CHEMOSPHERE
·
2023
·
IF 8.8
Jian Sun,Huayi Qu,Waseem Ali,Yan Chen,Tao Wang,Yonggang Ma,Yan Yuan,Jianhong Gu,Jianchun Bian,Zongping Liu,Hui Zou
Microplastics (MPs) and cadmium (Cd) are important environmental pollutants, that damage the liver. However, the effect and mechanism of combined Cd and MPs exposure on liver fibrosis are still largely unknown. In this study investigated, Cd + MPs exposure increased superoxide anion production and promoted extracellular ATP release compared with exposure to Cd or MPs individually. Cd + MPs increased inflammatory cell infiltration , activated the P2X7-NLRP3 signaling pathway, and promoted inflammatory factor release. Cd + MPs aggravated Cd- or MPs-induced liver fibrosis and induced liver inflammation. In AML12/HSC-T6 cell in vitro poisoning model, exposure of AML12 cells to Cd + MPs increased the opening of connexin hemichannels and promoted extracellular ATP release. Treatment of HSC-T6 cells with the supernatant of AML12 cells exposed to Cd + MPs significantly promoted HSC-T6 cell activation. Treatment of HSC-T6 cells with different concentrations of ATP produced similar results. TAT-Gap19TFA, an inhibitor of connexin hemichannels, significantly inhibited the ATP release and activation of Cd + MPs-treated HSC-T6 cells. Finally, the expression of the ATP receptor P2X7 was silenced in HSC-T6 cells, which significantly inhibited their activation. In conclusion, exposure to Cd + MPs promoted liver fibrosis through the ATP-P2X7 pathway and synergistically affected liver inflammation and fibrosis.
研究领域:
环境科学
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毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
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 PHYSIOLOGY AND BIOCHEMISTRY
·
2022
·Vol. 79
·期 2
·287-295
·
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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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2024
·
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
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chai Yuhui,Cai Yawen,Fu Yu,Wang Yingdi,Zhang Yiming,Zhang Xue,Zhu Lingpeng,Miao Mingxing,Yan Tianhua
Depression is a common and serious mental disorder. Data on its pathogenesis remain unclear and the options of drug treatments are limited. Here, we explored the role of pyroptosis, a novel pro-inflammatory programmed cell death process, in depression as well as the anti-depression effects and mechanisms of salidroside (Sal), a bioactive extract from Rhodiola rosea L. We established a corticosterone (CORT)-induced or lipopolysaccharide (LPS)-induced mice in vivo, and CORT, or nigericin (NLRP3 agonist)-induced PC12 cells in vitro. Our findings demonstrated that Sal profoundly mediated CORT or LPS-induced depressive behavior and improved synaptic plasticity by upregulating the expression of brain-derived neurotrophic factor (BDNF) gene. The data showed upregulation of proteins associated with NLRP3-mediated pyroptosis, including NLRP3, cleaved Caspase-1, IL-1β, IL-18, and cleaved GSDMD. The molecular docking simulation predicted that Sal would interact with P2X7 of the P2X7/NF-κB/NLRP3 signaling pathway. In addition, our findings showed that the NLRP3-mediated pyroptosis was regulated by P2X7/NF-κB/NLRP3 signaling pathway. Interestingly, Sal was shown to ameliorate depression via suppression of the P2X7/NF-κB/NLRP3 mediated pyroptosis, and rescued nigericin-induced pyroptosis in the PC12 cells. Besides, knock down of the NLRP3 gene by siRNA markedly increased the inhibitory effects of Sal on pyroptosis and proinflammatory responses. Taken together, our findings demonstrated that pyroptosis plays a crucial role in depression, and Sal ameliorates depression by suppressing the P2X7/NF-κB/NLRP3-mediated pyroptosis. Thus, our study provides new insights into the potential treatment options for depression.
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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免疫学
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精神病学
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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
Journal of Neuroinflammation
·
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
·
神经病学
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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
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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DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2024
·Vol. 103
·期 4
·e14522
·
IF 3.2
Wanting Fu,Ziyuan Liu,Yingzhou Wang,Xindi Li,Xiang Yu,Yang Li,Zejun Yu,Yinsheng Qiu,Zhinan Mei,Lingyun Xu
Pyroptosis is a programmed cell death process that frequently occurs in many diseases, including hyperuricemic nephropathy (HN). In HN, a range of stimuli mediates inflammation, leading to the activation of inflammasomes and the production of gasdermin D (GSDMD). Baicalin (BA), a natural flavonoid renowned for its antioxidant and anti-inflammatory properties, was investigated for its role in HN in this study. Initially, HN-like inflammation and pyroptosis were induced in HK-2 cells with treatment of monosodium urate (MSU), followed by the BA treatment. The expression of pyroptosis-associated genes, Panx-1 and P2X7, at both mRNA and protein levels was assessed through real-time polymerase chain reaction (RT-qPCR) and Western blotting (WB) without or with BA treatment. The results showed that expression of Panx-1 and P2X7 at mRNA and protein levels was increased in MSU-treated HK-2 cells, which subsequently decreased upon the BA treatment. Further experiments showed that BA could combine NLRP3 inflammasome and GSDMD, destabilizing GSDMD protein. Moreover, BA protected the cell membrane from MSU-induced damage, as evidenced by Hoechst 33342 and PI double staining, lactate dehydrogenase (LDH) assays, and electron microscopy observations. These results suggest that BA is involved in the regulating Panx-1/P2X7 pathways and thus inhibits pyroptosis, highlighting its potential therapeutic effect for HN.
研究领域:
药理学
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细胞生物学
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分子生物学
·
肾病学
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DOI
PubMed
高影响因子
EJNMMI Research
·
2026
·Vol. 16
·期 1
·76
·
IF 2.7
Bi Lei,He Kun,Wang Lu,Ye Peizhen,Liu Yongshan,Yang Min,Wei Junjie,Ma Jie,Wei Huiyi,Zhou Weiyan,Yuan Yifan,Chen Liang,Guan Yihui,Yue Qi,Li Guiting,Wang Mingfang,Xie Fang,Jin Hongjun
Background Increasing evidence of the role of neuroinflammation in pathophysiology has highlighted the importance of P2X7 receptor (P2X7R)-targeted neurodegeneration diseases. The safety, biodistribution, pharmacokinetics and dosimetry of a promising F-18-labeled PET tracer [ 18 F]GSK1482160 for imaging P2X7R were evaluated. The absorbed dose (AD) and effective dose (ED) of nonhuman primates (NHPs) and human adult volunteers were estimated. The total volume distribution (V T ) was calculated via the 2-tissue compartment model (2TCM) and Logan plot (LoganAIF). Results There were no adverse events after [ 18 F]GSK1482160 dosing. Radioactivity accumulated predominantly in the hepatobiliary system, kidney, spleen, and brain. Organ dosimetry revealed the liver as the critical organ with a mean AD of 30.1 µGy/MBq, followed the adrenals at 22.8 µGy/MBq. The overall ED of the female and male human volunteers were 10.9 µSv/MBq and 8.88 µSv/MBq, respectively. [ 18 F]GSK1482160 has the ability to cross the blood–brain barrier and is distributed throughout the whole brain with low region specificity. The 2TCM and LoganAIF models had good correlation and agreement, and the input functions of the image-derived and blood-sampling methods had good correlation but poor correspondence. The AD and ED produced by [ 18 F]GSK1482160 were within typical levels for fluorine-18-labeled tracers. Conclusions [ 18 F]GSK1482160 is a safe PET tracer with hepatorenal metabolism and it is up to 250 MBq (6.7 mCi) for human adults of [ 18 F]GSK1482160 can be administered of a total effective dose of 2.73 mSv (0.273 rem) with the critical organ, the liver, receiving the maximum allowed exposure of 50 mSv (5 rem) in accordance with ICRP 103 recommendations. 2TCM and LoganAIF using a blood-sampling input function with blood metabolite correction are accurate methods for quantifying the tracer binding of P2X7R in the brain.
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DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Pengfei Tang,Ze Zheng,Mengmeng Yu,Danyang Zhang,Zhiqi Xiao,Lingyi Kong,Jun Luo
Ethnopharmacological relevance Sarcandra glabra ( S. glabra ) has been traditionally used to promote diuresis and reduce swelling, which is employed to treat facial and lower limb edema, one of the earliest and most visible external signs of chronic kidney disease (CKD). The alleviating effect of S . glabra on CKD and its mechanism remains unclear. Aim of the study This study aims to determine the therapeutic effect of trishizukaol A (TSA), a lindenane sesquiterpenoid isolated from S. glabra , on CKD and investigate its underlying mechanism. Methods First, the biolayer interferometry (BLI) method was used to screen compounds from S . glabra targeting P2X7. Next, the effects of TSA on different stages of CKD were examined. The protein differences between P2X7 KO and WT mice were assessed using proteomic methods. Then, a series of biochemical methods was employed to explore the mechanism by which TSA alleviates CKD through P2X7. Results In mouse models of CKD, TSA significantly reduced urinary albumin excretion and decreased KIM-1 and NGAL, supporting that TSA has a notable ameliorative effect on CKD. Target screening results showed that TSA bound to and inhibited the P2X7 protein. Furthermore, we found that P2X7 was highly expressed in the tubular epithelial cells (TECs) of CKD mice, and blocking this receptor attenuated renal injury. In vivo , proteomic analysis comparing shP2X7 and shCTRL mice identified significant differential protein expression. P2X7 knockdown was predominantly associated with proteasome pathways. In vitro , siP2X7 and siPSME3 inhibited 20s proteasome activation, activated autophagy, and reduced TEC injury. At the same time, activation of autophagy can inhibit the proteasome. These results supported that P2X7 can regulate the crosstalk between proteasome and autophagy and promote TEC injury. In conclusion, TSA alleviates CKD in mice and regulates the P2X7/PSME3 axis, leading to the inactivation of the 20S proteasome hyper-activation and promoting autophagy in TECs. Conclusions This study reveals that TSA alleviates CKD by inhibiting P2X7/PSME3-driven hyperactivation of the 20S proteasome. TSA serves as a mechanistic probe and lead scaffold for dissecting the P2X7-proteasome axis in CKD.
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高影响因子
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