EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2023
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IF 4.6
Xiaohui Tang,Munire Kurban,Ipargul Hafiz,Qi Shen,Mei Wang
Aims To prepare hyaluronic acid-loaded Harmine polymeric micelles with CD 44 targeting properties and to investigate their anti-breast cancer effects in vitro . Methods The carboxyl group on hyaluronic acid is coupled to the amino group on 3,5-bis(trifluoromethyl)benzylamine by an amidation reaction. And the polymeric micelles self-assemble to encapsulate the Harmine in a hydrophobic core, characterized the polymer micelles by IR, 19 F-NMR, Malvern particle sizing, release, hemolysis, and other experiments. Used CD 44 -positive MDA-MB-231 cells and CD 44 -negative MCF-7 cells as tumor models. The effect of polymer micelles on breast cancer cells in vitro by cytotoxicity assay, confocal, and flow cytometry. Results The prepared polymer micelles had a uniform particle size of about 200 nm, good dispersion, PDI < 0.3, encapsulation rate up to 87%, drug loading of 4.12±0.03%, and negative charge. Hyaluronidase has a good enzymatic effect on polymeric micelles, with a hemolysis rate of less than 1%. It showed some dose-dependent toxicity to both MDA-MB-231 and MCF-7, with increased uptake of polymer micelles by CD 44 -positive MDA-MB-231 compared to CD 44 -negative MCF-7 cells and significant effects of polymer micelles on apoptosis and cycling in both cell types. These results suggest that the hyaluronic acid-loaded Harmine polymer micelles designed in this study are effective in killing breast cancer cells while at the same time reducing the toxicity of Harmine and improving its slow-release targeting.
研究领域:
药剂学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncotarget
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2015
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IF 6.359
Siwen Li,Aqin Wang,Fan Gu,Zhaohui Wang,Caiping Tian,Zhiyu Qian,Liping Tang,Yueqing Gu
Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo . Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy.
研究领域:
药理学
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肿瘤学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2019
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IF 4.527
Gaofeng Cui,Haiqi Yuan,Zhiyan Jiang,Jing Zhang,Zhipeng Sun,Guohua Zhong
The widely distributed β-carboline alkaloids exhibit promising psychopharmacological and biochemical effects. Harmine, a natural β-carboline, can inhibit insect growth and development with unclear mechanisms. In this study, harmine (at 0-200 mg/L) showed a dose-dependent inhibitory effect on the pupal weight, length, height, pupation rate and eclosion rate of fruit flies Drosophila melanogaster , which was similar to the inhibition induced by the well-known botanical insect growth regulator azadirachtin . Moreover, the expression levels of major regulators from the developmental signaling network were down-regulated during the pupal stage except Numb , Fringe , Yorkie and Pten . The Notch, Wnt, Hedgehog and TGF-β pathways mainly played vital roles in coping with harmine exposure in pupae stage, while the Hippo, Hedgehog and TGF-β elements were involved in the sex differences. Notch , Hippo , Hedgehog , Dpp and Armadillo were proved to be suppressed in the developmental inhibition with fly mutants, while Numb and Punt were increased by harmine. In conclusion, harmine significantly inhibited the development of Drosophila by negatively affecting their developmental signaling network during different stages. Our results establish a preliminary understanding of the developmental signaling network subjected to botanical component-induced growth inhibition and lay the groundwork for further application.
研究领域:
昆虫学
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分子生物学
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发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2022
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IF 7.033
Yong-Yan Bei,Xiao-Feng Zhou,Ben-Gang You,Zhi-Qiang Yuan,Wei-Liang Chen,Peng Xia,Yang Liu,Yong Jin,Xiao-Juan Hu,Qiao-Ling Zhu,Chun-Ge Zhang,Xue-Nong Zhang,Liang Zhang
Lactose–palmitoyl–trimethyl–chitosan (Lac-TPCS), a novel amphipathic self-assembled polymer, was synthesized for administration of insoluble drugs to reduce their adverse effects. The central composite design was used to study the preparation technique of harmine (HM)-loaded self-assembled micelles based on Lac-TPCS (Lac-TPCS/HM). Three preparation methods and single factors were screened, including solvent type, HM amount, hydration volume, and temperature. The optimal preparation technique was identified after investigating the influence of two independent factors, namely, HM amount and hydration volume, on four indexes, ie, encapsulation efficiency (EE), drug-loading amount (LD), particle size, and polydispersity index (PDI). Analysis of variance showed a high coefficient of determination of 0.916 to 0.994, thus ensuring a satisfactory adjustment of the predicted prescription. The maximum predicted values of the optimal prescription were 91.62%, 14.20%, 183.3 nm, and 0.214 for EE, LD, size, and PDI, respectively, when HM amount was 1.8 mg and hydration volume was 9.6 mL. HM-loaded micelles were successfully characterized by Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and a fluorescence-quenching experiment. Sustained release of Lac-TPCS/HM reached 65.3% in 72 hours at pH 7.4, while free HM released about 99.7% under the same conditions.
研究领域:
药学
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药物递送系统
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纳米技术
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高分子科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Expert Opinion on Drug Delivery
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2014
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IF 4.116
Yong-Yan Bei,Zhi-Qiang Yuan,Liang Zhang,Xiao-Feng Zhou,Wei-Liang Chen,Peng Xia,Yang Liu,Ben-Gang You,Xiao-Juan Hu,Qiao-Ling Zhu,Chun-Ge Zhang,Xue-Nong Zhang,Yong Jin
Backgroud: Polymeric micelles is a safe and effective delivery system, which belong to the targeted delivery system (TDS). An anticancer drug, harmine(HM) is a hydrophobic drug with much adverse effects when used for treatment of liver cancer. Chitosan (CS) is a polysaccharide and can be modified to be an amphiphilic polmer which could self-assemble into micelles and be applied for delivery of hydrophobic drugs. Objectives: To synthesize three kinds of novel biodegradable polymers, designated as palmitoyl-trimethyl-CS (TPCS)1, TPCS2 and Lac-TPCS2, and investigate their efficiency and mechanism of delivery HM to liver tumors in vitro and in viro. Results: The self-assembled micelles presented satisfactory particle size (∼ 200 nm) and drug release characteristics in vitro. It's proved that Lac-TPCS2/HM may enter HepG2 cell through endocytosis. Antitumor experiments in vivo revealed that Lac-TPCS2/HM could significantly inhibit tumor growth and extend the lifetime of mice bearing H22 tumors after intravenous administration. Subsequently in vivo near-infrared fluorescence imaging results demonstrated a satisfactory liver tumor-targeting effect of Lac-TPCS2/HM. Conclusion: Three novel polymers hold great potential in the development of nanomedicine for treatment of liver tumors, in particular Lac-TPCS2 exhibits the greatest antitumor potential through active target effect.
研究领域:
药学
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纳米技术
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癌症研究
✓ 已验证
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2019
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IF 2.87
Benshui Shu,Jingjing Zhang,Zhiyan Jiang,Gaofeng Cui,Sethuraman Veeran,Guohua Zhong
Harmine , a useful botanical compound, has demonstrated insecticidal activity against some pests. However, harmine's mechanism of action has not been thoroughly elucidated to date. To preliminarily explore harmine's insecticidal mechanisms, the cytotoxicity of harmine against Spodoptera frugiperda Sf9 cells was comprehensively investigated. Our results indicated that harmine induced apoptosis in Sf9 cells, as evidenced by cellular and nuclear morphological changes, DNA laddering and increases in caspase-3-like activities. In addition, activation of the mitochondrial apoptotic pathway by harmine was confirmed by the generation of ROS, opening of mitochondrial permeability transition pores (MPTPs), increase in cytosolic Ca 2+ , changes in mRNA expression levels of genes involved in the mitochondrial apoptotic pathway and increase and release of Cytochrome c. Furthermore, lysosomal membrane permeabilization, release of cathepsin L from the lysosome into the cytosol and cleavage of caspase-3 were also triggered, which indicated that lysosomes were involved in this physiological process . Moreover, the effect of harmine on DNA topoisomerase I activity was investigated by in vivo and molecular docking experiments. These data not only verified that harmine induced apoptosis via comprehensive activation of the mitochondrial and lysosomal pathways and inhibition of DNA topoisomerase I activity in Sf9 cells but also revealed a mechanism of harmine insecticidal functions for pest control.
研究领域:
昆虫学
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分子生物学
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药理学
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毒理学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2018
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IF 3.04
Jie-Fei Miao,Yan-Fu Peng,Shi Chen,Wei-Jie Gao,Qiu-Xing Yang,Peng Zhu,Jing Guo,Jinhua Tao,Lin Luo,Yanan Zhang,Yong Ling
This study aims to design and synthesize a novel harmine derivative N -(4-(hydroxycarbamoyl) benzyl)-1-(4-methoxyphenyl)-9H-pyrido [3,4-b]indole-3-carboxamide (HBC) as histone deacetylase (HDAC) inhibitor, and evaluate its antitumor activities and anti-metastasis mechanism. HBC not only exerted significant ant-proliferation activity against five human cancer cell lines, especially for HepG2 cell with an IC 50 value of 2.21 μM, which is nearly three-fold lower than SAHA (IC 50 = 6.26 µM), but also showed selective HDAC1/6 inhibitory effects in vitro. However, HBC had little effect on normal hepatic cells LO2. Furthermore, HBC simultaneously increased the acetylation of histone H3 , H4, and α-tubulin, induced hypochromism by electrostatical interaction with CT-DNA, triggered more significant cancer cell apoptosis and cell cycle arrest at G2/M than SAHA by inhibition of both CDK1 and cyclin B in a concentration dependent manner. In addition, scratch and invasion assay showed that HBC also dose-dependently suppressed migration and invasion capacities of highly metastatic HCC HepG2 cells through down-regulated the expression of tumor metastasis related proteins MMP-2 and MMP-9, significantly better than SAHA. Finally, HBC showed low acute toxicity to mice and significant growth inhibition of the hepatoma tumor in vivo. These results demonstrate that novel harmine-based HDAC inhibitor HBC not only exhibited selective HDAC1/6 inhibitory activity and significant in vitro and in vivo antitumor activity, but also possessed DNA binding effect, apoptosis induction, cell cycle arrest effects, and potent anti-metastasis mechanisms, which may hold great promise as therapeutic agent targeting HDAC1/6 for the intervention of human cancers.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）