BIOMEDICAL CHROMATOGRAPHY
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2021
·Vol. 35
·期 10
·e5172
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IF 1.902
Cancan Duan,Weina Cheng,Qihong Chen,Xiaofei Li,Jianyong Zhang
A sensitive gas chromatography–mass spectroscopy method was established for the determination of cantharidin (CTD) in rat plasma and liver homogenates. During the experiment, rats were randomly divided into two groups (low, high) and were administered aqueous extract of Mylabris compound for 7 days. Then, plasma and tissue samples were taken at different time points to study the pharmacokinetics and tissue distribution of CTD in rats. The selected reaction monitoring transitions for CTD and clofibrate (internal standard) were m / z 128 → 85 and m / z 169 → 141, respectively. The calibration curve ranged from 10.26 to 3,078 ng/ml for plasma and from 10.26 to 246.24 ng/ml for liver homogenates. The lower limits of quantification were 10.26 ng/ml for both plasma and liver. The intra- and inter-day precision and accuracy were <20% for both plasma and liver homogenates. Extraction recovery ranged from 89.21 to 103.61% for CTD in rat plasma and liver and from 83.79 to 102.74% for IS in rat plasma and liver. Matrix effects ranged from 93.06 to 110.44% for CTD and from 91.65 to 110.80% for IS.
研究领域:
药理学
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分析化学
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毒理学
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PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 40
·期 11
·1526-1533
·
IF 2.997
Yalei Yu,Youyou Zhang,Jie Zhang,Chuhuai Guan,Liang Liu,Liang Ren
Cantharidin is of high medicinal value but has strong toxicity. Nowadays, multiple research has focused on the mechanism of its antitumor activity while research on toxicological profiles associated with cantharidin poisoning is still limited. Its hepatotoxicity has attracted attention recently for the crucial role of the liver in detoxification. Here, we aim to find a potential mechanism for cantharidin-induced acute hepatotoxicity with a view to assisting subsequent research or clinical use or detoxification. Twenty-one male Sprague-Dawley rats were randomly divided into control, low-dose (1.34 mg/kg) and high-dose (2.67 mg/kg) cantharidin exposure groups. We used hematoxylin-eosin to observe pathological changes and used immunofluorescent staining, western blotting and real-time quantitative polymerase chain reaction to detect the expression of the markers. The main pathological changes in livers of cantharidin-treated rats were necrosis, inflammatory infiltration and hemorrhage. We found coexpression of tumor necrosis factor alpha (TNF-α), IkappaB kinase-alpha (IKK-α) and caspase3 by immunofluorescent staining in livers of cantharidin-treated rats. Compared with the control, the levels of TNF-α, IKK-α and caspase3 increased significantly in the experimental groups ( P < .05). The ratio of B-cell lymphoma-2 (Bcl-2)/Bax increased in the low-dose group but decreased in the high-dose group ( P < .05). Cantharidin exposure raised IKK-α mRNA and caspase3 mRNA levels ( P < .05). In conclusion, the participation of TNF-α, IKK-α, Bcl-2, Bax and caspase3 uncovered a novel mechanism underlying cantharidin-induced acute hepatotoxicity, and the mechanism needs to be studied further.
研究领域:
药理学
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毒理学
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分子生物学
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PubMed
高影响因子
ENZYME AND MICROBIAL TECHNOLOGY
·
2014
·
IF 2.966
Xue-Qing Yang,Ya-Lin Zhang
Glutathione S -transferases (GSTs) play a key role in detoxification of xenobiotics in organisms. However, their other functions, especially response to the natural toxin cantharidin produced by beetles in the Meloidae and Oedemeridae families, are less known. We obtained GST cDNAs from three sources: Cydia pomonella ( CpGSTd1 ), Sus scrofa ( SsGSTα1 ), and Triticum aestivum ( TaGSTf3 ). The predicted molecular mass is 24.19, 25.28 and 24.49 kDa, respectively. These proteins contain typical N-terminal and C-terminal domains. Recombinant GSTs were heterologously expressed in Escherichia coli as soluble fusion proteins. Their optimal activities are exhibited at pH 7.0–7.5 at 30 °C. Activity of CpGSTd1 is strongly inhibited by cantharidin and cantharidic acid, but is only slightly suppressed by the demethylated analog of cantharidin and cantharidic acid. Enzymatic assays revealed that cantharidin has no effect on SsGSTα1 activity, while it significantly stimulates TaGSTf3 activity, with an EC 50 value of 0.3852 mM. Activities of these proteins are potently inhibited by the known GST competitive inhibitor: S -hexylglutathione (GTX). Our results suggest that these GSTs from different sources share similar structural and biochemical characteristics. Our results also suggest that CpGSTd1 might act as a binding protein with cantharidin and its analogs.
研究领域:
生物化学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2026
·
IF 5.2
Ziyi Zhong,Aiqiu Wei,Yiming Zhang,Jincheng He,Haihe Pang,Xinhua Xia,Xiaoqing Zhang
Hepatocellular carcinoma (HCC) exhibits limited response to monotherapy owing to its complex signalling pathways and high heterogeneity. Combination therapy is therefore a promising strategy to improve HCC treatment. This study constructed folate (FA)-modified cantharidin (CTD) and staurosporine (STS) co-loaded targeted nanoliposomes (FA/CTD-STS/NLP) for multi-target synergistic therapy of HCC. The optimal CTD: STS mass concentration ratio was determined to be 588:1 using the Chou-Talalay method, and DSPE-PEG2000-FA functionalized nanoliposomes were prepared via a combined thin-film dispersion and embedding technique. The prepared FA/CTD-STS/NLP exhibited spherical morphology with a particle size of 116.4 nm, a PDI of 0.228, and high encapsulation efficiencies (90.1% for CTD, 93.4% for STS), along with good stability during storage and in serum. In vitro studies demonstrated that FA/CTD-STS/NLP enters H22 cells via folate receptor (FR)-mediated endocytosis, significantly inhibiting cell proliferation and promoting apoptosis. In the H22 tumor-bearing mouse model, FA/CTD-STS/NLP demonstrated enhanced tumor accumulation, achieving an 83.24% tumor inhibition rate even at reduced doses, with minimal systemic toxicity. Mechanistic studies indicate that FA/CTD-STS/NLP synergistically inhibit key target proteins in the mTOR/HIF-1α/VEGF signaling pathway, increase the Bax/Bcl-2 ratio to activate the mitochondrial apoptosis pathway, and upregulate CD4 and CD8 expression in tumor tissues, suggesting a potential immunomodulatory effect. This study developed FA/CTD-STS/NLP co-delivery system for the first time, achieving efficient tumor-targeted delivery through optimized drug combination ratio. It coordinately regulated the mTOR/HIF-1α/VEGF signaling pathway and the tumor immune microenvironment, providing a novel strategy for efficient and low-toxicity treatment of HCC.
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高影响因子
ACS Omega
·
2024
·
IF 3.7
Xiaotong Duan,Jingwen Ao,Ming Yu,Sali Li,Xiaofei Li,Jianyong Zhang
Cantharidin (CTD) is a compound of mylabris with antitumor activity, and CTD can potentially cause toxicity, especially hepatotoxicity. The classical Traditional Chinese Medicine prescription Shuganning injection (SGNI) exerts notable anti-inflammatory and hepatoprotective effects. However, the protective property and mechanism of SGNI against CTD-induced liver injury (CTD-DILI) have not yet been elucidated. To investigate the effective compounds, potential targets, and molecular mechanism of SGNI against CTD-DILI, network pharmacology combined with experiments were performed. This study found that SGNI could act with 62 core therapeutic targets, regulate multiple biological processes such as apoptosis, and oxidative stress, and influence apoptotic and p53 signaling pathways to treat CTD-DILI. Subsequently, HepaRG cell experiments demonstrated that SGNI pretreatment significantly increased the levels of GSH-Px and SOD, inhibiting the apoptosis induced by CTD. In vivo, according to H&E staining, SGNI can reduce the degeneration of hepatocytes and cytoplasmic vacuolation in mice exposed to CTD. Western blot analysis results indicated that SGNI pretreatment significantly suppressed the expressions of Caspase-3 and Bax while increasing the expression of Bcl-2. In conclusion, SGNI acted as a protective agent against CTD-DILI by inhibiting apoptosis.
研究领域:
药理学
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毒理学
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中药学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY
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2022
·
IF 6.76
Jiang Ling,Wenqi Zhang,Zijia Cheng,Yanjun Ding
Cantharidin (CTD), an effective component of Chinese herbal medicine with unique efficacy, caused poisoning or death constantly for incorrect use. Therefore, there is an intense need for a reliable, selective, sensitive and low-costing analytical method for monitoring the concentration of CTD in biological samples. In this work, a ratiometric fluorescent sensor (CdTe@MIPs/CDs@NIPs) was successfully constructed for selective determination of CTD by simply integrated the non-imprinted polymers coated CDs (CDs@NIPs) with cadmium telluride quantum dots coated with molecular imprinted polymers (CdTe@MIPs). CDs@NIPs were directly used as reference signal without addition of CTD templates and the as-prepared CdTe@MIPs were response signal. With the CTD addition, the fluorescence intensity of CdTe@MIPs decreased, while the fluorescence of CDs@NIPs remained approximately unchanged, resulting a detection limit as low as 0.15 nM. By spiked human blood samples, the ratiometric sensor was successfully applied to CTD detection with good recoveries of 96.12–107.40% and relative standard deviation (RSD) of 2.87–3.96%. Moreover, after centrifuging and re-eluting, the developed sensor could be effectively recycled and reused five times. Significantly, the proposed platform with low-cost and high-sensitivity opens a door towards the practical applications of ratiometric sensor and shows immense potential in pursuing the sensitive, reliable and low-cost determination of poisons in forensic toxicology analysis.
研究领域:
分析化学
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毒理学
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生物医学工程
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高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2016
·Vol. 13
·期 1
·287-296
·
IF 5.671
Xi Yang,Jun Tong,Liemei Guo,Zhongrun Qian,Qixian Chen,Ruogu Qi,Yongming Qiu
Neuroblastoma (NB) is one of the most commonly seen malignancies in childhood and infancy. Cantharidin is a highly potent natural toxin that possesses potent anti-tumor properties on various cancers including NB. However, exposure to cantharidin can cause severe chemical burns and application of cantharidin for cancer therapy is limited. Here we report a strategy of bundling cantharidin within a hybrid platinum (IV) prodrug conjugate. This hydrophobic drug conjugate , ie, CanPt can be further formulated into liposome for drug delivery to minimize the exposure of cantharidin to normal cells for efficient chemotherapeutic agent against NB.
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DOI
高影响因子
BIOORGANIC CHEMISTRY
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2026
·
IF 5.1
Yinyue Wang,Ruyi Zhang,Yangjiao Xu,Hongtao Shi,Xueyao Hu,Nairong Yu,Yu-Qiang Zhao,Baomin Fan,Guangzhi Zeng
NCTD-01 shows anti-inflammatory and cytotoxic effects in vitro and in vivo. • NCTD-01 exhibits low in vivo toxicity and a high oral MTD. • NCTD-01 suppresses AOM/DSS-induced colorectal cancer safely in mice. • NCTD-01 limits inflammation-to-cancer transition via NF-κB and Treg regulation. Although cantharidin (CTD) exhibits significant clinical efficacy against various cancers, its clinical utility is severely hampered by profound systemic toxicity. Thus, structural modification of CTD to obtain analogues with potent anticancer activity and lower toxicity is essential for advancing CTD-based therapeutics. Building on our previous synthesis of a series of C-5 alkynyl-substituted CTD analogues with potent anti-inflammatory properties, this study investigates the anticancer potential of a new analogue NCTD-01 demonstrated a favorable safety profile in mice, with the maximum tolerated dose (MTD) for oral administration exceeding 1852 mg/kg. In addition to exhibiting potent in vitro and in vivo anti-inflammatory activities comparable to its analogues, NCTD-01 displayed cytotoxicity against colon cancer cell lines and exhibited therapeutic efficacy in an azoxymethane/dextran sulfate sodium-induced orthotopic mouse model of colorectal cancer. Molecular analyses revealed that NCTD-01 reduced Ki-67 expression, suppressed the mRNA levels of pro-inflammatory and immunosuppressive mediators ( IL-1β , COX-2 , IL-6 , IL-10 , and TGF-β ) in colonic tumor tissues, and decreased serum levels of TNF-α and IL-1β. Furthermore, NCTD-01 treatment led to reduced expression of Foxp3, CD25, PD-1, and PD-L1, alongside enhanced CD8 and GITR expression in colorectal tissues, suggesting an effective modulation of tumor-associated immune responses. This study suggests that NCTD-01, a new C-5 alkynyl-substituted CTD analogue, may help alleviate the inflammation-to-cancer transition through tumor-associated immune modulation while maintaining a favorable safety profile, pointing to its potential as a candidate for anticancer drug discovery. Download: Download high-res image (99KB) Download: Download full-size image
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DOI
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2024
·
IF 2.7
Weina Cheng,Wenzhong Feng,Guanghuan Tian,Jingxian Liu,Zhixun Ba,Ming Yu,Rong Yan,Liu Liu,Yanmei He,Xiaofei Li,Jianyong Zhang
The clinical application of cantharidin (CTD) is seriously limited due to its nephrotoxicity. Therefore, this study aims to investigate sensitive biomarkers for the evaluation and prediction of nephrotoxicity induced by CTD in rat. A total of 80 rats were randomly divided into four groups: control group and three doses of CTD groups. After 0, 1, 5, 15, and 28 days of intragastric administration, rat serum and urine were collected for biochemical indexes, then serum was used for metabolomic analyses, and rat kidney was collected for pathological and ultrastructural observation. The levels of serum crea (Scr), blood urea nitrogen (BUN), urea, urine crea (Ucrea), and urinary microalbumin (UmALB) were significantly increased after administration of different doses of CTD ( p < 0.05). Additionally, histopathology and cell ultrastructure observation of kidney showed significant cell inflammatory infiltration and glomerular edema. Seven metabolic biomarkers including 6-hydroxymelatonin were significantly disturbed by CTD. The CatBoost Classifier prediction model was used to establish the CTD nephrotoxicity prediction model, and the prediction accuracy and precision were 0.645 and 0.640, respectively. Moreover, 6-hydroxymelatonin was found to be most useful biomarkers for evaluating the CTD nephrotoxicity. Finally, the seven metabolic biomarkers were found mainly involved in pyruvate metabolism, pantothenate and CoA biosynthesis.
研究领域:
药理学
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毒理学
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代谢组学
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动物模型研究
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
·
IF 3.3
Ruxia Liu,Changfu Yang,Xin Yang,Jia Yu,Wenchao Tang
As a protein kinase inhibitor , cantharidin (CTD) exhibits antitumor activities . However, CTD is highly toxic, thereby limiting clinical applications. Moreover, relatively few studies have investigated CTD-induced reproductive toxicity , thus the underlying mechanism remains unclear. In this study, the toxic effects of CTD on mouse testis were confirmed in vivo and the potential mechanism was predicted by network toxicology (NT) and molecular docking technology. Proteins involved in the signaling pathways and core targets were verified. The results showed that different concentrations of CTD induced weight loss increased the testicular coefficient, and caused obvious pathological damage to testicular cells. The NT results showed that the main targets of CTD-induced testicular injury (TI) included AKT1, Caspase 3 , Bcl-2, and Bax. The results of pathway enrichment analysis showed that CTD-induced TI was closely related to apoptosis and the PI3K/AKT and HIF-1 signaling pathways. Molecular docking methods confirmed high affinity between CTD and key targets. Western blot analysis showed that CTD inhibited expression of PI3K, AKT, and the anti-apoptotic protein Bcl-2, while promoting expression of the pro-apoptotic proteins Bax and Caspase 3. These results suggest that CTD-induced TI involves multiple targets and pathways, and the underlying mechanism was associated with inhibition of the apoptosis-related PI3K/AKT signaling pathway.
研究领域:
药理学
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生殖生物学
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分子生物学
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DOI
PubMed
高影响因子
Scientific Reports
·
2020
·Vol. 10
·期 1
·1-9
·
IF 3.998
Zhang Youyou,Yu Yalei,Zhang Jie,Guan Chuhuai,Liu Liang,Ren Liang
Postmortem diagnosis of cantharidin-induced myocardial injury and postmortem interval estimation (PMI) are the challenges in forensic science. Cardiac biomarkers play an important role in the prediction and diagnosis of myocardial injury and can be used to determine the PMI. Based on the evidence, we aimed to explore the biomarkers which may be used for the postmortem diagnosis of cantharidin-induced myocardial injury and PMI estimation using the study of the proteins expression of TN-T, VEGF and HIF-1α by ELISA. Results of this study suggested that postmortem pathological changes were difficult to identify due to the autolysis of myocardium 72 h after death in cantharidin poisoning group. The plasma levels of TN-T and HIF-1α/TN-T are cardiac biomarkers with higher diagnostic accuracy for postmortem diagnosis of cantharidin-induced myocardial injury, VEGF/HIF-1α promises to be a biomarker for PMI estimation. Further studies are needed to verify these biomarkers, based on population, for being a useful tool in postmortem diagnosis of cantharidin-induced myocardial injury and PMI estimation.
研究领域:
法医学
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病理学
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毒理学
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2020
·
IF 7.242
Zhaoming Guo,Ye Liu,Xiao Cheng,Dong Wang,Shubin Guo,Mingli Jia,Kun Ma,Changhao Cui,Li Wang,Hao Zhou
The heat shock response (HSR) induced by photothermal therapy (PTT), which can cause tumor cells to resist apoptosis, has increasingly attracted the attention of researchers. Synergistic treatment of tumors using multiple means to improve therapeutic efficiency would be a promising strategy for effective cancer treatment. In this study, a cancer cell membrane-camouflaged nanocarrier was developed and loaded with tellurium (Te) and cantharidin (CTD) for efficient combinatorial therapy. The designed nanoparticles ( [email protected] ) used a 4T1 cell membrane coating as the shell with homologous targeting capability, CTD as an the HSR inhibitor and antitumor drug, and Te as a PTT and photodynamic therapy (PDT) photosensitizer . An in vivo study indicated that the tumor inhibition rate of this combinatorial therapy could reach approximately 82.3% in 4T1 mammary tumor models. This study suggested that [email protected] , as a versatile biomimetic nanoplatform, provides a new alternative for more precise and effective tumor treatment. Statement of significance In this work, we constructed cell membrane-coated biomimetic nanoparticles ( [email protected] ) to suppress cancer effectively through synergistic treatment. The developed [email protected] nanoparticles presented strong homologous targeting capabilities. The encapsulated Te triggered PDT and PPT under the near-infrared laser irradiation. Subsequently, the PTT triggered the release of CTD, which could suppress the HSR of tumor and achieve chemotherapy. In addition, due to the presence of outer cell membrane coating, these [email protected] nanoparticles showed good biocompatibility to healthy cells.
研究领域:
纳米技术
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癌症治疗
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生物医学工程
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药学
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产品关联
DOI
PubMed
高影响因子
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