WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
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2024
·Vol. 41
·期 1
·1-12
·
IF 4
Li Yang-Nan,Zhu Chen-Yuan,Xu Chen-Lu,Yu Shen,Huan Tong,Zhang Ye-Wang
A heparinase III ( Ns Hep-III) from Niabella sp . was identified, cloned, and expressed as soluble form in E. coli BL21 (DE3). With heparin as substrate, the maximum activity of Ns Hep-III of 90.0 U·mg − 1 was achieved at pH 7.1 Tris-HCl (containing 15 mM Mg 2+ ) and 30 o C. The half-life of Ns Hep-III was determined to be 5 h at 30 o C. The interactions between Ns Hep-III and substrates were studied by molecular docking. The combination of Ns Hep-III and a heparinase I from Bacteroides eggthii ( Be Hep-I) was employed to cleave heparin. Analysis of the enzymatic products of Ns Hep-III by SAX-HPLC showed seven different modified disaccharides, indicating that Ns Hep-III has a wide range of substrate specificity. The results of GPC analysis demonstrated that the average molecular weight of the product of heparin cleavage by the combination of Ns Hep-III/ Be Hep-I was reduced to 3969 Da, which accounted for 90% of all the components, and complied with the requirements of the European Pharmacopoeia. Ns Hep-III has notable activity and efficiency in cleaving heparin, which is potentially useful for the industrial production of low molecular weight heparin.
研究领域:
生物化学
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药学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Xuemin Shen,Zhenfeng Liu,Junhui Li,Dongmei Wu,Meng Zhu,Lufeng Yan,Guizhu Mao,Xingqian Ye,Robert J. Linhardt,Shiguo Chen
Low molecular weight heparins (LMWHs) are currently used as an anticoagulant agent since unfractionated heparin (UFH) can cause serious adverse drug reactions. LMWHs are commercially prepared using different methods such as nitrous acid cleavage and β-elimination under strong reaction conditions or with harsh chemicals, which may cause the saccharide units within the polysaccharide backbone to be decomposed and noticeably modified. This study demonstrates an effective method for depolymerizing heparin via the production of large amounts of free radicals from H 2 O 2 /ascorbic acid and ultrasonic power; this results in highly pure products because ascorbic acid can decompose during the reaction, which is different from the previously reported H 2 O 2 /Cu 2+ method. The reaction conditions—including concentration of ascorbic acid, reaction temperature and intensity of ultrasonic power—were investigated and optimized. We found that the degradation behavior of heparin in this combined physicochemical process conformed to first-order reaction kinetics . The chemical composition and structures of different LMWHs were analyzed. The results showed the primary structure and sulfate esters were well preserved after the depolymerization , the major repeat units are (1–4)-linked glucosamine and iduronic acid . The further in vitro assays indicated that the LMWHs produced by H 2 O 2 /ascorbic acid with ultrasonic power have an anti-metastatic effect in A549 cells, which suggested the LMWHs rapidly prepared in this physicochemical way have a potential for anti-tumor metastatic function.
研究领域:
药理学
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生物化学
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2020
·Vol. 31
·期 3
·2004550
·
IF 16.836
Yaping He,Ting Xiong,Siyu He,Hongyu Sun,Chenxi Huang,Xiaohong Ren,Li Wu,Laurence H. Patterson,Jiwen Zhang
Lung cancer is a serious threat to human health with the highest morbidity and mortality; metastatic lung cancer accounts for a majority of cancer-related deaths. Hence, there is considerable interest in developing efficient lung-targeted drug delivery systems to improve overall survival and quality of life of lung cancer patients. Based on the lung-targeting characteristics of cubic crosslinked cyclodextrin metal–organic framework (CDF) nanoparticles, this study shows the synthesis of a nanoplatform using RGD-functionalized CDF to co-deliver low-molecular-weight heparin (LMWH) and doxorubicin (DOX) for treatment of lung cancer. Rational design of the DOX-loaded RGD-CDF-LMWH nanoplatform (RCLD) is carried out. RCLD nanoparticles are efficiently targeted to lung tumors following intravenous administration; RCLD accumulation in the lung is 5.8 times greater than that in the liver. Moreover, RCLD inhibits migration and invasion of cancer cells in vitro and significantly diminishes lung tumor nodule count and area of spread in human A549 and murine B16F10 lung cancer models in vivo. Furthermore, RCLD does not show serum enzyme or histopathologic indicators of tissue damage or adverse hematologic effects. Therefore, the multiple antitumor activities of this novel RCLD nanoplatform, alongside its safety profile for normal tissues, strongly support its use for targeted treatment of lung cancer.
研究领域:
药剂学
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肿瘤学
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纳米医学
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DOI
高影响因子
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Yan Yan,Ying Sun,Pengchong Wang,Rui Zhang,Chuanchuan Huo,Tingting Gao,Chenghua Song,Jianfeng Xing,Yalin Dong
Low molecular weight heparin (LMWH) is reported to have therapeutic action on ulcerative colitis (UC). To facilitate its oral administration and improve the colon-targeting property, LMWH-loaded nanoparticles (TMC-NPs and SA-TMC-NPs) are prepared and evaluated by a series of studies, including their stabilities, drug release profiles, mucosal permeation, mucoadhesion, cytotoxicities, cellular uptake profiles, anticoagulant and anti-inflammatory activities, mucosal healing properties, biosafety and ameliorative effects on experimental colitis. Consequently, oral administration of LMWH-loaded NPs for 5 days perform significant therapeutic effects on mice, which are manifested as improved body weight gains, colon length, DAI score, MPO activity and histological characteristics. Besides, SA-TMC-NPs show better colon-targeting property than TMC-NPs that is demonstrated by lower oral absorption (ATPP 38.95 s) and stronger mucoadhesion (kcps reduces 36.46 %) to inflamed colon tissues. Therefore, TMC-based NPs are proved to be as promising oral colon-targeting drug delivery systems of LMWH and has potential application in UC treatment.
研究领域:
药剂学
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炎症性肠病研究
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2016
·
IF 7.441
Yuanke Li,Yuanyuan Wu,Leaf Huang,Lei Miao,Jianping Zhou,Andrew Benson Satterlee,Jing Yao
The potential of low molecular weight heparin (LMWH) in anti-angiogenic therapy has been tempered by poor in vivo delivery to the tumor cell and potentially harmful side effects, such as the risk of bleeding due to heparin's anticoagulant activity . In order to overcome these limitations and further improve the therapeutic effect of LMWH, we designed a novel combination nanosystem of LMWH and ursolic acid (UA), which is also an angiogenesis inhibitor for tumor therapy. In this system, an amphiphilic LMWH-UA (LHU) conjugate was synthesized and self-assembled into core/shell nanodrugs with combined anti-angiogenic activity and significantly reduced anticoagulant activity. Furthermore, DSPE-PEG-AA-modified LHU nanodrugs (A-LHU) were developed to facilitate the delivery of nanodrugs to the tumor. The anti-angiogenic activity of A-LHU was investigated both in vitro and in vivo . It was found that A-LHU significantly inhibited the tubular formation of human umbilical vein endothelial cells (HUVECs) (p < 0.01) and the angiogenesis induced by basic fibroblast growth factor (bFGF) in a Matrigel plug assay (p < 0.001). More importantly, A-LHU displayed significant inhibition on the tumor growth in B16F10-bearing mice in vivo . The level of CD31 and p-VEGFR-2 expression has demonstrated that the excellent efficacy of antitumor was associated with a decrease in angiogenesis. In conclusion, A-LHU nanodrugs are a promising multifunctional antitumor drug delivery system.
研究领域:
药理学
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肿瘤学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Coatings
·
2023
·Vol. 13
·期 7
·1248
·
IF 3.4
Jincan Lei,Haiyan Wang,Qi Dang,Xiang Wang,Chungong Li,Jing Huang,Jingzhou Hou,Kejing Fang,Shixian Zhao
Activated carbon (AC) is an effective adsorbent for creatinine removal in hemoperfusion. However, the hemocompatibility and adsorption capacity of AC was required to be improved further. Heparin has different anticoagulant mechanisms due to its different molecular weights. Thus, it was necessary to study the surface modification with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) on improvement of hemocompatibility and adsorption. In this study, UFH and LMWH were, respectively, grafted on AC through polyethyleneimine as an intermediate layer. The modification of AC regarding morphology, mechanical strength, and pore structure was characterized by X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), texture analyzer (TA), and surface area analyzer. It was found that, compared with AC, the morphology and mechanical strength of AC-UFH and AC-LMWH could be well maintained, but the specific surface area was decreased due to the grafting of macromolecules. Furthermore, AC-UFH and AC-LMWH showed better hemocompatibility on protein adsorption, clotting time, and platelet activation compared with AC, in which AC-LMWH had lower fibrinogen adsorption and longer clotting time than AC-UFH. In addition, it was found that AC, AC-UFH, and AC-LMWH had no significant effect on blood cell composition. Finally, the adsorption capacity of adsorbents for creatinine was evaluated. Although there was no significant difference between AC-UFH and AC-LMWH, it was found that heparin could be interacted with creatinine to enhance the adsorption capacity when compared with polyethyleneimine-modified AC. This study deepened the understanding of anticoagulation of heparinized surface and provided a theoretical basis for adsorption in hemoperfusion.Keywords:heparin;hemocompatibility;activated carbon;adsorption
研究领域:
生物医学工程
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材料科学
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血液透析
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
·
IF 5.7
Chen-Lu Xu,Chen-Yuan Zhu,Yang-Nan Li,Jian Gao,Ye-Wang Zhang
A novel heparinase III from Pedobacter schmidteae (PsHep-III) with high activity and good stability was successfully cloned, expressed, and characterized. PsHep-III displayed the highest specific activity ever reported of 192.8 U mg–1 using heparin as the substrate. It was stable at 25 °C with a half-life of 323 h in an aqueous solution. PsHep-III was employed for the depolymerization of heparin, and the enzymatic hydrolyzed products were analyzed with gel permeation chromatography and high-performance liquid chromatography. PsHep-III can break glycosidic bonds in heparin like →4]GlcNAc/GlcNAc6S/GlcNS/GlcNS6S/GlcN/GlcN6S(1 → 4)ΔUA/ΔUA2S[1 → and efficiently digest heparin into seven disaccharides including N-acetylated, N-sulfated, and N-unsubstituted modification, with molecular masses of 503, 605, 563, 563, 665, 360, and 563 Da, respectively. These results indicated that PsHep-III with broad substrate specificity could be combined with heparinase I to overcome the low selectivity at the N-acetylated modification binding sites of heparinase I. This work will contribute to the application of PsHep-III for characterizing heparin and producing low-molecular-weight heparin effectively.
研究领域:
生物化学
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分子生物学
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制药工程
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2012
·
IF 3.212
Fatima Zohra Dahmani,Hui Yang,Jianping Zhou,Jing Yao,Ting Zhang,Qiang Zhang
In order to enhance paclitaxel oral bioavailability, mixed polymeric micelles that comprised of pluronic copolymers and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate were developed. PTX-loaded mixed polymeric micelles (MPMs) were prepared by dialysis method with high drug loading 26.92 ± 2.08% and 25.82 ± 1.9% for F127/LHR and P188/LHR MPMs respectively, and were found to be spherical in shape with an average size of around 140 nm and a narrow size distribution. In vitro release study showed that pluronic/LHR MPMs exhibited delayed release characteristics compared to Taxol and faster drug release profile compared to LHR plain polymeric micelles (PPMs). The cytotoxic activity of PTX-loaded pluronic/LHR MPMs was slightly higher than LHR PPMs in MCF-7 cells ( p < 0.01). In situ effective permeability of PTX through rat small intestine was 5- to 6-fold higher with mixed micelles than that of Taxol. Moreover, pluronic/LHR MPMs achieved significantly higher AUC and C max level than both of LHR PPMs and Taxol. This enhancement might be due to the inhibition of both P-glycoprotein efflux system and cytochrome P450 metabolism by pluronic copolymers. The current results encourage further development of paclitaxel mixed polymeric micelles as an oral drug delivery system .
研究领域:
药剂学
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肿瘤学
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DOI
PubMed
高影响因子
CHROMATOGRAPHIA
·
2015
·Vol. 78
·期 11
·833-837
·
IF 1.411
Zhang Mingyu,Qiu Danye,Kang Jingwu
A simple, sensitive and environmentally friendly capillary electrophoresis method for the determination of free sulfate anions in heparin and low-molecular-weight heparin with indirect UV detection is reported. The background electrolyte consists of 20 mM nitrate (pH 5.5) containing 0.2 mM CTAB. The use of nitrate as the probe anion is based on the consideration that nitrate has a very close electrophoretic mobility to that of sulfate, leading to a very narrow peak shape. Moreover, the apparent molar absorptivity of nitrate at 202 nm (8413 L mol −1 cm −1 ) is much higher than that of the commonly used probe anion chromate at 254 nm (2400 L mol −1 cm −1 ). The combination of the narrow peak shape with the high apparent molar absorptivity of the probe ion improved the limit of detection by 2.4 times and the limit of quantitation by 3.2 times. The effect of various CE parameters on the separation of sulfate from chloride was investigated and optimized. The method displays linearity in the range from 0.05 to 20 mM. The RSD % for intraday ( n = 6), and interday ( n = 3) repeatability in terms of migration times and peak areas were all less than 3 %. The limit of detection ( S / N = 3) and limit of quantitation ( S / N = 10) for sulfate were determined as 18 and 53 µM, respectively. The method was successfully applied for the quantification of sulfate anions in heparin and low-molecular-weight heparins.
研究领域:
分析化学
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药学
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2014
·
IF 3.785
Hailong Zhang,Jie Mi,Yayu Huo,Xiaoyan Huang,Jianfeng Xing,Akira Yamamoto,Yang Gao
Absorption enhancing effects of chitosan oligomers with different type and varying concentration on the intestinal absorption of low molecular weight heparin (LMWH) were examined by an in situ closed loop method in different intestinal sections of rats. Chitosan hexamer with the optimal concentration of 0.5% (w/v) showed the highest absorption enhancing ability both in the small intestine and large intestine. The membrane toxicities of chitosan oligomers were evaluated by morphological observation and determining the biological markers including amount of protein and activity of lactate dehydrogenase (LDH) released from intestinal epithelium cells. There was no obvious change both in levels of protein and LDH and morphology in the intestinal membrane between control and various chitosan oligomers groups, suggesting that chitosan oligomers did not induce any significant membrane damage to the intestinal epithelium. In addition, zeta potentials became less negative and amount of free LMWH gradually decreased when various chitosan oligomers were added to LMWH solution, revealing that electrostatic interaction between positively charged chitosan oligomers and negative LMWH was included in the absorption enhancing mechanism of chitosan oligomers. In conclusion, chitosan oligomers, especially chitosan hexamer, are safe and efficient absorption enhancers and can be used promisingly to improve oral absorption of LMWH.
研究领域:
药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
NANOTECHNOLOGY
·
2017
·Vol. 28
·期 7
·075102
·
IF 3.44
Wenming Cheng,Fatima Zohra Dahmani,Juan Zhang,Hui Xiong,Yuanyuan Wu,Lifang Yin,Jianping Zhou,Jing Yao
Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl–UA (UA–NH2) with the carboxylic groups of LMWH. The resulting LMWH–UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200–250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH–UA. Meanwhile, the in vivo antitumor effect of LMWH–UA was also evaluated using a B16F10 mouse melanoma model. LMWH–UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH–UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH–UA as a new therapeutic remedy for cancer therapy.
研究领域:
药理学
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肿瘤学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2018
·
IF 3.909
Haifeng Sun,Dinglingge Cao,Hao Wu,Huan Liu,Xue Ke,Tianyuan Ci
Tumor metastasis is the primary obstacle in cancer treatment and is always the leading cause of human death. And heparin and its derivatives are potential anti-metastatic agents with good biocompatibility. In this work, low molecular weight heparin (LMWH) based LMWH-Cholesterol (LHC) conjugates were prepared for intravenous delivery of doxorubicin (DOX). The DOX/LHC nanoparticles (DOX/LHC NPs) exhibited a spherical shape with a mean diameter of 135.5 ± 2.2 nm and had a longer circulation time than that of DOX. The in vitro results confirmed that the DOX/LHC NPs was more effectively taken up by 4T1 cells and showed a stronger anti-metastatic effect by cell invasion and cell migration compared with DOX. Meanwhile, DOX/LHC NPs also exhibited superior anti-metastatic effects in the pulmonary metastasis model compared with other groups. The reason may be account for the synergistic effect between the cytotoxic drug of DOX and its drug carrier of LMWH based nanoparticles, which is capable of anti-metastatic and anti-angiogenic efficiency. Thus DOX/LHC nanoparticles could be a promising anti-metastatic drug delivery system for postoperative chemotherapy.
研究领域:
药学
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肿瘤学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）