ANALYTICAL AND BIOANALYTICAL CHEMISTRY
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2024
·Vol. 416
·期 29
·7043-7062
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IF 3.8
Liu Wen-Ya,Xu Di,Meng Hui-Hui,Wang Cheng-Yao,Feng Xin,Wang Jun-Song
Cucurbitacin B (CuB) is a natural triterpenoid with diverse pharmacological effects including potent anticancer activity. However, its oral bioavailability is hampered by limited metabolism in vivo. We characterized CuB’s in vivo metabolism in rats to uncover bioactive metabolites retaining therapeutic potential, using a robust UHPLC-Q-TOF–MS/MS workflow. This workflow combined molecular networking, fragmentation filtering, and mass defect filtering to identify CuB metabolites in rat urine, plasma, and feces following oral administration. Thirteen metabolites were identified and seven were confirmed. Major phase I transformations involved hydrolysis, reduction, epoxidation, and amination. Phase II conjugation included cysteine, glutathione, glucuronide, and gluconic acid conjugates. Notably, one of the main metabolites formed was the cysteine conjugate CuB-Cys. CuB-Cys maintained similar in vitro antiproliferative activity to CuB on HepG2, MCF-7, and PANC-1 cancer cell lines. However, it demonstrated lower cytotoxicity towards non-cancerous L02 cells, highlighting improved therapeutic selectivity. Mechanistically, CuB-Cys induced greater apoptotic signaling in HepG2 cells than CuB via enhanced caspase activation and disrupted BAX-Bcl-2 balance. This represents the first systematic characterization of CuB’s in vivo metabolic pathway. The identification and confirmation of CuB-Cys provide insight for drug development efforts aiming to maintain therapeutic efficacy while reducing toxicity, via metabolite-based approaches. Our findings shed light on strategies for improving CuB’s clinical potential. Graphical Abstract
研究领域:
药理学
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代谢组学
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肿瘤学
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DOI
PubMed
高影响因子
Journal of Orthopaedic Translation
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2021
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IF 5.191
Wen-Xiang Cheng,Yan-Zhi Liu,Xiang-Bo Meng,Zheng-Tan Zheng,Ling-Li Li,Li-Qing Ke,Ling Li,Cui-Shan Huang,Guo-Yuan Zhu,Hu-Dan Pan,Ling Qin,Xin-Luan Wang,Peng Zhang
Objectives Vascularization is an essential step in successful bone tissue engineering. The induction of angiogenesis in bone tissue engineering can be enhanced through the delivery of therapeutic agents that stimulate vessel and bone formation. In this study, we show that cucurbitacin B (CuB), a tetracyclic terpene derived from Cucurbitaceae family plants, facilitates the induction of angiogenesis in vitro. Methods We incorporated CuB into a biodegradable poly (lactide-co-glycolide) (PLGA) and β-tricalcium phosphate (β-TCP) biomaterial scaffold (PT/CuB) Using 3D low-temperature rapid prototyping (LT-RP) technology. A rat skull defect model was used to verify whether the drug-incorporated scaffold has the effects of angiogenesis and osteogenesis in vivo for the regeneration of bone defect. Cytotoxicity assay was performed to determine the safe dose range of the CuB. Tube formation assay and western blot assay were used to analyze the angiogenesis effect of CuB. Results PT/CuB scaffold possessed well-designed bio-mimic structure and improved mechanical properties. CuB was linear release from the composite scaffold without affecting pH value. The results demonstrated that the PT/CuB scaffold significantly enhanced neovascularization and bone regeneration in a rat critical size calvarial defect model compared to the scaffold implants without CuB. Furthermore, CuB stimulated angiogenic signaling via up-regulating VEGFR2 and VEGFR-related signaling pathways. Conclusion CuB can serve as promising candidate compound for promoting neovascularization and osteogenesis, especially in tissue engineering for repair of bone defects. The translational potential of this article This study highlights the potential use of CuB as a therapeutic agent and strongly support its adoption as a component of composite scaffolds for tissue-engineering of bone repair.
研究领域:
生物医学工程
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组织工程
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药理学
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再生医学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2020
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IF 10.317
Kaiyuan Wang,Hao Ye,Xuanbo Zhang,Xia Wang,Bin Yang,Cong Luo,Zhiqiang Zhao,Jian Zhao,Qi Lu,Haotian Zhang,Qiming Kan,Yongjun Wang,Zhonggui He,Jin Sun
Metastasis is closely associated with high breast cancer mortality. Although nanotechnology-based anti-metastatic treatments have developed rapidly, the anti-metastasis efficiency is still far from satisfactory, mainly due to the poor recognition of circulating tumor cells (CTCs) in blood. Herein, we developed an exosome-like sequential-bioactivating prodrug nanoplatform (EMPCs) to overcome the obstacle. Specifically, the reactive oxygen species (ROS)-responsive thioether-linked paclitaxel-linoleic acid conjugates (PTX-S-LA) and cucurbitacin B (CuB) are co-encapsulated into polymeric micelles , and the nanoparticles are further decorated with exosome membrane (EM). The resulting EMPCs could specifically capture and neutralize CTCs during blood circulation through the high-affinity interaction between cancer cell membrane and homotypic EM. Following cellular uptake, EMPCs first release CuB, remarkably blocking tumor metastasis via downregulation of the FAK/MMP signaling pathway . Moreover, CuB obviously elevates the intracellular oxidative level to induce a sequential bioactivation of ROS-responsive PTX-S-LA. In vitro and in vivo results demonstrate that EMPCs not only exhibit amplified prodrug bioactivation, prolonged blood circulation, selective targeting of homotypic tumor cells, and enhanced tumor penetration, but also suppress tumor metastasis through CTCs clearance and FAK/MMP signaling pathway regulation. This study proposes an integrated approach for mechanism-based inhibition of tumor metastasis and manifests a promising potential of programmable-bioactivating prodrug nanoplatform for cancer metastasis inhibition .
研究领域:
纳米技术
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癌症生物学
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Pei Liu,Xiao-ying Tan,Huang-qin Zhang,Ke-lei Su,Er-xin Shang,Qing-ling Xiao,Sheng Guo,Jin-ao Duan
Ethnopharmacological relevance The herbal pair of Trichosanthis Pericarpium (TP) - Trichosanthis Radix (TR) can be seen in the famous formula “Beimu Gualou San”. It is a commonly selected combination of medicinal herbs for the treatment of cough with lung heat. Both drugs are derived from Trichosanthes kirilowii Maxim, a medicinal plant known for its ability to clear heat, resolve phlegm, produce saliva, and alleviate dryness. However, the optimal combination ratio and active ingredients of TP-TR have yet to be determined. Aim of the study This study aims to investigate the optimal combination ratio of TP-TR and its anti-inflammatory active ingredients in cough treatment. Materials and methods A zebrafish ( Danio rerio ) inflammatory injury model and response surface method were applied in the present study to determine the appropriate proportion of TP-TR. Chemical constituents in TP-TR were identified using HPLC-ELSD and UPLC-MS/MS methods. Subsequently, a cough mouse model was created using an ammonia solution to evaluate the effectiveness of the optimal TP-TR ratio. Network pharmacology and intestinal flora sequencing were used to validate the anti-inflammatory components of TP-TR. Results The herbal pair of TP - TR at the ratio of 1:2 showed an optimal anti-inflammatory effect, with a composite inflammatory factor score of 119.645 in the zebrafish experiment. TP-TR combination facilitated the dissolution of glutamine, inosine , cytosine , isoquercetin , and other substances. In the animal model, the TP-TR (1:2) treatment significantly reduced the frequency of coughs and prolonged cough latency compared to the model group. Results of the network pharmacology indicated that inflammatory-related factors such as TLR4 , STAT3, EGFR, and AKT1 played crucial roles in cough treatment with TP-TR, consistent with the validation experiment. The 16s rDNA sequencing results revealed a significant increase in the abundance of Clostridia_UCG-014, Lachnospiraceae , Christenella, Ruminococcus , and other species in the intestinal tract of mice after modelling. TP-TR (1:2) reduced the abundance of pro-inflammatory flora such as Clostridium_UCG-014 and Lachnospira , which were closely associated with L-lysine and trans-4-hydroxy-L-proline present in TP-TR according to correlation analysis. Conclusion TP-TR may promote the dissolution of glutamine, thymidine , inosine, cytosine, isoquercetin, and other components through their combination, thereby regulating the abundance of Clostridium_UCG-014 and Lachnospira and exerting an antitussive effect. This study, for the first time, showed that TP-TR at a 1:2 ratio exhibits superior anti-inflammatory effects. In addition to inflammatory mediators like EGFR, TLR4, AKT1, and STAT3, gut microbes could also serve as potential regulatory targets of TP-TR in the treatment of cough. 2'-Deoxyguanosine monohydrate, L-lysine, L-leucine, γ-aminobutyric acid, L-valine, L-tryptophan, L-proline, trans-4-hydroxy-L-proline, L-methionine, uridine , 2'-deoxyinosine, guanosine , cucurbitacin B and cucurbitacin D were identified as its anti-inflammatory active ingredients.
研究领域:
药理学
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民族药理学
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炎症
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中药
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动物模型
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网络药理学
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微生物组
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD COMPOSITION AND ANALYSIS
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2026
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IF 5.3
Huan Liu,Liying Liang,Minggang Wang,Qinfeng Huang,Yu Pan,Xiaojie Wei,Wenchao Zhang
The naturally occurring pentacyclic triterpenoid compounds ursolic acid (UA) and oleanolic acid (OA) are commonly found together in various fruits and find broad applications in pharmaceuticals, cosmetics, food and agricultural fields. In this study, a sensitive and practical icELISA method was developed based on a monoclonal antibody (mAb) YC23-101, with a median inhibitory concentration (IC 50 ) of 15.56 ng/mL and a linear range of 5.26 to 54.1 ng/mL. The limits of detection (LOD) ranges from 0.98-5.11 ng/mL in fruit matrices and the recoveries were 94.03-112.21% with coefficients of variation below 5.73%. Cross-reactivity analysis showed that mAb YC23-101 could also specifically recognize OA with similar sensitivity to UA, indicating feasibility for the simultaneously quantification of UA and OA in fruits. The developed icELISA was applied to several fruits, and the results showed good correlation with that of HPLC. Molecular docking analysis predicted equal binding energy of UA and OA to the mAb with hydrophobic interactions playing a predominant role. All these findings demonstrated that this icELISA is reliable, sensitive, and suitable for the high-throughput quantification of total UA and OA content in fruits composition analysis.
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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）