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Evaluation of the metabolism of PEP06,an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells

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Journal of Pharmaceutical Analysis 2022年第5期12卷 766-773页

作者： Liyun Niu Huiyu Zhou Yueru Lian Ya Gao Yulu Liu Ruolan Gu Zhuona Wu Xiaoxia Zhu Hui Gan Zhiyun Meng guifang dou State Key Laboratory of Drug Metabolism and Pharmacokinetics Department of Pharmaceutical SciencesBeijing Institute of Radiation MedicineBeijing100850China Henan University KaifengHenan475004China

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp(RGDRGD)30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus.The active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral effect.However,little is known about the kinetics and degradation products of PEP06 in vitro or in vivo.In this study,we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species;we further identified the degradation characteristics of its cleavage products.PEP06 underwent rapid enzymatic degradation in multiple types of living cells,and the liver,kidney,and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06.We identified metabolites of PEP06 using full-scan mass spectrometry(MS)and tandem MS(MS2),wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide,formed by successive losses of amino acids.The metabolites were C and N terminal truncated products of PEP06.The structures of 11 metabolites(M6,M7,M16,M17,M21,M25,M33,M34,M39,M40,and M42)were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites.We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06,which can support further drug research.

关键词： PEP06 HRMS Metabolic stability Metabolites identification

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放创复合伤动物模型的研究进展

中国辐射卫生 2024年第2期33卷 209-214页

作者：郝若林窦桂芳孟志云叶彤李南熹朱晓霞顾若兰吴卓娜甘慧军事科学院军事医学研究院辐射医学研究所北京100850

放射损伤合并创伤称为放创复合伤。放创复合伤由于结合放射伤和创伤,具有创口反复溃烂,持久难愈的特点,是难愈性创伤的重点研究对象。动物模型的建立是放创复合伤相关研究的关键环节,合理的动物模型是可靠实验结果的有力保障。本文从辐... 详细信息

放射损伤合并创伤称为放创复合伤。放创复合伤由于结合放射伤和创伤,具有创口反复溃烂,持久难愈的特点,是难愈性创伤的重点研究对象。动物模型的建立是放创复合伤相关研究的关键环节,合理的动物模型是可靠实验结果的有力保障。本文从辐射类型、动物种类、致伤类型、致伤位置等多方面概述和归纳目前各类放创复合伤动物模型的研究进展,为放创复合伤标准化动物模型的建立、伤情机制研究以及防治功效评估提供科学基础。

关键词：放创复合伤动物模型难愈创伤辐射

A phaseⅠtrial of an oral subtype-selective histone deacetylase inhibitor,chidamide,in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer

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Chinese Journal of Cancer Research 2016年第4期28卷 444-451页

作者： Xingsheng Hu Lin Wang Lin Lin Xiaohong Han guifang dou Zhiyun Meng Yuankai Shi Department of Medical Oncology Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted DrugsNational Cancer Center/Cancer HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China Laboratory of Drug Metabolism and Pharmacokinetics Beijing Institute of Transfusion MedicineBeijing 100850China

Objective： This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase （HDAC） inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer （NSCLC）. Methods： Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel （175 mg/m2） and carboplatin [area under the curve （AUC） 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacoldnetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients. Results： Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response （PR）. Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment. Conclusions： Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.

关键词： Chidamide HDAC inhibitor phase I paclitaxel and carboplatin non-small cell lung cancer

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放射性核素污染伤口去污膜的研制与表征

中华放射医学与防护杂志 2024年第4期44卷 247-254页

作者：田庄何琪乔璇李林涛胡瑄全晓筱叶彤甘慧吴卓娜顾若兰朱晓霞孙云波刘曙晨窦桂芳孟志云军事科学院军事医学研究院辐射医学研究所北京100850

目的研发一款适用于放射性核素污染的去污膜,对其物理性质、核素清除效果和安全性进行考察。方法以海藻酸钠和壳聚糖为基质膜,负载复方洗消剂配方制备去污膜。通过将去污膜置于生理盐水中,测试其溶胀性能;通过拉力机测试去污膜的断裂应... 详细信息

目的研发一款适用于放射性核素污染的去污膜,对其物理性质、核素清除效果和安全性进行考察。方法以海藻酸钠和壳聚糖为基质膜,负载复方洗消剂配方制备去污膜。通过将去污膜置于生理盐水中,测试其溶胀性能;通过拉力机测试去污膜的断裂应力与应变。以生理盐水、基质膜、1%二乙烯三胺五乙酸五钠(DTPA-5Na)基质膜组作为对照组,在豚鼠完整皮肤与伤口模型上检测去污膜对铀、铯、钴、铈和锶的清除效果。采用噻唑蓝比色法(MTT)测试去污膜的浸提液对小鼠上皮样成纤维细胞(L929)的毒性;将去污膜的浸提液注射到Kunming(KM)小鼠体内,测试其全身急性毒性。将去污膜覆盖于新西兰兔背部测试皮肤刺激性。结果去污膜成膜时间为1.5 min,溶胀率为(134.96±3.49)%,断裂应力为(393.88±53.53)kN/m2,断裂应变为(163.00±35.29)%。在完整皮肤上,去污膜对铀的清除率为(95.38±0.23)%,对铯为(96.57±0.49)%。在伤口模型上,去污膜对铀、铯、锶、钴和铈的清除率分别为(92.16±0.52)%、(90.44±1.16)%、(92.03±0.87)%、(92.79±0.51)%和(92.85±0.82)%,均优于生理盐水、基质膜与1%DTPA-5Na基质膜组(t=3.81~4498.55,P<0.001)。安全性评价试验表明,去污膜符合国家医疗器械生物学评价标准。结论去污膜能够快速成膜且对多种核素均有良好的清除效果,安全性良好,适用放射性核素污染人员的完整皮肤或伤口去污,有望为核污染区域的工作人员提供安全保障。

关键词：洗消剂去污膜放射性污染

An UPLC-MS/MS method to monitor Estriol injection and comparison of pharmacokinetic characteristics after irradiation

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Radiation Medicine and Protection 2021年第2期2卷 72-78页

作者： Hanming Zhang Zhiyun Meng Tong Ye Taoyun Liu Jian Li Fei Ma Ruolan Gu Xiaoxia Zhu Zhuona Wu guifang dou Hui Gan Department of Pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing100850China

Objective:To develop an UPLC-MS/MS method for the accurate quantification of Estriol(E3),a new radioprotective agent,and observe the variation in pharmacokinetic characteristics of E3 after irradiation.As a hormone drug,the gender differences of E3 metabolism were also concerned here.Methods:Various chromatographic and mass spectrometric conditions of E3 were optimized.The specificity,linearity,precision and accuracy of UPLC-MS/MS method were validated.Twenty SD rats,half male and half female,were administered with intramuscular(im)injection of 2.7 mg/kg E3,and then divided randomly into two groups,sham-irradiated group(Con)and irradiated group(IR).IR group was irradiated to 7 Gy ofγ-rays.Blood samples were collected at different times post-irradiation and E3 concentrations were detected.The changes of concentration-time variation and pharmacokinetic parameters for E3 after irradiation were investigated,together with metabolic differences between male and female rats.Results:The range of the calibration curve of UPLC-MS/MS for E3 was 1.00–200.0 ng/mL.Con group reached maximum concentration(Cmax)(77.57±18.71)ng/mL at(0.68±0.29)h(Tmax)after im injection.The drug concentration-time profiles and pharmacokinetic parameters of E3 were consistent before and after irradiation.The areas under time curve(AUC0-t)of E3 were(353±74)h⋅ng/mL for Con group,and(299±74)h⋅ng/mL for IR group(P>0.05).There were also no statistical differences in pharmacokinetic parameters between female and male rats.The elimination half-lifes(T1/2)of males and females were(3.02±0.68)h and(3.01±0.42)h in Con group,and(3.64±0.51)h and(3.38±0.60)h in IR group,respectively(P>0.05).Conclusion:A rapid and sensitive UPLC-MS/MS method for determination of E3 was established.The pharmacokinetic characteristics of E3 in rat were not affected by 7 Gy irradiation and gender differences.This study provided a theoretical basis for the development and application of new radiation injury treatment drug。

关键词： Estriol(E3) Radioprotective agent Pharmacokinetics UPLC-MS/MS Irradiation

文冠果花提取物对良性前列腺增生具有抑制作用

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南方医科大学学报 2022年第10期42卷 1503-1510页

作者：王文晴马飞王帆均杨志远范珊窦桂芳甘慧冯素香孟志云河南中医药大学药学院河南郑州450046 军事科学院军事医学研究院辐射医学研究所北京100850 长春金赛药业有限责任公司吉林长春130000

目的探究文冠果花提取物对良性前列腺增生的抑制作用及可能的机制。方法通过MTT法检测文冠果花提取物对良性前列腺增生细胞(BPH-1)增殖能力的影响、Annexin V/PI双染色法检测细胞凋亡、流式细胞仪测定细胞周期、免疫印迹法检测BPH-1细... 详细信息

目的探究文冠果花提取物对良性前列腺增生的抑制作用及可能的机制。方法通过MTT法检测文冠果花提取物对良性前列腺增生细胞(BPH-1)增殖能力的影响、Annexin V/PI双染色法检测细胞凋亡、流式细胞仪测定细胞周期、免疫印迹法检测BPH-1细胞Bcl-2/Bax/Caspase3、PI3K/AKT蛋白表达水平。通过皮下注射丙酸睾酮建立大鼠良性前列腺增生(BPH)模型,文冠果花提取物给药28 d后取大鼠前列腺组织,通过HE染色观察组织病理变化,免疫印迹法检测前列腺组织中Bcl-2/Bax/Caspase3、PI3K/AKT的蛋白表达水平。结果文冠果花提取物在125-1000μg/mL的浓度范围内抑制BPH-1细胞的增殖(P<0.05);在G0/G1期产生周期阻滞,细胞的凋亡率与文冠果花提取物给药浓度正相关;文冠果花提取物处理后的细胞Bcl-2蛋白表达水平明显下调,Bax和Caspase3蛋白表达水平显著提升,PI3K/AKT蛋白磷酸化水平显著下调(P<0.05);在动物实验中,与模型组相比,文冠果花提取物中剂量组和高剂量组p-AKT、Bcl-2表达水平降低,Bax表达水平升高,低剂量组p-AKT表达水平下降(P<0.05)。结论通过BPH-1细胞和BPH动物模型,验证了文冠果花提取物对良性前列腺增生具有抑制作用。

关键词：文冠果花提取物细胞凋亡良性前列腺增生 Bcl-2/Bax/Caspase3

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蓝莓籽油与6种常用植物油营养成分差异分析

食品与发酵工业 2023年第13期49卷 304-310页

作者：李童刘慧蒙周慧雨顾若兰甘慧吴卓娜朱晓霞窦桂芳孟志云河南中医药大学药学院河南郑州450000 军事医学研究院辐射医学研究所北京100850

旨在评价蓝莓籽油脂肪酸营养价值和品质,探究蓝莓籽油与玉米油、大豆油、芝麻油、胡麻油、花生油、葵花籽油等常用植物油的营养成分差异。该实验通过GC-MS分析对比了蓝莓籽油与6种常用植物油中脂肪酸和微量营养物质的含量。结果表明,在... 详细信息

旨在评价蓝莓籽油脂肪酸营养价值和品质,探究蓝莓籽油与玉米油、大豆油、芝麻油、胡麻油、花生油、葵花籽油等常用植物油的营养成分差异。该实验通过GC-MS分析对比了蓝莓籽油与6种常用植物油中脂肪酸和微量营养物质的含量。结果表明,在7种植物油中,蓝莓籽油多不饱和脂肪酸相对含量最高、饱和脂肪酸相对含量最低,在脂肪酸营养价值评价中,有预防动脉粥样硬化和高胆固醇的优势;微量营养物质相对含量高,其中角鲨烯含量最高,菜油甾醇和β-谷甾醇的含量较高,蓝莓籽油具有明显营养价值优势。与其他6种常用植物油相比,蓝莓籽油具有高多不饱和脂肪酸和低饱和脂肪酸、高微量营养物质的含量特点,能够降低动脉粥样硬化和高胆固醇症的潜在患病风险,具有更高的营养价值,为植物油的营养评价、蓝莓籽资源开发利用和相关食品及保健品的产品研发提供理论依据。

关键词：植物油蓝莓籽油脂肪酸营养品质微量营养成分

药食同源组合物对小鼠急性酒精性肝损伤保护作用研究

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食品与发酵工业 2023年第20期49卷 259-264页

作者：周慧雨牛立云刘慧蒙陈广瑞孟志云甘慧顾若兰吴卓娜杨雯婕窦桂芳河南大学药学院河南开封475004 中国人民解放军军事科学院军事医学研究院北京100850 浙江蓝美生物技术有限公司浙江诸暨311899

蓝莓花青素、γ-氨基丁酸、杜仲雄花茶、米糠脂肪烷醇4种药食同源天然活性成分具有良好的抗氧化和保护肝脏的活性,具有开发成保护肝脏免受氧化损伤药物的潜力,可为急性酒精性肝损伤保护作用研究提供新思路。本研究首先通过DPPH自由基清... 详细信息

蓝莓花青素、γ-氨基丁酸、杜仲雄花茶、米糠脂肪烷醇4种药食同源天然活性成分具有良好的抗氧化和保护肝脏的活性,具有开发成保护肝脏免受氧化损伤药物的潜力,可为急性酒精性肝损伤保护作用研究提供新思路。本研究首先通过DPPH自由基清除能力、ABTS阳离子自由基清除能力实验,进行处方优化,确定以上4种药食同源天然活性成分的最佳比例。然后将小鼠随机分为空白对照组、模型组、给药组(低、高剂量),预防给药一周后,白酒灌胃构建小鼠急性酒精性肝损伤模型。通过计算肝脏指数,检测血清中谷草转氨酶(aspartate aminotransferase,AST)和谷丙转氨酶(alanine aminotransferase,ALT)的含量,检测肝脏组织中丙二醛(malondialdehyde,MDA)含量、超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-PX)的活性,最后通过HE染色分析肝脏组织形态变化。结果表明,预防服用这4种成分可以缓解肝水肿、降低血清中AST和ALT水平、提高肝脏中SOD和GSH-PX活性、降低MDA水平。HE染色结果显示,给药组小鼠肝组织损伤情况大大好转。药食同源组合物的预防服用具有较好的急性酒精性肝损伤保护作用。

关键词：蓝莓花青素 γ-氨基丁酸杜仲雄花茶米糠脂肪烷醇抗氧化急性酒精性肝损伤保护作用

氡气暴露后对机体肺功能及金属元素含量的影响

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中华放射医学与防护杂志 2022年第11期42卷 845-850页

作者：刘慧蒙王美玉陈广瑞周慧雨袁勇孟志云顾若兰甘慧吴卓娜窦桂芳解放军军事科学院军事医学研究院辐射医学研究所抗辐射药物研究室北京100850

目的:探索暴露于高浓度氡气后对机体肺功能的影响及金属元素水平的扰动。方法:按随机数表法将小鼠分为对照组、氡暴露30 WLM组、60 WLM组、120 WLM组,每组10只。达到累积剂量后,用无创肺功能检测仪检测小鼠肺功能,采集各组小鼠血样、肺... 详细信息

目的:探索暴露于高浓度氡气后对机体肺功能的影响及金属元素水平的扰动。方法:按随机数表法将小鼠分为对照组、氡暴露30 WLM组、60 WLM组、120 WLM组,每组10只。达到累积剂量后,用无创肺功能检测仪检测小鼠肺功能,采集各组小鼠血样、肺、心脏、肝脏、肾脏、脾脏组织。HE染色观察染氡小鼠肺组织病理改变,用电感耦合等离子体质谱(ICP-MS)检测组织中金属元素含量,包括机体必需微量元素:铬(Cr)、钼(Mo)、钴(Co)、硒(Se)、铜(Cu)、锌(Zn)、锰(Mn)、镍(Ni),以及具有潜在毒性的元素:砷(As)、锡(Sn)、铅(Pb)、铝(Al)、汞(Hg)、镉(Cd)、银(Ag)的含量。结果:与对照组相比,染氡组小鼠肺通气功能降低,肺泡结构破坏,肺部金属元素Cr、Al、Pb、Sn(F=0.34、0.66、3.14、1.16,P<0.05)以及血液中必需微量元素Mn、Cr、Zn、Mo(F=0.65、1.44、0.97、2.08,P<0.05)含量降低,而肺部Cu、Mo、Se、As元素升高(F=1.31、1.26、0.81、2.04,P<0.05),其余组织中元素含量也有波动。结论:吸入一定累积剂量的氡气会降低小鼠的肺通气功能,破坏肺泡结构,并使肺和血液中必需微量元素含量降低,体内金属元素含量出现波动。

关键词：氡气氡子体微量元素重金属