promoting ICC tumorigenesis and progression in vivo . Our study uncovers the important physiological function and mechanism of METTL1-mediated m 7 G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.
研究领域:
癌症生物学
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分子生物学
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转化医学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
IF 5.4
Xiangyun Tan,Yuan Yang,Junjie Hu,Yan Meng,Liang Chen,Guohua Zheng,Han Xiao,Zhenpeng Qiu
Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with insidious onset, limited treatments, and poor prognosis. Recent studies show celecoxib exerts marked cytotoxic effects on cholangiocarcinoma cell lines, suggesting its potential as an iCCA therapy. However, the potential molecular and cellular mechanisms that link celecoxib treatment to its toxicological outcomes remain unclear. In this study, we induced iCCA in mice by overexpressing AKT and YapS127A (hereafter referred to as AKT/YapS127A) and administered celecoxib continuously to evaluate its antitumor effects in vivo . The results demonstrate that celecoxib effectively inhibited tumor growth in AKT/YapS127A-driven iCCA mice. Mechanistically, celecoxib boosted levels of cell cycle inhibitors p21 Waf1/Cip1 and p27 Kip1 , leading to cell cycle arrest. It also promoted apoptosis by downregulating the expression of anti-apoptotic proteins Mcl-1 and Bcl-2. These effects were associated with the modulation of the AKT/mTORC1 signaling pathway. Consistently, celecoxib recapitulated AKT/mTORC1 inhibition and subsequent cell cycle/apoptotic regulator alterations in iCCA cell lines. Collectively, our study elucidates the molecular mechanisms through which celecoxib exerts its anti-tumor effects in iCCA, demonstrating its capacity to induce cytotoxic outcomes via the precise regulation of the AKT/mTORC1 pathway. These findings deepen understanding of the toxicological actions of celecoxib and provide critical insights for developing targeted iCCA therapies.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
肝病学
·
细胞信号传导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
WORLD JOURNAL OF GASTROENTEROLOGY
·
2015
·
IF 2.369
Gui-Li Huang,Dong-Yan Shen,Cheng-Fu Cai,Qiu-Yan Zhang,Hong-Yue Ren,Qing-Xi Chen
AIM: To develop a safe and effective agent for cholangiocarcinoma (CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in combination with chemotherapy on CCA cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells (QBC939, Sk-ChA-1, and MZ-ChA-1). Immunocytochemistry was used to detect the expression of P-glycoprotein (P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, pS9-GSK3β, pT216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting. RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil (5-FU) cells to 5-FU, vincristine sulfate (VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone ( P < 0.05). In addition, the combination of β-escin (20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the mRNA and protein expression of P-gp was down-regulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3a resulted in up-regulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner. CONCLUSION: β-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Bai Yang,Chen Jiaqi,Hu Weijian,Wang Lei,Wu Yulian,Yu Shi’an
Background: Silibinin is widely utilized drug in various cancer treatments, though its application in cholangiocarcinoma has not yet been explored. For the first time, we evaluated the anticancer potential and underlying molecular mechanism of silibinin in treatment of cholangiocarcinoma treatment.Methods: HuCCT-1 and CCLP-1 cells were chosen to be an in vitro study model and were exposed to various concentrations of silibinin for indicated times. Cell viability was evaluated by the cell counting kit-8 (CCK-8) assay and half maximal inhibitory (IC50) concentrations were calculated. Cell proliferation capacity was determined through the use of colony formation and 5-Ethynyl-2′- deoxyuridine (EdU) assays. Cell apoptosis and cycle arrest were assessed by Live/Dead staining assay and flow cytometry (FCM). The protein levels of extracellular regulated protein kinases (ERK)/mitochondrial apoptotic pathway were evaluated through western blotting (WB). Mitochondrial membrane potential changes were determined via 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1). A cholangiocarcinoma cell line xenograft model was used to assess the anti-tumor activity of silibinin in vivo.Results: Inhibition of the ERK protein by silibinin led to a significant decrease in mitochondrial membrane potential, which, in turn, caused Cytochrome C to be released from the mitochondria. The activation of downstream apoptotic pathways led to apoptosis of cholangiocarcinoma cells. In general, silibinin inhibited the growth of cholangiocarcinoma cell line xenograft tumors.Conclusions: Silibinin is able to inhibit cholangiocarcinoma through the ERK/mitochondrial apoptotic pathway, which makes silibinin a potential anti-tumor drug candidate for cholangiocarcinoma treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
·
2023
·
IF 4.4
Xuetong Qu,Bin He,Zekuan Li,Xinrong Jiang,Xingyue Liu,Xisheng Chen,Xiaoming Chen,Xiao Liang,Zhijun Jiang,Jianmin Wu
Cholangiocarcinoma (CCA) is an aggressive malignant tumor with a poor prognosis. Carbohydrate antigen 19-9 is an essential biomarker for CCA diagnosis, but its low sensitivity (72%) makes the diagnosis unreliable. To explore potential biomarkers for the diagnosis of CCA, a high-throughput nanoassisted laser desorption ionization mass spectrometry technique was constructed. We performed serum lipidomics and peptidomics analyses from 112 patients with CCA and 123 patients with benign biliary diseases. Lipidomics analysis showed that various lipids, such as glycerophospholipids, glycerides, and sphingolipids, were perturbed. Peptidomics analysis revealed perturbations of multiple proteins involved in the coagulation cascade, lipid transport, and so on. After data mining, 25 characteristic molecules including 20 lipids and 5 peptides were identified as potential diagnostic biomarkers. After screening various machine learning algorithms, artificial neural network was selected to construct a multiomics model for CCA diagnosis with 96.5% sensitivity and 96.4% specificity. The sensitivity and specificity of the model in the independent test cohort were 93.8 and 87.5%, respectively. Furthermore, integrated analysis with transcriptomic data in the cancer genome atlas confirmed that genes altered in CCA significantly affected multiple lipid- and protein-related pathways. Data are available via MetaboLights with the identifier MTBLS6712.
研究领域:
医学
·
分子生物学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Photodiagnosis and Photodynamic Therapy
·
2013
·
IF 2.243
Xiaofeng Deng,Li Xiong,Liangwu Lin,Guangzhong Xiong,Xiongying Miao
Summary Background Nanoparticles have been explored recently as an efficient means to deliver photosensitizers for photodynamic therapy . However, it is largely unknown if polyhematoporphyrin (C 34 H 38 N 4 NaO 5 , Photosan-II, PS) or other photosensitizers can be efficiently delivered by hollow silica nanoparticles (HSNP). Methods Polyhematoporphyrin (C 34 H 38 N 4 NaO 5 , Photosan-II, PS) was loaded into hollow silica nanoparticles (HSNP) by one-step wet chemical-based synthetic route. Dynamic light scattering (DLS) and polydispersive index (PDI) were used for measurement of the particles size and size distribution. Transmission electron microscope and scanning electron microscopy were used for the microstructure, morphological and chemical composition analysis. Fourier transform infrared spectrometry spectra and fluorescence emission spectrum were obtained. The photobiological activity of the PS-loaded HSNP was evaluated on human cholangiocarcinoma QBC939 cells. The cellular viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic and necrotic cells were measured by flow cytometry. Results DLS measurements showed that the size of the particles is in the range of 25–90 nm. PDI of the PS-loaded HSNP is 0.121 ± 0.01, indicating that samples have excellent quality with narrow size distribution to monomodal systems. In MTT assay , PS-loaded HSNP and free PS of the same concentration killed about 95.3% ± 2.0% and 55.7% ± 1.9% of QBC939 cells, respectively. The flow cytometry demonstrated that the laser induced cell death with PS-loaded HSNP was much more severe than that of free PS ( P < 0.05). Conclusions Photosan-II-loaded hollow silica nanoparticles not only can quickly deliver Photosan-II into cells but also can reach a more high concentration than free Photosan-II. HSNP is a desirable vehicle and the release system that shows promises for photodynamic therapy use, which not only improve the aqueous solubility, stability and transport efficiency of PS, but also increase its photodynamic efficacy compared to free PS.
研究领域:
生物医学工程
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）