Clinical and Translational Medicine
·
2023
·Vol. 13
·期 6
·e1297
·
IF 10.6
Jie Yang,Hu Tan,Mengjia Sun,Renzheng Chen,Zhao Jian,Yuanbin Song,Jihang Zhang,Shizhu Bian,Bo Zhang,Yi Zhang,Xubin Gao,Zhen Chen,Boji Wu,Xiaowei Ye,Hailin Lv,Zhen Liu,Lan Huang
Background Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types. Methods Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro. Results In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model ( Tbx5 +/− ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. Conclusions This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.
研究领域:
心血管病学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2020
·
IF 4.268
Jian Sheng,Qingfen Meng,Zhenzhong Yang,Jianli Guan,Yu Zhao,Jide Zhang,Yingchao Wang,Lu Zhao,Yi Wang
Background Thromboembolic events are leading causes of mortality and morbidity all over the world. Tongmai (TM) is a botanical drug with valid clinical efficacy and safety in the management of thrombosis and ischemic cardiovascular diseases, however, its active compounds and underlying mechanism are largely unclear. Purpose To investigate the endogenous effects, therapeutic mechanism and active compounds of TM in thrombus formation. Study design Combined with transgenic zebrafish models and high-content imaging system, this study evaluated the endogenous antithrombotic effects of TM and screened for the active compounds. Methods The PHZ-induced thrombotic model in erythrocytes or platelets labeled transgenic zebrafish were established, to dynamically evaluate the antithrombotic effects of TM. The oxidative damage levels were analyzed by specific fluorescent probes, and the expression levels of key factors in coagulation cascades and platelet activation were examined by QPCR. TM were dissected into fractions by reverse phase chromatography and subsequently screened for their antithrombotic effects in the transgenic fish models. The compounds of the active TM fraction were then analyzed by UPLC-Q-TOF analysis and further verified for their antithrombotic effects and mechanisms. Results In PHZ-induced zebrafish thrombotic model, TM incubation markedly increased cardiac blood flow, decreased peripheral erythrocytes aggregation, and recovered peripheral platelet circulation. Besides, the levels of oxidative stress and lipid peroxidation were increased in the PHZ-induced thrombotic fish, which were greatly decreased by TM treatment. Moreover, TM significantly reduced the expression of coagulation factor II (thrombin) and the downstream fibrinogen. In order to identify the active compounds of TM, four fractions were separated from the extract by reverse phase chromatography, which were subsequently screened for their antithrombotic effects in the fish model. As a result, fraction 4 showed the strongest effect in inhibiting thrombosis. Finally, through UPLC-Q-TOF analysis and endogenous screening, cryptotanshione was identified as the main active compound with antithrombotic effects. Conclusion Our study demonstrated the endogenous antithrombotic effects of TM, which is possibly mediated by inhibiting oxidative stress and coagulation cascade. Cryptotanshione was identified as a major compound with antithrombotic activity and is a promising candidate for novel antithrombotic therapy.
研究领域:
药理学
·
心血管疾病
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Marine Drugs
·
2024
·Vol. 22
·期 10
·439
·
IF 4.9
Huiwen Zhang,Chen Sun,Qing Xia,Peihai Li,Kechun Liu,Yun Zhang
Existing antithrombotic drugs have side effects such as bleeding, and there is an urgent need to discover antithrombotic drugs with better efficacy and fewer side effects. In this study, a zebrafish thrombosis model was used to evaluate the antithrombotic activity and mechanism of Brevianamide F, a deep-sea natural product, with transcriptome sequencing analysis, RT-qPCR analysis, and molecular docking. The results revealed that Brevianamide F significantly attenuated the degree of platelet aggregation in the thrombus model zebrafish, leading to an increase in the number of circulating platelets, an augmentation in the return of blood to the heart, an elevated heart rate, and a significant restoration of caudal blood flow velocity. Transcriptome sequencing and RT-qPCR validation revealed that Brevianamide F may exert antithrombotic effects through the modulation of the MAPK signaling pathway and the coagulation cascade reaction. Molecular docking analysis further confirmed this result. This study provides a reference for the development of therapeutic drugs for thrombosis.
研究领域:
药理学
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分子生物学
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血栓研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Juan Wu,Zhenhua Huang,Dong Zhang,LaiqiangTong,Fan Gao,Fangping Chen,Changsheng Liu
Massive hemorrhage poses a serious threat to human health and even life. Access to rapid and potent hemostatic materials is crucial for lowering mortality rates. Starch-based materials exhibit good biocompatibility and are extensively utilized in hemostatic. However, existing starch-based hemostatic products suffer from limited hemostatic efficacy. Serotonin, an indoleamine naturally occurring in the human body, is recognized for its potent platelet-activating properties. Therefore, this study focused on enhancing the procoagulant activity of starch by incorporating serotonin into the starch backbone via esterification and amidation reactions, yielding a novel serotonin-loaded starch-based hemostatic sponge (SLS sponge). The SLS sponges featured exceptional porosity (≥80 %) and water absorption capacity (≥2000 %), which rapidly initiated the coagulation cascade reaction, promoted the adhesion and aggregation of red blood cells and platelets, and intensified platelet activation. This multifaceted approach synergistically enhanced hemostasis via both active and passive coagulation mechanisms. Notably, the SLS sponges adhered firmly to the wound surfaces without pressure. Compared with gelatin sponges, the SLS sponges significantly reduced blood loss by approximately 40.5 % and shortened the time to achieve hemostasis by approximately 28.9 %. These findings indicate that the newly developed SLS sponges are a promising active hemostatic material, particularly effective in managing non-compressible hemorrhages.
研究领域:
血液学
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材料科学
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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
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2024
·
IF 3.6
Chengzhi Wang,Dayang Jiang,Huipeng Ge,Jianping Ning,Xia Li,Mingmei Liao,Xiangcheng Xiao
Anticoagulation treatment for patients with high bleeding risk during hemodialysis is challenging. Contact between the dialysis membrane and the blood leads to protein adsorption and activation of the coagulation cascade reaction. Activated coagulation Factor X (FXa) plays a central role in thrombogenesis, but anticoagulant modification of the dialysis membrane is rarely targeted at FXa. In this study, we constructed an anticoagulant membrane using the polydopamine coating method to graft FXa inhibitors (apixaban and rivaroxaban) on the membrane surface. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM) were used to characterize the membranes. The apixaban- and rivaroxaban-modified membranes showed lower water contact angles, decreased albumin protein adsorption, and suppressed platelet adhesion and activation compared to the unmodified PES membranes. Moreover, the modified membranes prolonged the blood clotting times in both the intrinsic and extrinsic coagulation pathways and inhibited FXa generation and complement activation, which suggested that the modified membrane enhanced biocompatibility and antithrombotic properties through the inhibition of FXa. Targeting FXa to design antithrombotic HD membranes or other blood contact materials might have great application potential.
研究领域:
材料科学
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生物医学工程
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血液透析
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药学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Chengwei Wang,Haoyi Niu,Xiaoyu Ma,Hua Hong,Yuan Yuan,Changsheng Liu
Massive bleeding control and anti-infection are the major challenges for urgent trauma with deep and noncompressible hemorrhage in both clinic and battlefield. Inspired by the coordinated primarily blood clot formation and secondly coagulation cascade activation in natural hemostasis process, an injectable, quaternized hydroxyethyl cellulose/mesocellular silica foam (MCF) hydrogel sponge (QHM) for both hemorrhage control and antibacterial activities were prepared via one-pot radical graft copolymerization. The as-prepared QHMs exhibited instant water-triggered expansion and superabsorbent capacity and thereby effectively facilitated blood components concentration. Moreover, the QHM1 with appropriate amount of MCF (9.82 w/w %) could further activate the coagulation factors. Synergistically, the QHM1 could reduce the plasma clotting time to 59 ± 4% in vitro and showed less blood loss than commercially available hemostatics in vivo noncompressible hemorrhage models of lethal rabbit-liver defect. Furthermore, the QHM with a quaternary ammonium groups density of 2.732 mmol/g exhibited remarkable antibacterial activities and excellent cytocompatibility. With the efficient hemostasis efficacy and excellent antibacterial behavior, QHM dramatically facilitated the wound healing in a full-thickness skin defect model in vivo. Thus, this QHM represents a promising hemostatic in more widespread clinical application.
研究领域:
材料科学
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生物材料
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生物医学工程
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止血
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伤口愈合
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组织工程
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产品关联
DOI
PubMed
高影响因子
FIBERS AND POLYMERS
·
2023
·Vol. 24
·期 3
·801-810
·
IF 2.5
Wang Yi,Qin Hui,Chen Shuyi,Liu Yuan,Luo Jun,Nie Shengqiang
In this study, a highly efficient, convenient, and universal protocol of in situ cross-linking copolymerization of 2-hydroxyethyl methacrylate and sodium p-styrenesulfonate in polyvinylidene fluoride (PVDF) solution was presented to prepare blood-contacting material with good blood compatibility. The modified PVDF membranes were prepared by liquid–liquid-phase inversion technology, which could induce the enrichment of hydrophilic groups including sulfonic acid and hydroxyl groups on the surface of the modified PVDF membranes. The hydrophobic-fluorinated PVDF surfaces with hydrophilic sulphonic acid and hydroxyl groups exhibited high performance with prolonged clotting time (activated partial thromboplastin time and thrombin time) and low activation of blood components (platelets, coagulation cascade, and complements) when they contacted blood. On the other hand, the ultrafiltration experiment results revealed the improvement in the antifouling properties of the modified PVDF membranes after the introduction of hydrophilic groups on the membranes surface. The results indicate that the blood-compatible PVDF membranes may have potential to be used in the field of blood purification, and can be used as long-term blood-contacting materials as well.
研究领域:
材料科学
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生物医学工程
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血液相容性
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膜技术
✓ 已验证
产品关联
DOI
高影响因子
Drug Design Development and Therapy
·
2024
·
IF 4.7
Yule Wang,Yiran Li,Yue Zhou,Yue Gao,Lu Zhao
Background Currently, ischemic stroke (IS) continues to significantly contribute to functional deterioration and reduced life quality. Regrettably, the choice of neuro-rehabilitation interventions to enhance post-IS outcomes is limited. Guanxinning tablet (GXNT), a multi-component medicine composed of Danshen and Chuanxiong, has demonstrated neuroprotective potential against ischemic brain injury and diabetic encephalopathy. However, the therapeutic impact of GXNT on post-IS functional outcomes and pathological injury, as well as the underlying molecular mechanisms and anti-IS active substances, remain unclear.Methods To answer the above questions, neurological and behavioral assessment, cerebral lesions, and blood-brain barrier (BBB) integrity were combined to comprehensively investigate GXNT’s pharmacodynamic effects against post-IS injury. The possible molecular mechanisms were revealed through transcriptome sequencing coupled with experimental verification. Furthermore, the brain tissue distribution of main components in GXNT, behavioral changes of IS zebrafish, and molecular docking were integrated to identify the anti-IS active compounds.Results Treatment with GXNT significantly mitigated the functional deficits, cerebral cortex lesions, and BBB disruption following IS. Transcriptome sequencing and bioinformatics analysis suggested that complement and coagulation cascades as well as inflammation might play crucial roles in the GXNT’s therapeutic effects. Molecular biology experiments indicated that GXNT administration effectively normalized the abnormal expression of mRNA and protein levels of key targets related to complement and coagulation cascades (eg C3 and F7) and inflammation (eg MMP3 and MMP9) in the impaired cortical samples of IS mice. The locomotor promotion in IS zebrafish as well as favorable affinity with key proteins (C3, F7, and MMP9) highlighted anti-IS activities of brain-permeating constituents (senkyunolide I and protocatechuic acid) of GXNT.Conclusion Taken together, these intriguing findings indicate that GXNT intervention exerts a beneficial effect against post-IS injury via regulating the complement and coagulation cascades pathway and mobilizing inflammatory network. Senkyunolide I and protocatechuic acid show promise as anti-IS active compounds.
研究领域:
神经科学
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药理学
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分子生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Li Jun,Liu Hao,Yang Zhenzhong,Yu Qingqing,Zhao Lu,Wang Yi
Thrombosis is a key pathological event in cardiovascular diseases, and is also the most important targeting process for their clinical management. New drug development in thrombosis treatment is still in great demand. According to the traditional Chinese medicine (TCM) theory, thrombosis belongs to the syndrome of blood stasis. Salvia miltiorrhiza Bunge and Ligusticum striatum DC. are two common TCM herbs with long-term documented function in promoting blood circulation and inhibiting thrombosis, especially when used together. Guanxinning Tablet, a modern Chinese drug which contains extracts of the two herbs, also showed strong therapeutic effects in coronary heart disease. However, the pharmacological mechanism is still lacking for the compatibility of the two herbs. Here, through zebrafish-based in vivo fluorescence screening, we demonstrated the synergistic effects between S. miltiorrhiza Bunge and L. striatum DC. in regulating endogenous thrombosis. Moreover, combined with high-resolution mass spectrometry, the main compounds of the botanical drugs were analyzed and screened in our model system. Interestingly, cryptotanshinone and senkyunolide I, two representative compounds, respectively derived from the two herbs, also showed synergistic antithrombotic effects. Further analysis suggested that they may regulate thrombi formation at different levels via multiple signaling pathways, including oxidative stress, platelet activation and coagulation cascade. Taken together, our findings provided solid biological supports toward the drug compatibility theory of TCM, and suggested cryptotanshinone and senkyunolide I as promising drug candidates in thrombosis management.
研究领域:
药理学
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心血管疾病
·
传统中药
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斑马鱼模型
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药物开发
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 11
·期 6
·1331-1343
·
IF 7.571
Wenjie Huang,Juan Wu,Zhenhua Huang,Dong Zhang,Fangping Chen,Changsheng Liu
Uncontrolled bleeding remains one of the direct causes of high mortality. There is an urgent need for developing emergency hemostats capable of coping with uncontrolled bleeding. The commercial starch-based hemostatic powder (PerClot®) requires compression during application, which limits its application in hemostasis of irregular and non-compressed wounds. Herein, a boronic acid-modified thiol starch sponge (St-SP sponge) with self-gelling properties was developed for hemorrhage control. The results show that the St-SP sponge could quickly absorb blood, self-gel and self-heal to seal the bleeding sites. In addition, the St-SP sponge can rapidly initiate the coagulation cascade and promote the adhesion and aggregation of erythrocytes and platelets. The St-SP sponge exhibited significantly improved in vitro and in vivo hemostatic abilities as compared with PerClot. Notably, the St-SP sponge attained complete hemostasis without any compression in 61.5 s and made a great difference compared to PerClot (169 s) for the irregular wound constructed on the rabbit liver. In addition, the St-SP sponge had good hemocompatibility and cytocompatibility. It turns out that the newly developed St-SP sponge is a promising material for first-aid hemostasis of irregular and non-compressed wounds.
研究领域:
材料科学
·
生物医学工程
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止血
·
急诊医学
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产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2021
·
IF 7.328
Jiawen Chen,Liping Qiu,Qinglin Li,Jie Ai,Haiqing Liu,Qinhui Chen
It is important to control bleeding and prevent bacterial infection for the wound people. The effective way is to fabricate an asymmetric Janus matrial for realizing rapid hemostasis and promoting wound healing. Herein, mesoporous silica nanoparticles (MSN) modified by tannic acid (TA), silver nanoparticles, and calcium ions ( [email protected] ) with Janus structure were prepared via redox and coordination reactions. These anisotropic snowman-like particles possess obvious chemical compartition, in which silver nanoparticles are embedding in large MSN body. During blood coagulation, TA with catechol structure acts as a vasoconstrictor. Then, [email protected] with high specific surface area (510.62 m 2 ·g −1 ) and large pore volume (0.48 m 3 ·g −1 ) induces red blood cell aggregation to form three-dimensional network structure with fibrin. Additionally, calcium ions as clotting factor IV and negative charge of [email protected] accelerate coagulation cascade reaction. These three synergistic effects on animal model showed that hemostatic time of [email protected] was shortened by nearly 50% compared to that of MSN. Moreover, [email protected] possessed good blood compatibility, biocompatibility and antibacterial activity (~99%) against E. coli and S. aureus . The anisotropic Janus particles of [email protected] with hemostatic performance and antibacterial activity will be a promising biomaterial for designing wound dressings in clinical application.
研究领域:
材料科学
·
纳米技术
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生物医学工程
·
伤口护理
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Fenghua Wang,Jiahua Sun,Hui Shi,Jie Zhou,Xiaoke Ma,Xiaolu Song,Xianhao Su,Lei Liu
Hemostasis and anti-infection are crucial for emergency treatment of severe trauma. Developing functional biomaterial with efficient hemostasis, antibacterial activity and wound healing is of great social significance and clinical value to fast stop bleeding and save lives, but it is still challenged. Here we designed a series of multifunctionalized SA/PDA cryogels by using two-step cross-linking of dopamine and sodium alginate. The resulting interpenetrating network structure had good swelling ratio, excellent mechanical and shape memory properties. Compared with cotton gauze and gelatin sponge, the cryogels exhibited excellent activation of coagulation cascade, more blood cells and platelet adhesion . Due to the action of polydopamine, the cryogel also showed good antioxidant activity and photothermal antibacterial ability assisted by near-infrared radiation, as well as better wound healing performance than gelatin sponge and Tegaderm™ film. Moreover, in the tests of mouse tail docking model, rat femoral artery hemostasis model and non-compressible rabbit liver defect model, the treatment by SA/PDA cryogels presented less blood loss and shorter hemostasis time than cotton gauze and gelatin sponge. Therefore, SA/PDA cryogels with simple preparation process, low cost, and good biocompatibility would be applied in the variety of great clinical applications in bleeding control, anti-infection and wound healing, etc.
研究领域:
生物材料
·
止血
·
抗菌材料
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伤口愈合
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生物医学工程
✓ 已验证
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）