Scientific Reports
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2020
·Vol. 10
·期 1
·1-8
·
IF 3.998
Zhang Youyou,Liu Liang,Ren Liang
A rapid, sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination and quantification of cantharidin in rats liver and kidney. After grinding with methanol, the supernatant was determined by LC-MS/MS using an Thermo Accucore C18 column (100 mm×2.1 mm, 2.6 μm) with a gradient elution of 0.1% formic acid and 0.1% acetonitrile, and in the subsequent analysis using selected reaction monitoring mode, three ion transitions were monitored for analyte. The limit of detection (LOD) was 0.741 ng/ml and the limit of quantitation (LOQ) was 2.471 ng/ml. Good linearity (R 2 = 0.9998) was observed for the analyte over the linear range (5–400 ng/ml). The LC-MS/MS method was applied to the analysis of rats liver and kidney in different postmortem intervals (6 h, 12 h, 24 h, 48 h, 72 h and 168 h after death) after a single dose (4 mg/kg) of cantharidin administration by gavage. At 72 h after death, the cantharidin concentration in livers and kidneys were significantly higher than that in other postmortem intervals. Linear regression equations between postmortem interval and lg postmortem cantharidin concentration in rats liver and kidney were Y = 0.007455*X + 1.332(R 2 = 0.863) and Y = 0.002689*X + 1.433 (R 2 = 0.115) respectively. The animal experiment demonstrated LC-MS/MS method can be used to determine the postmortem cantharidin concentration in rats liver and kidney and the determination of cantharidin in the rats liver after death has potential value for postmortem interval estimation in cantharidin poisoning.
研究领域:
毒理学
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分析化学
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法医学
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DOI
PubMed
高影响因子
BMC BIOTECHNOLOGY
·
2019
·Vol. 19
·期 1
·1-11
·
IF 2.303
Zeng Liya,Liu Yongchang,Pan Jun,Liu Xiaowen
Background Norcantharidin (NCTD), a demethylated derivative of cantharidin (defensive toxin of blister beetles), has been reported to exhibit insecticidal activity against various types of agricultural pests. However, NCTD applications are limited by its poor water solubility and high dosage requirement. Nanoemulsions have attracted much attentions due to the transparent or translucence appearance, physical stability, high bioavailability and non-irritant in nature. In general, nanoemulsions with small droplet size can enhance the bioavailability of drugs, whereas this phenomenon is likely system dependent. In present study, NCTD nanoemulsions were developed and optimized to evaluate and improve the insecticidal activity of NCTD against Plutella xylostella (Lepidotera: Plutellidae) by a spontaneous emulsification method.Results Triacetin, Cremophor EL and butanol were selected as the constituents of NCTD nanoemulsions via solubility determination, emulsification efficiency and ternary phase diagram construction. Insecticidal activity of NCTD nanoemulsion was associated with the content of surfactant and cosurfactant: (1) Higher effective toxicity exhibited at Smix (surfactant to cosurfactant mass ratio) = 3:1 that may be associated with the changes in interfacial tension; (2) NCTD nanoemulsion at 3:7 < SOR (surfactant to oil mass ratio) < 6:4 was more effective at lower surfactant level, which was attributed to the relatively slow diffusion rate of NCTD hindering by excess surfactant. Interestingly, nanoemulsions with smaller droplets were not found to be more effective in our study.Conclusion sThe optimized NCTD nanoemulsion (triacetin/Cremophor EL/butanol (60/20/20, w/w)) exhibited effective insecticidal activity (LC50 60.414 mg/l, LC90 185.530 mg/l, 48 h) than the NCTD acetone solution (LC50 175.602 mg/L, LC90 303.050 mg/L, 48 h). Spontaneous emulsifying nanoemulsion employed to formulate this poor water-soluble pesticide is a potential system for agriculture application.
研究领域:
农业科学
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昆虫学
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药剂学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
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
TALANTA
·
2023
·
IF 6.1
Ying Sun,Qimeng Wu,Quanyou Fu,Hailin Cong,Youqing Shen,Bing Yu,Hao Hu
Combination chemotherapy is a common strategy to enhance treatment efficacy and avoid multidrug resistance (MDR) in clinical practice. However, it is difficult to ensure the co-enrichment and reasonable ratio of synergistic drugs in the lesion site after intravenous administration. Integrating synergistic drugs into a nanocarrier can improve drug stability, targeting, drug loading, and importantly, ensure that synergistic drugs work at one destination. This study uses 10-hydroxycamptothecin (HCPT) to construct a polymeric prodrug micelle , and the demethylcantharidin (DMC) is proportionally encapsulated within the micelle. Triggered by reactive oxygen species (ROS), HCPT and DMC were released simultaneously from the co-delivery platform in tumor cells. DMC promotes abnormal cell division by inhibiting the synthesis of the cell cycle checkpoint kinase Protein phosphatase 2A (PP2A), leading to increased cell vulnerability to DNA damage, disordered replication, and death. The co-delivery platform exhibited satisfactory biosafety and antitumor efficacy in vivo . The proposed co-delivery platform may provide a valuable reference for the translation of clinical combination chemotherapy regimens into nano-drug delivery systems.
研究领域:
药学
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肿瘤学
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纳米医学
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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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DOI
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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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
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
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2021
·
IF 3.963
Yifan Li,Hong Sun,Hassan Yasoob,Zhen Tian,Yue Li,Ruichi Li,Shengli Zheng,Jiyuan Liu,Yalin Zhang
Cantharidin (CTD) is a natural toxin with effective toxicity to lepidopteran pests. Nevertheless, little information is available on whether pests develop resistance to CTD. After being exposed to CTD (50 mg/L to 90 mg/L) or 10 generations, the resistance ratio of laboratory selected cantharidin-resistant Mythimna separata (Cantharidin-SEL) strain was only elevated 1.95-fold. Meanwhile, the developmental time for M. separata was prolonged (delayed1.65 in males and 1.84 days in females). The reported CTD target, the serine/threonine phosphatases (PSPs), have not been shown significant activity variation during the whole process of CTD-treatment. The activity of detoxification enzymes (cytochrome monooxygenase P450, glutathione-S-transferase (GST) and carboxylesterase) were affected by CTD selection, but this change was not mathematically significant. More importantly, no obvious cross-resistance with other commonly used insecticides was observed in the M. separata population treated with CTD for 10 generations (resistance ratios were all lower 2.5). Overall, M. separata is unlikely to produce target-site insensitivity resistance, metabolic resistance to CTD. Meanwhile, cantharidin-SEL is not prone to develop cross-resistance with other insecticides. These results indicate that CTD is a promising biogenetic lead compound which can be applied in the resistance management on M. separata .
研究领域:
昆虫学
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害虫管理
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毒理学
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2021
·Vol. 35
·期 10
·e5172
·
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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2013
·
IF 2.596
Xiaofen Xu,Yanggong Li,Yuanyuan Shen,Shengrong Guo
Norcantharidin-conjugated chitosan conjugates (NCTD-CSs) with different degrees of substitution ( DS , 60.2% and 97.9%) were synthesized and characterized by 1 H NMR, FT-IR, and XRD. In comparison with CS, the NCTD-CSs had lower crystallinity and better water solubility. Less than 6% NCTD was released from the NCTD-CSs through the hydrolysis of ester bonds in phosphate-buffered solution (PBS, pH 5.0 and 7.4) within 16 days, showing sustained drug release characteristic. The result of cytoxicity study showed that the NCTD-CSs were cytotoxic to MGC80-3 cells and their cytotoxicity was lower than that of NCTD. Fluorescence microscope and flow cytometry analysis demonstrated that the amount of the NCTD-CSs uptaken by MGC80-3 cells increased as incubation time. Confocal microscopy study showed that the NCTD-CSs were internalized into cells by endocytosis and mainly localized in lysosomes within 24 h. It was found that the NCTD-CSs arrested MGC80-3 cell cycle at G2/M phase and induced cell death via cell apoptosis similarly to NCTD. These results indicated that the NCTD-CSs might be an efficient NCTD delivery system for cancer therapy.
研究领域:
药学
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肿瘤学
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材料科学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Yihang Wu,Zixiu Liu,Zhenxiu He,Jumei Yi,Xingfang Qiao,Chunbin Tan,Yajing Xing,Yaobo Zeng,Dajian Yang,Junlin Yin,Baomin Fan,Guangzhi Zeng
Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα , and NF-κB p65 , and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.
研究领域:
药理学
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炎症
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药物发现
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 40
·期 8
·1153-1161
·
IF 2.997
Zhang Youyou,Yu Yalei,Zhang Jie,Guan Chuhuai,Liu Liang,Ren Liang
Early diagnosis of cantharidin-induced myocardial injury is the key to reduce the fatality rate in clinical practice. The purpose of the present study was to explore biomarkers that can be used for the prediction and diagnosis of cantharidin-induced myocardial injury. Of 65 male Sprague-Dawley rats weighing 200-230 g, 25 rats were divided into five groups according to the administration dose of cantharidin (0, 1.34, 2.67, 4 and 5.34 mg/kg; n = 5 per group) and the other 40 rats were treated with 2.67 mg/kg cantharidin and divided into nine groups according to the administration time (0, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours; n = 4 per group). Pathological changes of hypoxia, necrosis and inflammation were confirmed in heart samples that were exposed to cantharidin by hematoxylin-eosin staining and overall scores of pathological changes among heart samples in cantharidin exposure groups showed an increasing trend compared with in the control group. Coexpression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α) and caspase9 was shown in the myocardium by immunofluorescence staining. Western blotting results showed that expression of VEGF, HIF-1α and caspase9 in cantharidin-treated rat hearts showed an increasing trend compared with in the control group. Results of enzyme-linked immunosorbent assay suggested that plasma levels of troponin T (TN-T), VEGF and HIF-1α were elevated at different intervals after cantharidin administration, and VEGF and HIF-1α had a significant linear relationship with TN-T that was verified by multiple linear regression analysis. Preliminary results serve to illustrate that TN-T, VEGF and HIF-1α might be valuable molecular markers in cantharidin-induced myocardial injury and that diagnostic accuracy needs to be studied further.
研究领域:
毒理学
·
药理学
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心脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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