Camptotheca acuminata Decaisne is a tree unique to China, producing terpenoid indole alkaloid (TIA), camptothecin (CPT), and 10-hydroxycamptothecin (HCPT), which possesses strong anti-cancer bioactivity. The dynamics ...Camptotheca acuminata Decaisne is a tree unique to China, producing terpenoid indole alkaloid (TIA), camptothecin (CPT), and 10-hydroxycamptothecin (HCPT), which possesses strong anti-cancer bioactivity. The dynamics of HCPT and CPT during seed maturation, seed germination, postgerminative development and daily growth were measured by High Performance Liquid Chromatography (HPLC). This article provides some evidence for presenting the theory that each characteristic of HCPT and CPT accumulation is under developmental regulation and then attempt to elucidate the metabolic relationships between them. HCPT accumulates particularly in young tissues and organs and is relatively unstable, while the distribution of CPT is more ubiquitous and stable. Their different distribution properties suggest that HCPT and CPT are differentially regulated and play distinct roles:during development.展开更多
Plants interact with their environment by producing a diverse array of secondary metabolites, one of which is alkaloid. In this study, alkaloids, including camptothecin (CPT) and 10-hydroxycamptothecin (HCPT), malondi...Plants interact with their environment by producing a diverse array of secondary metabolites, one of which is alkaloid. In this study, alkaloids, including camptothecin (CPT) and 10-hydroxycamptothecin (HCPT), malondialdehyde (MDA) and chlorophyll contents were measured during heat shock in seedlings of Camptotheca acuminata Decaisne unique to China. Responses of different tissues, including young leaves, old leaves, buds and barks, to heat shock were examined in alkaloid changes. CPT and HCPT concentrations reached their peak values separately at 38 degreesC and 40 degreesC, which were below the lethal heat-shock temperature indicated by MDA and chlorophyll, and their great changes took place in young leaves. These results indicated that CPT and HCPT were involved in the C acuminata resistance against heat shock from its environment. Furthermore, plant rigidly observed the cost-benefit principle and mobilized and allocated limited alkaloid sources to young and reproductive tissues preferentially. In addition, HCPT displayed well-regulated changes during incubation at sublethal temperature, and this indicated that HCPT might play a more positively defensive role in enhancement of plant thermotolerance than CPT does.展开更多
Previous study has shown that 10-hydroxycamptothecin（HCPT） has well-established pharmacological effects in vitro.However,its in vivo bioavailability is very poor due to various problems,which severely restricts its ...Previous study has shown that 10-hydroxycamptothecin（HCPT） has well-established pharmacological effects in vitro.However,its in vivo bioavailability is very poor due to various problems,which severely restricts its clinical applications.In the present study,phospholipid complex（PC） technology was employed to improve the solubility and bioavailability of HCPT.XRD data confirmed the formation of HCPT-PC.However,our previously prepared HCPT-PC is too sticky,which may result in the slow dissolution rate and negative effects on its absorption.Therefore,we prepared HCPT-PC-solid dispersion（HCPT-PC-SD）and lipid-based formulations of HCPT-PC through simple preparation process.The results showed that the dissolution rate of HCPT-PC was effectively improved by solid dispersion technology,which reached 91.73%in 45 min.Pharmacokinetic study revealed that the AUC_（0-t） of HCPT-PC-SD and HCPT-PC lipid-based formulations was effectively further increased compared with HCPT-PC.Moreover,we found that the combination of SD technology and lipid-base formulations could be a promising drug-delivery system to improve the oral bioavailability of HCPT-PC.In addition,we showed that the bioavailability of HCPT-PC lipid-base formulations was even greater than that of HCPT-PC-SD.In particular,lipid-base formulations could be prepared just by a simple method,suggesting its feasibility of industrialization.展开更多
10-Hydroxycamptothecin （HCPT） is a broad-spectrum anticancer drug, while its low solubility and instability severely limit its application. In this study, HCPT nanosuspension （HCPT-NSP）, also known as nanocrystal,...10-Hydroxycamptothecin （HCPT） is a broad-spectrum anticancer drug, while its low solubility and instability severely limit its application. In this study, HCPT nanosuspension （HCPT-NSP）, also known as nanocrystal, was prepared by micro-precipitation combined with high-pressure homogenization method. This nanosuspension was characterized by size, shape, zeta potential, drug loading efficiency and in vitro drug release behavior. Preferred formulation and process showed that particle size was （129.8±13.9） nm, PDI was 0.20±0.07, and drug loading efficiency was 36.5%±9.5%. Moreover, HCPT nanocrystal concentration reached （1.35±0.2） mg/mL in HCPT-NSP, which was more than 1000-fold higher than that of HCPT. Transmission electron microscopy （TEM） results showed that the nanosuspension was short rod in shape. X-ray powder diffraction （XRD）, thermogravimetric analysis （TGA）, derivative thermogravimetric analysis （DTA） and differential scanning calorimetry （DSC） further elaborated the crystal state of the HCPT. The drug concentration-time curve of HCPT-NSP in rats was in accordance with the three-compartment model, showing prolonged half-life. Taken together, our data suggested that HCPT-NSP was a promising drug delivery system.展开更多
A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield ...A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.展开更多
The binding reaction between 10-hydroxycamptothecin （10-HCPT） and human serum albumins （HSA） is studied by means of fluorescence spectroscopy, UV-Vis absorption spectrum, IH NMR spectrum, and molecular simulation....The binding reaction between 10-hydroxycamptothecin （10-HCPT） and human serum albumins （HSA） is studied by means of fluorescence spectroscopy, UV-Vis absorption spectrum, IH NMR spectrum, and molecular simulation. The results indicate that the binding reaction of 10-HCPT and HSA is a single static quenching process, and the binding equilibrium constant for 10-HCPT binding with HSA is estimated K0-4.93×10^4 L · mol-I at 25 ℃ with the molar ratio of I ： 1. The distance （r） and energy transfer efficiency（E） between donor （HSA） and acceptor （10-HCPT） are obtained as follows, r=3.51 nm; E-0.27. The enthalpy change （△Hφ） and entropy change （△Sφ） are calcu- lated at different temperatures, and the hydrophobic force and shidipole force are the functions in the reaction. The results show that 10-HCPT binds within the subdomain II A of HSA by the hydrophobic force, and the 10-OH and 20-OH of 10-HCPT bind with both residue Leu-238 of HSA and Ala 291 of HSA by hydrogen bonds.展开更多
Tumor progression is usually characterized by proliferation,migration,and angiogenesis,which is essential for supplying both nutrients and oxygen to the tumor cells.Therefore,targeting angiogenesis has been considered...Tumor progression is usually characterized by proliferation,migration,and angiogenesis,which is essential for supplying both nutrients and oxygen to the tumor cells.Therefore,targeting angiogenesis has been considered a promising therapeutic strategy for cancer prevention and treatment.In the present study,we demonstrated that in addition to suppressing lung cancer cell proliferation and migration in vitro,10-hydroxycamptothecin(10-HCPT)is also capable of inhibiting angiogenesis in vivo with a miR-181a-dependent manner.Mechanistically,by upregulating miR-181a,which in turn downregulating FOXP1,10-HCPT can inhibit the PI3K/Akt/ERK signaling pathwaymediated angiogenesis.Furthermore,reduced levels of miR-181a have been found in both lung cancer cell lines and xenograft with concurrently elevated levels of FOXP1,VEGF,bFGF,and HDGF.Consistent with the findings from the in vitro experiments,miR-181a impairs neovascularization in our xenograft model.In summary,our findings have not only established the anti-oncogenic role of miR-181a in lung cancer angiogenesis but also suggest that 10-HCPT could be a potential therapeutic reagent for lung cancer treatment.展开更多
The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of it...The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of its impurities namely Imp A and Imp B along with degradation products generated from forced degradation studies. The drug was subjected to stress conditions of hydrolysis (acid, base and neutral), oxidative, photolytic and thermal stress degradation. Degradation was observed when subjected to treatment with peroxides or under conditions normally used for typical acid and base hydrolysis. The drug was found to be stable under other stress conditions attempted such as photolytic and thermal. Successful separation and isolation of the drug from related impurities and degradation products formed under stress conditions was achieved on an Inertsil ODS-3V (250 mm × 4.6 mm, 5 μm) column using a phosphate buffer, acetonitrile, methanol and Nanopure water. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, robustness and solution stability. The assay method was found to be linear in the range of 0.16 mg/mL to 0.24 mg/mL with a correlation coefficient of 0.999 and the linearity of the impurities was established from 0.02% (LOQ) to 0.3%. Recoveries of assay and impurities were found between 99.4% and 100.3%. The developed HPLC method can be used to determine the related substances and assay determinations of 10-HCTN and also to evaluate the quality and long term stability of production samples.展开更多
The determination method of 10-hydroxycamptothecin in Camptotheca acuminata fruits by high-performance liquid chromatogram (HPLC) was studied. The HPLC analysis was performed on a HIQ sil C18(4.6×250 mm) column w...The determination method of 10-hydroxycamptothecin in Camptotheca acuminata fruits by high-performance liquid chromatogram (HPLC) was studied. The HPLC analysis was performed on a HIQ sil C18(4.6×250 mm) column with mobile phase of acetonitrilewater (3:7, V:V), flow rate 1 mLmin-1 and UV detective wavelength 266 nm. Extracting 10-hydroxycamptothecin by ultrasonic method from fruits of C. acuminata to prepare samples for analysis was systematically discussed. The optimal extraction condition was carried out by 60% alcohol solution at 60℃ for 50 minutes.展开更多
The improved 3 step preparation of a key antitumor agent, 7 ethyl 10 hydroxycamptothecin(SN 38), which consists of ethylation, oxidation and photo chemical rearrangement, is described. The proposed reaction mech...The improved 3 step preparation of a key antitumor agent, 7 ethyl 10 hydroxycamptothecin(SN 38), which consists of ethylation, oxidation and photo chemical rearrangement, is described. The proposed reaction mechanism is also discussed.展开更多
针对玉米杂草识别过程中因光照变化导致识别精确度低及漏检问题,该研究以幼苗期玉米及其伴生杂草为研究对象,设计一种基于WEED-YOLOv10的玉米杂草检测方法。首先,通过无人机快速采集田间高分辨率图像构建了玉米杂草数据集;其次,以YOLOv...针对玉米杂草识别过程中因光照变化导致识别精确度低及漏检问题,该研究以幼苗期玉米及其伴生杂草为研究对象,设计一种基于WEED-YOLOv10的玉米杂草检测方法。首先,通过无人机快速采集田间高分辨率图像构建了玉米杂草数据集;其次,以YOLOv10n为基线网络,将骨干网络替换为ConvNeXtV2以增强特征提取能力;继而,为避免因模块拼接可能带来的信息冗余或丢失问题提升对光照干扰的鲁棒性,嵌入CBAM注意力机制;然后,引入SlimNeck结构优化网络计算效率,有效平衡了模型计算资源消耗与特征表征能力;最后,使用Focaler-EIoU损失函数进一步提高模型定位精度。试验结果表明,WEED-YOLOv10在精确率、召回率、mAP@50、mAP@50:95和F1分数上分别达到85.4%、88.1%、90.9%、48.5%和86.7%,较基准模型分别提升了2.4、2.9、3.5、7.0、2.6个百分点,各项精度指标均优于其他对比模型,部署在NVIDIA Jetson orin NX上的图片推理速度达到28.7帧/s,实现了检测速度与精度的平衡。进一步地,基于WEED-YOLOv10开发对靶喷药系统,该系统实时捕捉并解析来自模型的识别信号,实现对除草喷施装置的精准调控。田间试验结果显示,对靶喷药系统施药准确率为93.7%,喷洒覆盖率为90.5%,对靶偏差为1.45cm,杂草实时检测速度为20.1帧/s,实现了自动化的玉米田间除草作业。该研究为复杂光照场景下农田杂草治理提供了可靠的技术方案,对推动农业智能化作业具有重要意义。展开更多
文摘Camptotheca acuminata Decaisne is a tree unique to China, producing terpenoid indole alkaloid (TIA), camptothecin (CPT), and 10-hydroxycamptothecin (HCPT), which possesses strong anti-cancer bioactivity. The dynamics of HCPT and CPT during seed maturation, seed germination, postgerminative development and daily growth were measured by High Performance Liquid Chromatography (HPLC). This article provides some evidence for presenting the theory that each characteristic of HCPT and CPT accumulation is under developmental regulation and then attempt to elucidate the metabolic relationships between them. HCPT accumulates particularly in young tissues and organs and is relatively unstable, while the distribution of CPT is more ubiquitous and stable. Their different distribution properties suggest that HCPT and CPT are differentially regulated and play distinct roles:during development.
文摘Plants interact with their environment by producing a diverse array of secondary metabolites, one of which is alkaloid. In this study, alkaloids, including camptothecin (CPT) and 10-hydroxycamptothecin (HCPT), malondialdehyde (MDA) and chlorophyll contents were measured during heat shock in seedlings of Camptotheca acuminata Decaisne unique to China. Responses of different tissues, including young leaves, old leaves, buds and barks, to heat shock were examined in alkaloid changes. CPT and HCPT concentrations reached their peak values separately at 38 degreesC and 40 degreesC, which were below the lethal heat-shock temperature indicated by MDA and chlorophyll, and their great changes took place in young leaves. These results indicated that CPT and HCPT were involved in the C acuminata resistance against heat shock from its environment. Furthermore, plant rigidly observed the cost-benefit principle and mobilized and allocated limited alkaloid sources to young and reproductive tissues preferentially. In addition, HCPT displayed well-regulated changes during incubation at sublethal temperature, and this indicated that HCPT might play a more positively defensive role in enhancement of plant thermotolerance than CPT does.
基金Science and Technology Department of Henan province Fund Project(Grant No.144300510019)
文摘Previous study has shown that 10-hydroxycamptothecin（HCPT） has well-established pharmacological effects in vitro.However,its in vivo bioavailability is very poor due to various problems,which severely restricts its clinical applications.In the present study,phospholipid complex（PC） technology was employed to improve the solubility and bioavailability of HCPT.XRD data confirmed the formation of HCPT-PC.However,our previously prepared HCPT-PC is too sticky,which may result in the slow dissolution rate and negative effects on its absorption.Therefore,we prepared HCPT-PC-solid dispersion（HCPT-PC-SD）and lipid-based formulations of HCPT-PC through simple preparation process.The results showed that the dissolution rate of HCPT-PC was effectively improved by solid dispersion technology,which reached 91.73%in 45 min.Pharmacokinetic study revealed that the AUC_（0-t） of HCPT-PC-SD and HCPT-PC lipid-based formulations was effectively further increased compared with HCPT-PC.Moreover,we found that the combination of SD technology and lipid-base formulations could be a promising drug-delivery system to improve the oral bioavailability of HCPT-PC.In addition,we showed that the bioavailability of HCPT-PC lipid-base formulations was even greater than that of HCPT-PC-SD.In particular,lipid-base formulations could be prepared just by a simple method,suggesting its feasibility of industrialization.
基金NSFC(Grant No.81473156,81673365)Fangzheng Foundation for funding of the work
文摘10-Hydroxycamptothecin （HCPT） is a broad-spectrum anticancer drug, while its low solubility and instability severely limit its application. In this study, HCPT nanosuspension （HCPT-NSP）, also known as nanocrystal, was prepared by micro-precipitation combined with high-pressure homogenization method. This nanosuspension was characterized by size, shape, zeta potential, drug loading efficiency and in vitro drug release behavior. Preferred formulation and process showed that particle size was （129.8±13.9） nm, PDI was 0.20±0.07, and drug loading efficiency was 36.5%±9.5%. Moreover, HCPT nanocrystal concentration reached （1.35±0.2） mg/mL in HCPT-NSP, which was more than 1000-fold higher than that of HCPT. Transmission electron microscopy （TEM） results showed that the nanosuspension was short rod in shape. X-ray powder diffraction （XRD）, thermogravimetric analysis （TGA）, derivative thermogravimetric analysis （DTA） and differential scanning calorimetry （DSC） further elaborated the crystal state of the HCPT. The drug concentration-time curve of HCPT-NSP in rats was in accordance with the three-compartment model, showing prolonged half-life. Taken together, our data suggested that HCPT-NSP was a promising drug delivery system.
基金the Natural Science Foundation of Jiangsu Province,China(No.BK2007168)
文摘A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.
基金Supported by the Foundation of Shandong Province Educa-tion Bureau (J06060)
文摘The binding reaction between 10-hydroxycamptothecin （10-HCPT） and human serum albumins （HSA） is studied by means of fluorescence spectroscopy, UV-Vis absorption spectrum, IH NMR spectrum, and molecular simulation. The results indicate that the binding reaction of 10-HCPT and HSA is a single static quenching process, and the binding equilibrium constant for 10-HCPT binding with HSA is estimated K0-4.93×10^4 L · mol-I at 25 ℃ with the molar ratio of I ： 1. The distance （r） and energy transfer efficiency（E） between donor （HSA） and acceptor （10-HCPT） are obtained as follows, r=3.51 nm; E-0.27. The enthalpy change （△Hφ） and entropy change （△Sφ） are calcu- lated at different temperatures, and the hydrophobic force and shidipole force are the functions in the reaction. The results show that 10-HCPT binds within the subdomain II A of HSA by the hydrophobic force, and the 10-OH and 20-OH of 10-HCPT bind with both residue Leu-238 of HSA and Ala 291 of HSA by hydrogen bonds.
基金supported by the National Natural Science Foundation of China(Nos.81702296,81772281)the Shandong Science and Technology Committee(Nos.2017GSF18124,ZR2019PC019,ZR2019MH022)+1 种基金the Health Commission of Shandong Province(Nos.2017WS737,2019KJK014)the Shandong Province Taishan Scholar Project(No.ts201712067).
文摘Tumor progression is usually characterized by proliferation,migration,and angiogenesis,which is essential for supplying both nutrients and oxygen to the tumor cells.Therefore,targeting angiogenesis has been considered a promising therapeutic strategy for cancer prevention and treatment.In the present study,we demonstrated that in addition to suppressing lung cancer cell proliferation and migration in vitro,10-hydroxycamptothecin(10-HCPT)is also capable of inhibiting angiogenesis in vivo with a miR-181a-dependent manner.Mechanistically,by upregulating miR-181a,which in turn downregulating FOXP1,10-HCPT can inhibit the PI3K/Akt/ERK signaling pathwaymediated angiogenesis.Furthermore,reduced levels of miR-181a have been found in both lung cancer cell lines and xenograft with concurrently elevated levels of FOXP1,VEGF,bFGF,and HDGF.Consistent with the findings from the in vitro experiments,miR-181a impairs neovascularization in our xenograft model.In summary,our findings have not only established the anti-oncogenic role of miR-181a in lung cancer angiogenesis but also suggest that 10-HCPT could be a potential therapeutic reagent for lung cancer treatment.
文摘The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of its impurities namely Imp A and Imp B along with degradation products generated from forced degradation studies. The drug was subjected to stress conditions of hydrolysis (acid, base and neutral), oxidative, photolytic and thermal stress degradation. Degradation was observed when subjected to treatment with peroxides or under conditions normally used for typical acid and base hydrolysis. The drug was found to be stable under other stress conditions attempted such as photolytic and thermal. Successful separation and isolation of the drug from related impurities and degradation products formed under stress conditions was achieved on an Inertsil ODS-3V (250 mm × 4.6 mm, 5 μm) column using a phosphate buffer, acetonitrile, methanol and Nanopure water. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, robustness and solution stability. The assay method was found to be linear in the range of 0.16 mg/mL to 0.24 mg/mL with a correlation coefficient of 0.999 and the linearity of the impurities was established from 0.02% (LOQ) to 0.3%. Recoveries of assay and impurities were found between 99.4% and 100.3%. The developed HPLC method can be used to determine the related substances and assay determinations of 10-HCTN and also to evaluate the quality and long term stability of production samples.
基金This paper was supported by National Natural Science Foundation of China (No. 30070086).
文摘The determination method of 10-hydroxycamptothecin in Camptotheca acuminata fruits by high-performance liquid chromatogram (HPLC) was studied. The HPLC analysis was performed on a HIQ sil C18(4.6×250 mm) column with mobile phase of acetonitrilewater (3:7, V:V), flow rate 1 mLmin-1 and UV detective wavelength 266 nm. Extracting 10-hydroxycamptothecin by ultrasonic method from fruits of C. acuminata to prepare samples for analysis was systematically discussed. The optimal extraction condition was carried out by 60% alcohol solution at 60℃ for 50 minutes.
文摘The improved 3 step preparation of a key antitumor agent, 7 ethyl 10 hydroxycamptothecin(SN 38), which consists of ethylation, oxidation and photo chemical rearrangement, is described. The proposed reaction mechanism is also discussed.
文摘针对玉米杂草识别过程中因光照变化导致识别精确度低及漏检问题,该研究以幼苗期玉米及其伴生杂草为研究对象,设计一种基于WEED-YOLOv10的玉米杂草检测方法。首先,通过无人机快速采集田间高分辨率图像构建了玉米杂草数据集;其次,以YOLOv10n为基线网络,将骨干网络替换为ConvNeXtV2以增强特征提取能力;继而,为避免因模块拼接可能带来的信息冗余或丢失问题提升对光照干扰的鲁棒性,嵌入CBAM注意力机制;然后,引入SlimNeck结构优化网络计算效率,有效平衡了模型计算资源消耗与特征表征能力;最后,使用Focaler-EIoU损失函数进一步提高模型定位精度。试验结果表明,WEED-YOLOv10在精确率、召回率、mAP@50、mAP@50:95和F1分数上分别达到85.4%、88.1%、90.9%、48.5%和86.7%,较基准模型分别提升了2.4、2.9、3.5、7.0、2.6个百分点,各项精度指标均优于其他对比模型,部署在NVIDIA Jetson orin NX上的图片推理速度达到28.7帧/s,实现了检测速度与精度的平衡。进一步地,基于WEED-YOLOv10开发对靶喷药系统,该系统实时捕捉并解析来自模型的识别信号,实现对除草喷施装置的精准调控。田间试验结果显示,对靶喷药系统施药准确率为93.7%,喷洒覆盖率为90.5%,对靶偏差为1.45cm,杂草实时检测速度为20.1帧/s,实现了自动化的玉米田间除草作业。该研究为复杂光照场景下农田杂草治理提供了可靠的技术方案,对推动农业智能化作业具有重要意义。
