Journal of Inflammation Research
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2024
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IF 4.2
Fengxia Zhan,Wei Song,Yong Fan,Fangjian Wang,Qian Wang
Purpose Cucurbitacins, which are found in a variety of medicinal plants, vegetables and fruits, were known for their diverse pharmacological and biological activities, including anticancer, anti-oxidative and anti-inflammatory effects. Cucurbitacin E, one of the major cucurbitacins, was recently proved to inhibit inflammatory response.Methods To explore the therapeutic effects of cucurbitacin E on colitis and the underlying mechanisms, male mice drunk water containing 2.5% dextran sulfate sodium (DSS) to establish colitis model and administrated with cucurbitacin E during and after DSS treatment. The disease activity index was scored and colonic histological damage was observed. Intestinal tight junction and inflammatory response were determined. 16S rRNA and transcriptome sequencing were performed to analyze gut microbiota composition and gene expression, respectively.Results We found that cucurbitacin E alleviated DSS-induced body weight loss and impaired colonic morphology. Cucurbitacin E decreased the expression of inflammatory cytokines and cell apoptosis, and maintained barrier function. Additionally, cucurbitacin E retrieved DSS-induced alterations in the bacterial community composition. Furthermore, a variety of differentially expressed genes (DEGs) caused by cucurbitacin E were enriched in several pathways including the NFκB and TNF signaling pathways as well as in Th17 cell differentiation. There was a close relationship between DEGs and bacteria such as Escherichia-Shigella and Muribaculaceae.Conclusion Our results revealed that cucurbitacin E may exert protective effects on colitis via modulating inflammatory response, microbiota composition and host gene expression. Our study supports the therapeutic potential of cucurbitacin E in colitis and indicates that gut microbes are potentially therapeutic targets.
研究领域:
药理学
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免疫学
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微生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF ONCOLOGY
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2024
·Vol. 64
·期 4
·1-12
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IF 4.5
Sujuan Li,Sen Wang,Anping Zhang,Lixia Luo,Jie Song,Guoli Wei,Zhijun Fang
The immunogenic cell death (ICD) has aroused great interest in cancer immunotherapy. Doxorubicin (DOX), which can induce ICD, is a widely used chemotherapeutic drug in liver cancer. However, DOX‑induced ICD is not potent enough to initiate a satisfactory immune response. Cucurbitacin IIa (CUIIa), a tetracyclic triterpene, is a biologically active compound present in the Cucurbitaceae family. The present study assessed the effects of the combination of DOX and CUIIa on the viability, colony formation, apoptosis and cell cycle of HepG2 cells. In vivo anticancer effect was performed in mice bearing H22 tumor xenografts. The hallmark expression of ICD was tested using immunofluorescence and an ATP assay kit. The immune microenvironment was analyzed using flow cytometry. The combination of CUIIa and DOX displayed potent apoptosis inducing, cell cycle arresting and in vivo anticancer effects, along with attenuated cardiotoxicity in H22 mice. The combination of DOX and CUIIa also facilitated ICD as manifested by elevated high‑mobility group box 1, calreticulin and ATP secretion. This combination provoked a stronger immune response in H22 mice, including dendritic cell activation, increment of cytotoxic T cells and T helper 1 cells. Moreover, the proportion of immunosuppressive cells including myeloid‑derived suppressor cells, T regulatory cells and M2‑polarized macrophages, decreased. These data suggested that CUIIa is a promising combination partner with DOX for liver cancer treatment, probably via triggering ICD and remolding the immune microenvironment.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
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
MOLECULES
·
2022
·Vol. 27
·期 16
·5350
·
IF 4.927
Lili Chen,Yunyun Liu,Yifei Li,Wu Yin,Yongxian Cheng
Two new guaiane sesquiterpenes, aquisinenoids A and B (1and2), two new eudesmane-type sesquiterpenoids, aquisinenoids C and D (3and4), one new cucurbitacin, aquisinenoid E (5), and five known cucurbitacins (6–10) were isolated from agarwood ofAquilaria sinensis. The structures of these new compounds, including their absolute configurations, were characterized by spectroscopic and computational methods. The biological evaluation showed that compounds3and9had an anti-cancer effect on most of the cancer cells at 5 μM, especially in human breast cancer cells. Interestingly, the new compound3exhibited more sensitivity on cancer cells than normal cells, highlighting its potential as a novel anti-cancer agent. Mechanically, compound3treatment increased the ROS generation and triggered apoptosis of human breast cancer cells.Keywords:Aquilaria sinensis;agarwood;sesquiterpenes;cucurbitacins;anti-cancer
研究领域:
药理学
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化学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2025
·
IF 4.1
Yinyin Zhao,Binyuan Jiang,Shengnan Zuo
Purpose Cucurbitacins have demonstrated anti-inflammatory effects and show promise for inflammatory bowel diseases. However, the underlying mechanisms by which cucurbitacins affect colitis remain largely unknown.Methods In this study, we investigated the impact of cucurbitacin IIa on dextran sulfate sodium (DSS)-induced colitis in rats and the alterations in intestinal extracellular vesicles (EVs). EVs were isolated and characterized, followed by analysis of the small RNAs and proteins encapsulated within them using small RNA sequencing and proteomics, respectively.Results Our results revealed that cucurbitacin IIa alleviated colitis symptoms in DSS-treated rats, along with changes in the morphology and composition of intestinal EVs. Notably, EVs from cucurbitacin IIa-treated rats also mitigated colitis symptoms in DSS-treated rats. Further analysis showed that cucurbitacin IIa modified the protein profiles and microRNA composition of EVs extracted from the feces of colitis rats. Specifically, microRNA-30b-5p, significantly increased by cucurbitacin IIa, was found to alleviate colitis symptoms in DSS-treated rats. In conclusion, cucurbitacin IIa appears to alleviate colitis by promoting the release of microRNA-30b-5p from host-derived extracellular vesicles.Conclusion These findings enhance our understanding of cucurbitacin IIa’s effects on intestinal health and offer potential new therapeutic targets for inflammatory bowel disease treatment.
研究领域:
药理学
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胃肠病学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Orthopaedic Translation
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2021
·
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
FOOD AND CHEMICAL TOXICOLOGY
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2019
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IF 3.775
Jie Zhang,Yifan Song,Yuan Liang,Haoyang Zou,Peng Zuo,Mi Yan,Siyuan Jing,Tiezhu Li,Yongjun Wang,Da Li,Tiehua Zhang,Zhengyi Wei
Cucurbitacin IIa (CuIIa), a tetracyclic triterpenoid harboring anticancer activity, was investigated in A549 cells to reveal its mechanism of targeting on epidermal growth factor receptor (EGFR) signaling pathway. Results showed that CuIIa was capable of inducing apoptosis and cell cycle arrest at G2/M phase. The transcription of EGFR pathway genes and their proteins accumulation was inconsistently influenced by CuIIa. Notably, transcription of Raf1 was significantly upregulated, nevertheless, MEK1 and ERK1 were significantly downregulated. On the other hand, the accumulation of the total and phosphorylated proteins of the most members in EGFR-mitogen-activated protein kinase (MAPK) pathway, as well as CylclinB1 and survivin were also shifted by CuIIa treatment. Remarkably, total MEK remained constant but survivin completely degraded. Moreover, phosphorylated BRAF continuously increased while Raf1 and MEK decreased continuously. CuIIa was further confirmed to be a tyrosine kinase inhibitor (TKI) of EGFR by kinase inhibition assay. The results of molecular simulation showed that the long side chain of CuIIa occupied the binding pocket of EGFR and the ligand was stabilized at the active site of EGFR. In view of the results above, it is suggested that CuIIa inhibits cell proliferation by interfering the EGFR-MAPK signaling pathway.
研究领域:
肿瘤学
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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
JOURNAL OF SEPARATION SCIENCE
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2021
·Vol. 44
·期 7
·1361-1370
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IF 3.645
Yan Chen,Xiao-Ting Zhen,Ya-Ling Yu,Min-Zhen Shi,Jun Cao,Hui Zheng,Li-Hong Ye
A rapid, efficient, and environmentally friendly matrix solid-phase dispersion microextraction was established to determine and quantify terpenoids in Radix Curcumae using ultra-high-performance liquid chromatography with a diode array detector. Various parameters affecting the extraction were investigated in detail, such as the grinding time, amount of adsorbent, type and concentration of elution solvent, and pH. The optimization of single-factor and response surface methodology was performed to confirm the best conditions in this procedure. The final optimized conditions were obtained by applying 70 mg of cucurbituril as adsorbent, 149 s as the optimum grinding time, and 228 mM of 3-(N,N-dimethylpalmitylammonio)propanesulfonate aqueous solution (pH 6.5) as the optimal elution solvent. The validated method showed a satisfactory linear range of 0.10–10 µg/mL for curdione and furanodiene, 0.01–10 µg/mL for isocurcumenol and germacrone, and 0.05–10 µg/mL for furanodienone, while the correlation coefficients ranged from 0.9945 to 0.9970. The recoveries of the investigated analytes at two spiked concentration levels (0.1 and 1.0 µg/mL) ranged from 96.53 to 104.60%. In addition, this method displayed acceptable reproducibility (relative standard deviation ≤ 3.66%). The results showed that the newly proposed matrix solid-phase dispersion microextraction method was successfully applied to analyze curdione, isocurcumenol, furanodienone, germacrone and furanodiene in Radix Curcumae samples.
研究领域:
分析化学
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药物分析
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天然产物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
·
IF 6.51
Qin Shi,Yuqing Tong,Yuzhao Zheng,Yanqi Liu,Tingjie Yin
The heterogeneity of tumor microenvironment leads to uneven distribution of bio-stimuli. Thus, the multi-site delivery efficiency of responsive drug delivery systems (DDS) inner tumor was always limited. Herein, we proposed a combination strategy of photodynamic therapy (PDT) with ROS-responsive nanosystem which was constructed from dextran-phenylboronic acid pinacol ester conjugates. This combination utilized PDT to amplify and homogenize tissular oxidation level, and achieve effective multi-site response and release of multi-target drugs like gambogic acid (GA). Our research demonstrated the successful preparation of GA and protoporphyrin IX (PpIX) co-loaded nanoparticles, and the PDT-mediated spatiotemporal controlled multi-site drug release in simulated conditions. Furthermore, data from in vitro and in vivo researches on B16F10 cells, HUVEC, and B16F10-bearing C57BL/6 mice potently confirmed the enhanced multi-mechanism regulations of GA mediated by the effective and homogeneous tumoral release. This tactic based on bio-stimuli amplification and homogenization proposes a paradigm to maximize the potency of multi-target drugs.
研究领域:
癌症治疗
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纳米医学
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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
Heliyon
·
2024
·
IF 3.4
Yinyin Zhao,Kangxiao Guo,Yongwang Yan,Binyuan Jiang
Cucurbitacin IIb, a member of the triterpenoid family, exerts beneficial effects on intestinal diseases, including enteritis and bacillary dysentery. However, its effects and mechanisms of action on colitis have not yet been explored. In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis and explored the effects of cucurbitacin IIb on colitis symptoms, inflammatory responses, microbiota, and metabolite profiles. The results showed that cucurbitacin IIb alleviated colitis symptoms including body weight loss, an increase in the disease activity index, and elevated levels of myeloperoxidase and eosinophil peroxidase content. Additionally, it ameliorated intestinal morphology impairment, reduced the phosphorylation of NFκB protein, and mitigated accumulation of pro-inflammatory cytokines IL-6 and IL-1β. Furthermore, cucurbitacin IIb alleviated alterations in gut microbial composition and metabolites in DSS-treated mice. However, antibiotic treatment diminishes the beneficial effects of cucurbitacin IIb on colitis. We further found that transplantation of fresh feces or heat-inactivated feces from mice treated with cucurbitacin IIb to DSS-treated mice alleviated colitis, similar to the effects of cucurbitacin IIb. Collectively, our results suggest that cucurbitacin IIb exerted anti-inflammatory effects in colitis by regulating the microbiota composition and metabolites, thereby alleviating colitis symptoms.
研究领域:
胃肠病学
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免疫学
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微生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
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
BIOMATERIALS
·
2020
·
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
·
癌症生物学
·
药学
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生物医学工程
✓ 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）