Polymer Chemistry
·
2013
·Vol. 4
·期 22
·5597-5602
·
IF 5.231
Zengchao Tang,Xiaoli Liu,Yafei Luan,Wei Liu,Zhaoqiang Wu,Dan Li,Hong Chen
A new strategy to regulate the attachment of plasminogen and its activator, t-PA, to a polyurethane surface is reported. The method is based on the one-step graft copolymerization of a lysine-containing methacrylic monomer and hydroxyethyl methacrylate (HEMA). The copolymer-modified PU surfaces showed high capacity for plasminogen and t-PA binding. The release of pre-adsorbed t-PA from the lysine-containing PU surfaces in contact with plasma was also investigated. It was shown that the interactions of plasminogen and t-PA on this type of surface can be controlled simply by changing the monomer feed ratio, and thus the relative quantities of HEMA and lysine in the grafts. This approach may be useful for the development of fibrinolytic, blood-contacting materials and, more generally, for controlling protein-surface interactions for biocompatibility.
研究领域:
生物材料学
·
医学工程
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DOI
高影响因子
Bioengineering-Basel
·
2024
·Vol. 11
·期 10
·1030
·
IF 3.8
Tuo Song,Xiaozhen Diao,Jun Cheng,Yang Man,Boyu Chen,Haixing Zhang,Wenhui Wu
As an essential thrombolytic agent, the tissue plasminogen activator receives increasing attention due to its longer half-life, lower immunogenicity, and easier administration, which are superior to other thrombolytic agents. In this study, the isolated and purified plasminogen activator from the sandworm (Perinereis aibuhitensis) was expressed inE.coli(Escherichia coli) to investigate its potential for simplifying the development process. The sandworm plasminogen activator was previously successfully cloned and expressed inE.coliwith low yield and activity in the culture supernatant. This low yield and activity prompted us to optimize its DNA sequence. Furthermore, to raise the efficiency in the separation of the target protein, the protein’s solubility was enhanced by fusing it with maltose-binding protein (MBP) tags. Eventually, the fibrinolytic activity was successfully restored after digestion with tobacco etch virus (TEV) protease. This study provides an innovative method of efficiently expressing and purifying plasminogen activators from sandworm inE.coliand broadens its applications in therapeutic treatment of cardiovascular diseases, including thrombosis, stroke, and coronary atherosclerotic heart disease.
研究领域:
生物化学
·
分子生物学
·
心血管疾病治疗
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DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Pengpeng Guan,Caijie Yuan,Jiali Li,Kun Yu,Ruiqi Xie,Enling Hu,Weiwei Ding,Guangqian Lan,Fei Lu
In the treatment of thrombosis, conventional nanocarriers inevitably have problems, such as adverse reactions and difficulties in synthesis. Inspired by the concept of ‘medicine food homology,’ we extracted and purified natural exosomes from mulberry leaves as carriers for the delivery of urokinase-type plasminogen activator (uPA) for targeted therapy. The obtained mulberry leaf exosomes (MLE) possessed a desirable hydrodynamic particle size (119.4 nm), a uniform size distribution (polydispersity index = 0.174), and a negative surface charge (−23.3 mv). Before loading with uPA, MLE were grafted with cyclic RGD (cRGD) to selectively bind activated platelets for thrombus targeting. The cytometry studies revealed that MLE@cRGD has a high thrombus targeting ability about 74.3 %. Animal tests demonstrated that the delivered uPA could dissolve clots almost completely in femoral vein thrombosis models. In addition, MLE could remodel venous microenvironments by effectively eliminating reactive oxygen species (ROS) and promoting the phenotypic transformation of macrophages from M1 to M2 for venous tissue repair.
研究领域:
药理学
·
纳米技术
·
治疗学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2017
·Vol. 8
·期 7
·2437-2443
·
IF 3.247
Guangpu Xue,Lihu Gong,Cai Yuan,Mingming Xu,Xu Wang,Longguang Jiang,Mingdong Huang
Quercetin is a member of the flavonoids and was previously demonstrated to inhibit trypsin-like serine proteases at micromolar potencies. Different molecular models were proposed to explain such inhibition. However, controversies remain on the molecular details of inhibition. Here, we report the X-ray crystal structure of quercetin in a complex with the urokinase-type plasminogen activator (uPA), an archetypical serine protease. The structure showed that quercetin binds to the specific substrate binding pocket (S1 pocket) of uPA mainly through its two neighboring phenolic hydroxyl groups. Our study thus provides unambiguous evidence to support quercetin binding to serine proteases and defines the molecular basis of the interaction. Our results further establish that natural products with two adjacent phenolic hydroxyl groups (or catechol) are likely to inhibit other trypsin-like serine proteases, a new mechanism formerly under-recognized.
研究领域:
生物化学
·
分子生物学
·
药理学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Shengjie Liu,He Yang,Xingyu Heng,Lihua Yao,Wei Sun,Qing Zheng,Zhaoqiang Wu,Hong Chen
To effectively solve the problem of significant loss of transplanted cells caused by thrombosis during cell transplantation, this study simulates the human fibrinolytic system and combines metabolic oligosaccharide engineering with strain-promoted azide–alkyne cycloaddition (SPAAC) click chemistry to construct a cell surface with fibrinolytic activity. First, a copolymer (POL) of oligoethylene glycol methacrylate (OEGMA) and 6-amino-2-(2-methylamido)hexanoic acid (Lys) was synthesized by reversible addition–fragmentation chain transfer (RAFT) copolymerization, and the dibenzocyclooctyne (DBCO) functional group was introduced into the side chain of the copolymer through an active ester reaction, resulting in a functionalized copolymer DBCO-PEG4-POL with ε-lysine ligands. Then, azide functional groups were introduced onto the surface of HeLa model cells through metabolic oligosaccharide engineering, and DBCO-PEG4-POL was further specifically modified onto the surface of HeLa cells via the SPAAC “click” reaction. In vitro investigations revealed that compared with unmodified HeLa cells, modified cells not only resist the adsorption of nonspecific proteins such as fibrinogen and human serum albumin but also selectively bind to plasminogen in plasma while maintaining good cell viability and proliferative activity. More importantly, upon the activation of adsorbed plasminogen into plasmin, the modified cells exhibited remarkable fibrinolytic activity and were capable of promptly dissolving the primary thrombus formed on their surfaces. This research not only provides a novel approach for constructing transplantable cells with fibrinolytic activity but also offers a new perspective for effectively addressing the significant loss of transplanted cells caused by thrombosis.
研究领域:
生物化学
·
细胞生物学
·
材料科学
·
药学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2025
·Vol. 36
·期 1
·1-18
·
IF 4.5
Fang Cuifu,Duan Qing,Tang Ying,Fu Lifeng,Chen Juzheng,Zhou Weimin,Liu Fengen
Venous thromboembolism ranks as the third most prevalent cardiovascular disease. Nanotechnology-based drug carriers show significant potential for thrombolytic therapy. However, existing systems face challenges, including environmental impact and limited accessibility. To address these, we developed a novel delivery system using human black hair-derived nanoparticles (HNPs). These HNPs were loaded with the thrombolytic agent urokinase plasminogen activator (uPA) and a minimal concentration of gold nanoparticles (AuNPs). These components were encapsulated within a polyvinyl alcohol (PVA) membrane to create the nanocapsule drug delivery system, uPA-Au@HNP@PVA. Upon intravenous injection into a rat model with venous thrombosis, the system leveraged targeted blood flow to reach thrombus sites. Under 1064 nm NIR irradiation, the PVA membrane dissolved, exposing and releasing the drugs for intelligent thrombolysis. This system demonstrated excellent thrombolytic efficacy both in vivo and in vitro, coupled with robust biocompatibility in various biological tests, suggesting a wide range of potential applications. Graphical Representation: a. Depiction of the uPA-Au@HNP@PVA synthesis process. b. Diagrammatic explanation of intelligent thrombolytic therapy for specific drug delivery in a rat venous thrombosis model: I. Intravenous administration of uPA-Au@HNP@PVA; II. Targeted delivery to thrombus sites, navigation of uPA-Au@HNP@PVA to the thrombus location through targeted blood circulation, whereupon exposure to 1064 nm NIR irradiation causes a temperature rise, resulting in PVA dissolution, and drug release; III. NIR-triggered drug release and thrombolysis. Intelligent thrombolysis facilitated by 1064 nm NIR irradiation.
研究领域:
纳米技术
·
生物医学工程
·
心血管医学
·
药学
·
光响应治疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Mengjuan Sun,Chang Liu,Ji Liu,Jing Wen,Tianjiao Hao,Daquan Chen,Yan Shen
Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.
研究领域:
心血管疾病
·
药学
·
纳米技术
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Caijie Yuan,Yaxin Ye,Enling Hu,Ruiqi Xie,Bitao Lu,Kun Yu,Weiwei Ding,Wenyi Wang,Guangqian Lan,Fei Lu
Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO 3 /cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.
研究领域:
药学
·
纳米技术
·
药物递送系统
·
血栓
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2018
·
IF 2.831
Li Li,Jing Kong,Chun-hua Yao,Xiu-feng Liu,Ji-hua Liu
The urokinase plasminogen activator (uPA) is regarded as the crucial trigger for plasmin generation, which is involved in several diseases especially for neoplasm metastasis. In this study, an efficient approach integrating ultrafiltration, LC/MS, bioassay and in silico docking, was proposed for rapidly detecting uPA ligands from Traditional Chinese Medicines (TCMs). Forty-two TCMs were initially assessed, and as illustrative case studies, Galla Chinensis and Sanguisorbae Radix, which appeared significant inhibitory activities on uPA, were chosen to develpe and verify the strategy. A total of seven uPA ligands were successfully detected and identified. Two of them, pentagalloylglucose and 28- O - β - d -glucopyranosyl pomolic acid, were demonstrated to be potential inhibitors, with IC 50 at 1.639 μM and 37.82 μM repectively. Furthermore, a combinatorial compound library screening combined with in silico docking assay, was revealed that ursolic acid (IC 50 = 2.623 μM) was also speculated to be a potent parent structure for inhibition of uPA. This approach offers a multidimensional perspective to discover uPA-binding leading compounds from TCMs or other complex mixtures, which would provide an efficient route for drug discovery.
研究领域:
药理学
·
生物化学
·
中药学
·
药物发现
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Yunbo Jia,Xiaoxi Xu,Yang Liu,Hongfei Shen,Siyu Sun,Guangwei Sun
Changes in sodium alginate and calcium ion concentrations have a considerable impact on the structural properties of calcium alginate gel (ALG) beads, consequently influencing the biological characteristics of the cells encapsulated within them. This study aimed to examine the effects of calcium on the metastatic potential of hepatocellular carcinoma (HCC) cells encapsulated in ALG beads. The results showed that the invasion ability of HCC cells significantly increased when they were encapsulated in beads prepared with a calcium concentration of 200 mM compared to those prepared with a calcium concentration of 50 mM. Furthermore, the expression levels of genes related to metastasis were significantly elevated in ALG beads prepared with a calcium concentration of 200 mM. Specifically, the expression of activated matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and urokinase-type plasminogen activator system proteins was found to be high. Conversely, the expression of phosphatase and tensin homolog deleted on chromosome 10 was observed to be significantly reduced. These findings indicate that manipulating the calcium ion concentration during the fabrication of ALG beads enables the generation of three-dimensional HCC cells with varying metastatic capacities. This model offers a valuable tool for investigating the mechanisms underlying liver cancer metastasis and screening potential therapeutic drugs.
研究领域:
癌症生物学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Xingping Quan,Chang Liu,Jinfen Chen,Yiyang Li,Zhen Yuan,Ying Zheng,Greta S. P. Mok,Ruibing Wang,Yonghua Zhao
Thromboembolic stroke constitutes the majority of brain strokes, resulting in elevated mortality and morbidity rates, as well as significant societal and economic burdens. Although intravenous thrombolysis serves as the standard clinical treatment, its narrow therapeutic window and the inflammatory response induced by tissue plasminogen activator (tPA) administration limit its efficacy. In the initial stages of stroke, the abrupt cessation of blood flow leads to an energy metabolism disorder, marked by a substantial decrease in adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, causing irreversible damage to neural cells. In this study, we introduce a neutrophil-mimetic, microalgae-derived upconversion photosynthetic nanosystem designed for targeted treatment of thromboembolic stroke. This system features upconversion nanoparticles coated with a thylakoid membrane and wrapped in an activated neutrophil membrane, further decorated with ROS-responsive thrombolytic tPA on its surface. The neutrophil-mimetic design facilitates high targeting specificity and accumulation at the thrombus site after intravenous administration. Upon exposure to elevated levels of reactive oxygen species (ROS) at the thrombus location, the nanosystem promptly demonstrated potent thrombolytic efficacy through the surface-modified tPA. Furthermore, near-infrared II (NIR-II) laser irradiation activated the generation of ATP and NADPH, which inhibited inflammatory cell infiltration, platelet activation, oxidative stress, and neuronal injury. This constructed nanoplatform not only showcases exceptional targeting efficiency at the stroke site and controllable release of the thrombolytic agent but also facilitates ATP/NADPH-mediated thrombolytic, anti-inflammatory, antioxidative stress, and neuroprotective effects. Additionally, it offers valuable insights into the potential therapeutic applications of microalgae-based derivatives in managing thromboembolic stroke.
研究领域:
纳米技术
·
生物医学工程
·
神经科学
·
药学
·
光化学
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DOI
PubMed
高影响因子
COMPOSITES PART B-ENGINEERING
·
2024
·
IF 12.7
Shifen Li,Wajiha Ahmed,Shuqin Wang,Xinman Hu,Beiduo Wang,Zhaoyi Wang,Liyin Shen,Yang Zhu,Changyou Gao
The adhesion between heart and chest post-operation raises a significant challenge for the application of cardiac patches due to its severe influences on the recovery of heart function and increased risk of re-treatment. Anabatic inflammatory response and increased oxidative stress aggravate the damage to heart functions. Herein, a multi-functional cardiac patch was manufactured by successive electrospinning of two types of novel selenium-containing polyurethanes (PU), followed by click grafting of poly (ethylene glycol) (PEG) molecules on the top layer. This patch possessed dual-functions of postoperative anti-adhesion and anti-oxidative stress for efficient therapy post myocardial infarction (MI). The high redox reactivity of diselenium bonds were introduced into the main chains of PU, which reduced the level of reactive oxygen species (ROS) and modulated the inflammatory environment, alleviating the synechia formation simultaneously. The cardiac patch could effectively resist fibroblast adhesion, regulate the expression of vinculin and tissue-type plasminogen activator (t-PA), and inhibit the synechia formation. Meanwhile, it also restored significantly the heart function post MI by decreasing the local inflammation, facilitating less collagen formation, and improving cell signal transduction and angiogenesis. Collectively, this novel patch achieved anti-adhesion and therapeutic effect synergistically, bringing advancement in cardiac patch design and potential for translation of medicinal devices.
研究领域:
生物材料
·
心血管工程
·
组织工程
·
再生医学
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DOI
高影响因子
危险品化学品经营许可证（带存储）