Scientific Reports
·
2016
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IF 5.228
Hengli Zhao,Xuan Zhang,Zhiqiang Dai,Yang Feng,Qiang Li,John H. Zhang,Xin Liu,Yujie Chen,Hua Feng
Blockading P2X7 receptor(P2X7R) provides neuroprotection toward various neurological disorders, including stroke, traumatic brain injury, and subarachnoid hemorrhage. However, whether and how P2X7 receptor suppression protects blood-brain barrier(BBB) after intracerebral hemorrhage(ICH) remains unexplored. In present study, intrastriatal autologous-blood injection was used to mimic ICH in rats. Selective P2X7R inhibitor A438079, P2X7R agonist BzATP, and P2X7R siRNA were administrated to evaluate the effects of P2X7R suppression. Selective RhoA inhibitor C3 transferase was administered to clarify the involvement of RhoA. Post-assessments, including neurological deficits, Fluoro-Jade C staining, brain edema, Evans blue extravasation and fluorescence, western blot, RhoA activity assay and immunohistochemistry were performed. Then the key results were verified in collagenase induced ICH model. We found that endogenous P2X7R increased at 3 hrs after ICH with peak at 24 hrs, then returned to normal at 72 hrs after ICH. Enhanced immunoreactivity was observed on the neurovascular structure around hematoma at 24 hrs after ICH, along with perivascular astrocytes and endothelial cells. Both A438079 and P2X7R siRNA alleviated neurological deficits, brain edema, and BBB disruption after ICH, in association with RhoA activation and down-regulated endothelial junction proteins. However, BzATP abolished those effects. In addition, C3 transferase reduced brain injury and increased endothelial junction proteins' expression after ICH. These data indicated P2X7R suppression could preserve BBB integrity after ICH through inhibiting RhoA activation.
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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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Jiajia Mu,Qiannan Sun,Nanyan Lin,Chenguang Yue,Jiaqiao Zhu,Hui Zou,Hongyan Zhao,Ruilong Song,Zongping Liu,Yonggang Ma
Ketosis in dairy cows is linked to endometritis, but the molecular mechanisms are unclear. We investigated whether P2X7R is crucial in ketosis-induced endometritis. Ketotic cows had higher levels of NLRP3, caspase-1, GSDMD, GSDME, and P2X7R in the uterine tissue. β-Hydroxybutyric acid (BHBA) exposure in bovine endometrial epithelial cells induced pyroptosis, increased pyroptosis protein and gene expression, and raised pyroptosis rates. P2X7R levels rose with BHBA, and BHBA also increased the level of extracellular ATP. Inhibitors of NLRP3, caspase-1, caspase-3, and P2X7R reduced BHBA-induced pyroptosis. P2X7R inhibition suppressed NLRP3, caspase-1, and caspase-3 activation, preventing pyroptosis. In P2rx7–/– mice with a ketosis model, blood BHBA was lower, and uterine tissue showed less pyroptosis-related protein expression compared to ketotic mice. P2X7R appears to regulate BHBA-induced pyroptosis through NLRP3 and caspase-3 signaling, suggesting it is a potential therapeutic target.
研究领域:
兽医学
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生殖生物学
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细胞生物学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
·
2023
·
IF 2.8
Yanli Song,Dongjie He,Shaoqi Shi,Tianwei Cui,Hui Zhang,Xianmin Zhao,Tingting Ni,Huidongzi Xiao,Aiwu Wei
BackgroundWomen with antiphospholipid syndrome (APS) or antiphospholipid antibodies (aPLs) are at high risk for obstetric complications, including recurrent pregnancy loss (RPL). However, effective treatments for RPL are lacking.ObjectiveThis study aimed to reveal the function and underlying mechanism of hyperoside (Hyp) in RPL associated with antiphospholipid antibodies (aCLs).MethodsThe pregnant rats (N = 24) were divided randomly into four groups: normal human-IgG (NH-IgG); aCL-pregnancy loss (aCL-PL); aCL-PL + Hyp (40 mg/kg/day); aCL-PL + low molecular weight heparin (LMWH, 525 μg/kg/day). HTR‐8 cells were treated with 80 μg/mL aCL to establish the cell models of miscarriage.ResultsIn pregnant rats, aCL-IgG injection raised the abortion rate of embryos, while Hyp treatment inhibited the effects. Additionally, Hyp inhibited the platelet activation and uteroplacental insufficiency caused by aCL. In vivo and in vitro experiments further suggested that Hyp suppressed aCL-induced inflammation and apoptosis by downregulating NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-related factors and decreasing apoptotic rates. After aCL administration, Hyp therapy downregulated the expression of purinergic ligand-gated ion channel 7 (P2X7), which is reported to induce cytokine release and apoptosis. Furthermore, we found that the treatment of 3′-O-(4-Benzoyl) benzoyl-ATP (BzATP, an agonist of the P2X7 receptor) reversed the inhibitory effects of Hyp on cell function.ConclusionsHyp exerts protective effects on aCL-induced pregnancy loss by preventing platelet activation-mediated P2X7/NLRP3 pathway. Therefore, Hyp may provide a feasible pharmaceutical strategy for the treatment of RPL.
研究领域:
妇产科学
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免疫学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2022
·Vol. 79
·期 2
·287-295
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IF 5.08
Ye Fan,Lv Jiahua,Shen Xinyu,Zhang Jian,Zong Yingxin,Zhu Chan,Yang Yan,Jia Keke,Jiang Yucui,Tang Zongxiang
Rutin is a natural anti-inflammatory ingredient widely found in medicinal plants. Studies have shown that rutin inhibits mast cell degranulation and the release of inflammatory mediators. Mast cell P2X7 receptor mediates mast cell degranulation and serves as a therapeutic target for inflammatory pain. Herein, the aim of this study was to investigate whether the anti-inflammatory mechanism of rutin is related to the mast cell P2X7 receptor. Our results showed that rutin could inhibit [Ca 2+ ] i elevation induced by 5 mM ATP or 30 μM BZATP in a concentration-dependent manner in mouse peritoneal mast cells. Rutin also suppressed the inward current mediated by P2X7 receptor. In vivo, rutin could significantly inhibit the mechanical hypersensitivity induced by 100 mM ATP that is associated with P2X7 receptor in mast cells. Moreover, molecular docking revealed the high affinity between rutin and the P2X7 receptor crystal structure. Collectively, this study demonstrated that rutin attenuated inflammatory pain by inhibiting the activity of P2X7 receptor in mast cells.
研究领域:
药理学
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免疫学
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疼痛研究
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DOI
PubMed
高影响因子
Redox Biology
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2024
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IF 10.7
Xin Zhong,Kangwei Wang,Yonghua Wang,Luya Wang,Sudan Wang,Weijian Huang,Zhuyin Jia,Shan-Shan Dai,Zhouqing Huang
Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the C-type domain form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.
研究领域:
心血管疾病
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Purinergic Signalling
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2020
·Vol. 16
·期 4
·585-599
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IF 3.065
Ge Huixiang,Sun Mengyun,Wei Xingyu,Zhang Mingming,Tu Hongcheng,Hao Yuanzhen,Chen Ruxin,Ye Miao,Gao Yun
Activated astrocytes play a key role in diabetic neuropathic pain and depression. We aimed to assess the protective effects of dihydromyricetin (DHM) on primary hippocampal astrocytes cultured with high glucose (HG), substance P (SP), and corticosterone (CORT). Culturing with HG + SP + CORT resulted in damage to primary hippocampal astrocytes, which simulates the clinical damage caused by comorbidity of diabetic neuropathic pain and depression. Western blot, qPCR, and immunofluorescence analyses revealed that HG + SP + CORT increased P2X 7 receptor expression in primary hippocampal astrocytes, which was reversed by DHM treatment. Further, HG + SP + CORT elevated TNF-α, IL-1β, free Ca 2+ , and ERK1/2 phosphorylation levels, which was inhibited by DHM or P2X 7 shRNA treatment. Moreover, DHM significantly reduced the P2X 7 agonist-activated currents in HEK293 cells transfected with the P2X 7 receptor. These findings suggest that DHM can protect primary hippocampal astrocytes cultured with HG + SP + CORT from P2X 7 receptor-mediated damage. Culturing cells with HG + SP + CORT might be a viable cell model for cellular injury exploration of diabetic comorbid pain and depression.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2017
·Vol. 14
·期 1
·1-18
·
IF 5.102
Zhao Hengli,Pan Pengyu,Yang Yang,Ge Hongfei,Chen Weixiang,Qu Jie,Shi Jiantao,Cui Gaoyu,Liu Xin,Feng Hua,Chen Yujie
Background Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H2S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-associated neuroinflammation in the central nervous system. However, the effects of H2S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown.Methods We employed a Sprague–Dawley rat of collagenase-induced ICH in the present study. The time course of H2S content and the spatial expression of cystathionine-β-synthase (CBS) after ICH, the effects of endogenous and exogenous H2S after ICH, the effects of endogenous and exogenous H2S on NLRP3 inflammasome activation under P2X7 receptor (P2X7R) overexpression after ICH, and the involvement of the P2X7R in the mechanism by which microglia-derived H2S prevented NLRP3 inflammasome activation were investigated.Results We found ICH induced significant downregulation of endogenous H2S production in the brain, which may be the result of decreasing in CBS, the predominant cerebral H2S-generating enzyme. Administration of S-adenosyl-l-methionine (SAM), a CBS-specific agonist, or sodium hydrosulfide (NaHS), a classical exogenous H2S donor, not only restored brain and plasma H2S content but also attenuated brain oedema, microglial accumulation and neurological deficits at 1 day post-ICH by inhibiting the P2X7R/NLRP3 inflammasome cascade. Endogenous H2S production, which was derived mainly by microglia and above treatments, was verified by adenovirus-overexpressed P2X7R and in vitro primary microglia studies.Conclusion sThese results indicated endogenous H2S synthesis was impaired after ICH, which plays a pivotal role in the P2X7R/NLRP3 inflammasome-associated neuroinflammatory response in the pathogenesis of secondary brain injury. Maintaining appropriate H2S concentrations in the central nervous system may represent a potential therapeutic strategy for managing post-ICH secondary brain injury and associated neurological deficits.
研究领域:
神经科学
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药理学
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炎症
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神经病学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Zhi Lu,Yiqun Yao,Jinhong Wang,J.-Y. Peng
Dioscin presents extents of pharmacological activities on several diseases, but its effect and mechanism on diabetes cognitive dysfunction (DCD) remains unclear. Herein, we conducted a series of pharmacological evaluation assays of purinergic receptor P2X7 (P2X7R) with dioscin. We uncovered that dioscin presented a clearly protective effect on diabetes cognitive dysfunction via a methylglyoxal-treated PC12 cell model and streptozocin (STZ)-induced rat models. Additionally, it found that P2X7R and NLRP3 inflammasome signals were activated in diabetes cognitive dysfunction via in vivo and in vitro detection. Moreover, it was demonstrated that P2X7R regulated NLRP3 inflammasome signals in methylglyoxal-treated PC12 cells. Meanwhile, it was showed that dioscin-induced anti-diabetes cognitive dysfunction effect was accompanied with an inhibition of P2X7R/NLRP3 signal. A deeper mechanical study indicated that an overexpression of P2X7R further enhanced the protective effect of dioscin. Whilst, an inhibition of P2X7R abolished the protective effect of dioscin. These results suggested that dioscin protected type 2 diabetes cognitive dysfunction through, at least partially, regulating the P2X7R/NLRP3 signal pathway. Our findings further indicate the great value of dioscin on preventing type 2 diabetes cognitive dysfunction.
研究领域:
药理学
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神经科学
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糖尿病
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炎症
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2025
·Vol. 22
·期 1
·1-16
·
IF 10.1
Ding Peng-Fei,Zhang Jia-Tong,Zhu Xiao-Long,Cui Yue,Chen Chun-Lei,Liu Xun-Zhi,Shen Jun-Da,Zou Le-Xuan,Lu Yue,Zhuang Zong,Hang Chun-Hua,Li Wei
Background
Subarachnoid hemorrhage (SAH) is a common acute condition in neurosurgery, with microglial function playing a crucial role in determining patient outcomes. However, the involved mechanisms are complex and demand thorough investigation. In our study, we combined transcriptomic and metabolomic approaches to identify key regulators of microglial function, offering novel insights for potential therapeutic strategies in SAH treatment.
Methods
The neurological function of SAH mice was evaluated using the open field test, rotarod test, and nissl staining. In an in vitro SAH model, key pathways and genes that regulate microglial function were identified through the integration of transcriptomics and metabolomics. Enzyme-Linked Immunosorbent Assay, Immunofluorescence, Western blot, Real-Time PCR, pHrodo, and Lyso-Tracker were employed to assess lysosomal and microglial function.
Results
In SAH mice, both neurological and microglial functions were significantly impaired on the first day but showed recovery over time. The combined results from transcriptomics and metabolomics identified 5-lipoxygenase (5-LOX) as a key target in regulating microglial function post-SAH. Administering resolvin D1 (RvD1) exogenously to inhibit 5-LOX nuclear translocation or directly supplementing lipoxin A4 (LXA4) to adjust the leukotriene B4 (LTB4)/LXA4 ratio, can improve lysosomal acidification, mitigate impaired lysosomal function, and enhance phagocytosis while reducing the inflammatory response. Protecting microglial function can also be achieved through JNJ or P2X purinoceptor 7 (P2X7) siRNA, which inhibit calcium/calmodulin-dependent protein kinase II (CaMKII) activation, prevent 5-LOX nuclear translocation, and improve lysosomal function. Furthermore, P2X7 siRNA also improved neurological function, lysosomal function and microglial function in SAH mice.
Conclusion
Activation of P2X7-CaMKII after SAH promotes 5-LOX nuclear translocation, increases the LTB4/LXA4 ratio, elevates intracellular Ca2+ concentration, and impairs lysosomal and microglial function.
研究领域:
神经科学
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神经病学
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分子生物学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2022
·
IF 5.78
Guolong Huang,Yifan Qiu,Lei Bi,Huiyi Wei,Guocong Li,Zhijun Li,Peizhen Ye,Min Yang,Yanfang Shen,Hao Liu,Lu Wang,Hongjun Jin
The P2X7 receptor (P2X7R) is a key neuroinflammation target in a variety of neurodegenerative diseases. Improved radiosynthesis was developed according to the previously reported P2X7R antagonist GSK1482160. Biodistribution, radiometabolite, and dynamic positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT-MRI) of the lipopolysaccharide (LPS) rat model and the transgenic mouse model of Alzheimer’s disease (AD) revealed a stable, low uptake of [18F]4A in the brain of healthy rats but a higher standardized uptake value ratio (SUVR) in LPS-treated rats (1.316 ± 0.062, n = 3) than in sham (1.093 ± 0.029, n = 3). There were higher area under curves (AUCs) in the neocortex (25.12 ± 1.11 vs 18.94 ± 1.47), hippocampus (22.50 ± 3.41 vs 15.90 ± 1.59), and basal ganglia (22.26 ± 0.81 vs 15.32 ± 1.76) of AD mice (n = 3) than the controls (n = 3) (p < 0.05). Furthermore, 50 min dynamic PET in healthy nonhuman primates (NHPs) indicated [18F]4A could penetrate the blood–brain barrier (BBB). In conclusion, [18F]4A from this study is a potent P2X7R PET tracer that warrants further neuroinflammation quantification in human studies.
研究领域:
神经科学
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分子生物学
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医学影像学
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药理学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2019
·Vol. 20
·期 6
·5084-5090
·
IF 1.851
Jinsan Yang,Cao Ma,Maoshu Zhang
Diabetes mellitus adversely affects human bones and increases the risk of developing osteoporosis. In the present study, treatment with 30 mmol/l glucose was used to establish a high glucose (HG) cell model in vitro. Plasmids were used to overexpress the P2X purinoceptor 7 (P2X7) gene. Brilliant blue G and (4‑benzoyl‑benzoyl)‑ATP were used as a P2X7 antagonist and agonist, respectively. Proliferation of osteogenic MC3T3‑E1 cells and alkaline phosphatase (ALP) activity were determined using MTT and colorimetric assays, respectively. Alizarin Red S was used to assess calcification of MC3T3‑E1 cells. Western blotting and reverse transcription‑quantitative PCR were performed to determine protein and mRNA expression levels. The results demonstrated that HG inhibited MC3T3‑E1 cell proliferation and P2X7 expression, reduced calcification, and downregulated the expression levels of ALP and osteocalcin (Ocn) in MC3T3‑E1 cells. Overexpression of P2X7 in HG conditions increased calcification and proliferation, and upregulated the levels of ALP and Ocn in MC3T3‑E1 cells. Inhibition of P2X7 downregulated the expressions of ALP and Ocn in MC3T3‑E1 cells under HG conditions. Therefore, the present results indicated that HG caused damage to osteogenic MC3T3‑E1 cells. Thus, P2X7 may be a regulatory factor that may be used to counteract the effects of HG on osteogenesis.
研究领域:
内分泌学
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细胞生物学
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分子生物学
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糖尿病研究
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骨骼生物学
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产品关联
DOI
PubMed
高影响因子
INFLAMMATION
·
2024
·
IF 4.5
Jin Guang-Nan,Wang Yu,Liu Yi-Ming,Lu Yu-Nan,Lu Jing-Mei,Wang Jing-He,Ma Jing-Wen,Quan Yan-Zhu,Gao Hong-Yan,Cui Yue-Xian,Xu Xiang,Piao Lian-Xun
Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii , has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC's capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC's therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC's neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经免疫学
✓ 已验证
DOI
PubMed
高影响因子
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