Advanced Science
·
2022
·Vol. 9
·期 20
·2200281
·
IF 17.521
Liwen Hong,Gaoxian Chen,Zhengwei Cai,Hua Liu,Chen Zhang,Fei Wang,Zeyu Xiao,Jie Zhong,Lei Wang,Zhengting Wang,Wenguo Cui
Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over-stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti-thrombosis and anti-inflammation competency is developed to impede this cycle, cross-linked by silver ion mediated metal-ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP-Ag-BSA, exhibits excellent self-healing ability, injectability, biocompatibility, and sustained drug release. HEP-Ag-BSA also demonstrates anti-coagulation and anti-inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP-Ag-BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP-Ag-BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the “inflammation and microthrombosis” cycle, providing a novel integrated approach against IBD.
研究领域:
药理学
·
生物医学工程
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Mengnan Yang,Yuqing Tong,Shaoping Yin,Hengchuan Zhang,Xiaowen Huang,Kai Yuan,Yanfei Hao,Jianping Zhou,Meirong Huo,Tingjie Yin
Local inhibition of the “patching” function of tumor-associated platelets against neutrophil infiltration-caused vascular breaches has been used as an “enhanced permeability and retention (EPR) amplification” strategy. Nevertheless, the vascular leakage-resulted elevation of interstitial fluid pressure (IFP) could impact tumoral perfusion and convection of nanodrugs. Especially for hypoperfused and desmoplastic pancreatic ductal adenocarcinoma (PDAC), solely relying on vascular destruction would predictably diminish tumoral drug perfusion. According to multi-thrombosis formation in PDAC, a microthrombi and matrix co-targeted dasatinib (DAS) nano-micelle (CPHD/DAS) synchronizing endothelial gap opening and matrix decompression was constructed for sustained augmentation of drug perfusion within PDAC. CPHD/DAS was composed of CREKA peptide-modified hyaluronic acid–deoxycholate conjugates co-assembled with DAS. In vitro and in vivo results demonstrated CPHD/DAS not only retarded tumor-associated platelet activation to enhance vascular permeability and expose subvascular matrix, but also inhibited pancreatic stellate cell activation to alleviate stroma barrier. Thus, the matrix decompression resisted IFP elevation caused by endothelial gap opening, facilitating sustained up-regulation of functional vessels. Based on superior tumor accumulation and penetration, CPHD/DAS exhibited favorable potency in Panc02 tumor model. This study provides a paradigm to improve the efficiency and application scope of “EPR amplification” strategy in antitumor therapy.
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Xiaoxuan Xu,Tingting Xu,Dongfang Liu,Jie Ding,Di Chang,Jinbing Xie,Shenghong Ju
The presence of cerebral ischemia/reperfusion (CI/R) poses a significant impediment to the complete restoration of neuronal functioning following the onset of ischemic stroke and the implementation of clinical thrombolytic treatments. The timely identification of microthrombus is crucial in the early recognition of microcirculatory complications and in facilitating informed clinical decisions. However, current assays, such as clinical pathological analysis and imaging detection, have not adequately met the requirements for intravital detection of microthrombus following CI/R. To address this limitation, this study introduces a dual-modality nanoprobe named GNC, specifically designed for intravital detection of fibrin-rich microthrombus. By combining high-temporal-resolution optical imaging and high-spatial-resolution magnetic resonance imaging, the GNC nanoprobe enables noninvasive real-time imaging of microthrombus at the nanoscale and guides subsequent therapeutic decisions. This innovative approach of the GNC nanoprobe showed great promise in the development of diagnostic and therapeutic tools for managing microthrombus following CI/R.
研究领域:
神经科学
·
生物医学工程
·
成像技术
·
纳米技术
·
临床诊断
✓ 已验证
产品关联
DOI
高影响因子
Neurotherapeutics
·
2024
·
IF 5.6
Zhiyuan Shen,Yuxuan Lu,Yingying Ren,Zhaoxia Wang,Jianwen Deng,Ding Nan,Jingjing Jia,Weiwei Yu,Yunyi Jin,Wei Sun,Yining Huang,Xiaozhong Qu,Haiqiang Jin
The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA 3 -Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.
研究领域:
神经科学
·
中风
·
微循环
·
氧测量
·
动物模型
✓ 已验证
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
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
·
2025
·
IF 5
Yue-Xin Ning,Ji-Ru Cai,Ting-Ting Wang,Yi-Han Wang,Yu Cui,Hui-Sheng Chen
Background Endovascular treatment (EVT) alone was not demonstrated to be non-inferior to intravenous alteplase bridging EVT in acute large vessel occlusion (LVO) stroke. Using cerebral ischemia/reperfusion (I/R) injury model, intravenous tenecteplase (TNK) was administrated after ischemia followed by reperfusion at various time points. Objectives To investigate whether intravenous TNK bridging EVT vs EVT alone could improve I/R injury, and this effect may be associated with the time from TNK to reperfusion. Methods Rats received intravenous TNK (1.4 mg/kg) or vehicle (sterile water) 1.0 hour after middle cerebral artery occlusion (MCAO), followed by reperfusion after 0.5 or 1.0 hour following TNK. Neurological deficit scores, infarct volume, and brain edema were measured at 24 hours after MCAO. Microthrombi were determined by immunofluorescence staining for CD31 + /fibrinogen + and CD31 + /thrombocyte + . Inflammatory cell infiltration in the ischemic brain region was determined by flow cytometry. Results Compared with vehicle, TNK significantly reduced neurological deficit scores, brain infarction, neuro-inflammation, and blood-brain barrier (BBB) disruption, and significantly reduced intravascular fibrin and platelet deposition, and brain inflammatory cell infiltration in penumbra of I/R rats. Furthermore, a better beneficial trend was found in TNK bridging reperfusion at 0.5 hour after TNK compared with TNK bridging reperfusion at 1.0 hour after TNK. Conclusions Our results demonstrate that intravenous TNK bridging reperfusion produced neuroprotective action through dissolving microvascular thrombus and alleviating inflammatory cell infiltration to improve microcirculation, with the result of maintaining BBB integrity and inhibiting neuroinflammation, and the neuroprotective benefit may be associated with the time from TNK to reperfusion.
研究领域:
神经科学
·
药理学
·
实验性卒中研究
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）