Matter
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2025
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IF 17.5
Yang An,Jihua Liu,Xiaoyu Cheng,Zhenzhen Dong,Yubiao Huang,Ge Sun,Jiarui Du,Guangjun Nie,Yinlong Zhang
Antiplatelet agents (APAs) are crucial for the clinical prevention and treatment of thrombotic diseases, but their long-term use has serious bleeding risk. In emergency situations, it is essential to rapidly reverse the effect of APAs and restore the hemostatic function of platelets. However, there are currently no specific antiplatelet reversal agents approved for clinical use. Here, we describe a click chemistry-functionalized gold nanoplatform for the reversal of APAs. The gold nanoparticles (AuNPs), modified with dibenzocyclooctyne or maleimide on their surface, are able to neutralize the antiplatelet activity of azido-modified ticagrelor and clopidogrel, respectively. The in vitro platelet aggregation assays and in vivo tail bleeding or liver injury experiments validate the effectiveness of the gold nanoplatform. In summary, our study introduces a gold nanoplatform that can be easily prepared through a simple method and has great potential to be used for the functional reversal of various APAs.
CAS / MDL:
研究领域:
药理学
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纳米医学
·
血液学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2019
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IF 6.054
Deyu Kong,Tao Xue,Bin Guo,Jianjun Cheng,Shunyin Liu,Jianhai Wei,Zhengyu Lu,Haoran Liu,Guoqing Gong,Tian Lan,Wenhao Hu,Yushe Yang
P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure–pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.
研究领域:
药理学
·
药物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Jingjing Lin,Jiayuan Lai,Jiaxiang Xu,Yicheng Lin,Qing Yan,Rongfang Lin,Wenjuan Ma
P2Y12 expression is elevated in circulating plasma cells and ASCs in SLE. • Ticagrelor attenuates plasma cell and ASC responses and CXCL12-directed migration. • Ticagrelor alters ATP-associated transcriptional programs in lupus-prone B cells. • Ticagrelor reduces autoantibody levels and lupus nephritis severity in MRL/lpr mice. Background Persistent plasma cell responses in systemic lupus erythematosus (SLE) sustain autoantibody production and immune complex formation, contributing to macrophage activation and renal inflammation. We investigated P2Y12 expression in plasma cell-related populations and evaluated the effects of ticagrelor on humoral and macrophage inflammatory responses in SLE. Methods P2Y12 expression was examined in peripheral blood mononuclear cells from patients with SLE and healthy controls and in renal tissues from patients with lupus nephritis. Functional studies were performed in SLE PBMCs, splenic B cells from MRL/lpr mice, bone marrow-derived macrophages, and RAW264.7 cells. CXCL12-directed migration, RNA sequencing, P2ry12 silencing, and macrophage stimulation with OVA-containing immune complexes or MRL/lpr serum were used to examine cellular responses. The effects of ticagrelor were further evaluated in vivo in MRL/lpr mice. Results Patients with SLE showed increased frequencies of circulating plasma cells, together with increased P2Y12 expression in plasma cells and antibody-secreting cells (ASCs). Plasma-cell P2Y12 expression was positively correlated with CXCR4 expression. Renal tissues from patients with lupus nephritis showed stronger P2Y12, IgG, and C3 signals. In SLE PBMC cultures, ticagrelor attenuated plasma cell and ASC responses, accompanied by lower BLIMP1 and BATF expression and reduced BTK/SYK phosphorylation. Ticagrelor also reduced CXCL12-directed migration of bone marrow B-lineage cells and plasma cells. In MRL/lpr splenic B cells, ticagrelor altered ATP-associated transcriptional responses involving immune activation and inflammatory pathways. In macrophages, ticagrelor attenuated inflammatory responses to OVA-containing immune complexes, LPS, and MRL/lpr serum, while P2ry12 silencing altered macrophage inflammatory phenotypes in the presence of ticagrelor. In vivo, ticagrelor reduced circulating immunoglobulin and autoantibody levels, splenic B-cell abnormalities, renal IgG and C3 deposition, macrophage-associated inflammatory changes, and renal histopathological injury in MRL/lpr mice. Conclusions P2Y12 expression was associated with plasma cell-related abnormalities in SLE, and ticagrelor attenuated humoral and macrophage inflammatory responses in both cellular and lupus-prone mouse models. These findings suggest that P2Y12-related immune regulation and the immunomodulatory actions of ticagrelor merit further investigation in SLE.
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Yang Liu,Chunling Wang,Pengfei Wei,Chengzhi Yang,Xiaoyu Cheng,Yinlong Zhang,Guangjun Nie
The severe bleeding complications of long-term antiplatelet therapy limit its broader application in the treatment or prevention of thrombosis-associated diseases. This risk is particularly serious when facing emergency surgeries where rapid restoration of normal platelet function is required. Timely reversal of the effects of antiplatelet agents becomes crucial in such scenarios. Despite the widespread use of clopidogrel and prasugrel for their potent antiplatelet activity, the absence of specific and effective reversal agents remains a notable challenge. The pharmacological activity of clopidogrel and prasugrel is mediated by sulfhydryl-containing active metabolites, which form disulfide bonds with P2Y 12 receptors on the surface of platelets to inhibit their aggregation. Taking advantage of this action mechanism of these “irreversible” antiplatelet drugs, click chemistry-functionalized mesoporous silica (SiO 2 -Mal) nanotraps are fabricated to capture the antiplatelet drugs' active metabolites and restore hemostasis. Subsequently, a comprehensive assessment of the effectiveness and safety of the SiO 2 -Mal nanotraps is conducted using mouse, rabbit, and pig animal models, highlighting their potential application as a functional reversal agent for clinically relevant thienopyridine antiplatelet drugs, believed until now to be irreversible in their inhibition of platelet activity.
研究领域:
药理学
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纳米医学
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血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
eLife
·
2023
·
IF 7.7
Yang He,Taohui Liu,Quansheng He,Wei Ke,Xiaoyu Li,Jinjin Du,Suixin Deng,Zhenfeng Shu,Jialin Wu,Baozhi Yang,Yuqing Wang,Ying Mao,Yanxia Rao,Yousheng Shu,Bo Peng
General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.
研究领域:
神经科学
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麻醉学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL RESEARCH
·
2026
·
IF 4.1
Mo Jiajia,He Emily M.,Zhao Yan,Shao Li,Yue Shaoyun,Xie Yanmei,Wu Shiqi,He Jianxun,Zou Yi,Chu Zhaoxing,He Guangwei,Xu Yungen
Purpose Patients with acute coronary syndrome (ACS) require rapid and potent antiplatelet therapy during percutaneous coronary intervention (PCI). Current first-line P2Y₁₂ inhibitors are limited by delayed efficacy or an ultrashort half-life. This study aims to characterize the metabolism and pharmacodynamics of HY-022619, a disodium phosphate ester salt of ticagrelor, to provide a theoretical basis for its clinical use in peri-PCI antithrombotic therapy. Methods The inhibitory activity of HY-022619 against the P2Y₁₂ receptor and ADP-induced platelet aggregation was evaluated in vitro . Molecular docking was performed to compare its receptor-binding mode with ticagrelor. Metabolic stability was assessed in whole blood, liver microsomes, and using recombinant enzymes. Pharmacodynamic profiles were investigated in rats and beagle dogs, with additional assessments of metabolic conversion and bleeding time in dogs. Results HY-022619 showed 22-fold greater P2Y₁₂ receptor inhibition and 15-fold stronger suppression of platelet aggregation than ticagrelor. Molecular docking revealed that enhanced activity was due to an additional salt bridge. HY-022619 remained stable in human and non-rodent whole blood (half-life > 60 min) and was primarily hydrolysed to ticagrelor in the liver by CES1 and CES2. In rats, intravenous administration produced rapid, dose-dependent platelet inhibition within 5 min. In dogs, HY-022619 acted rapidly with efficacy peaking at the end of infusion. It converted completely to ticagrelor within 5 min post-infusion, maintaining antiplatelet effects for 6 h, without significantly prolonging bleeding time compared to ticagrelor. Conclusion HY-022619 demonstrates rapid, potent, and sustained antiplatelet effects, supporting its potential clinical application. Graphical
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DOI
PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Bo Wei,Guo Cheng,Qianqian Bi,Cheng Lu,Qihang Sun,Li Li,Ningting Chen,Miner Hu,Haoran Lu,Xuancheng Xu,Genxiang Mao,Shu Wan,Zhechun Hu,Yan Gu,Jiaxin Zheng,Li Zhao,Xiao Z. Shen,Xiaoli Liu,Peng Shi
Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
研究领域:
神经科学
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心血管研究
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免疫学
✓ 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）