INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xue-Li Jiang,Chuang Liu,Zi-Ying Zhan,Xiao-Qi Lan,Yan-Ling Wu,Ji-Xing Nan,Cheng-Hua Jin,Li-Hua Lian
Liver fibrosis is a critical precursor to the progression of cirrhosis and liver cancer. However, the development of precision therapies for this condition has been impeded by incompletely elucidated molecular mechanisms. Activin receptor like kinase 5 (ALK5), termed TGF-β type I receptor (TGF-βRI), has been identified as a promising therapeutic target for antifibrotic drug development. In this study, we designed and synthesized two novel thiazole derivatives (J-1155 and J-1156) featuring enantiomeric amino acid moieties to selectively target ALK5 for hepatic fibrosis treatment. Our data demonstrated that both compounds effectively attenuate hepatic fibrosis and associated inflammation through dual inhibition of the TGF-β/Smad signaling pathway and blockade of the P2X7R-NLRP3 inflammasome axis. In comparison, J-1156 demonstrated superior overall therapeutic efficacy to J-1155 in terms of anti-fibrotic efficacy, while J-1155 exhibited superior modulation of Smurf2. Collectively, our observations demonstrate the potential of J-1155 and J-1156 as dual novel therapeutic agents targeting hepatic fibrosis.
研究领域:
药理学
·
分子生物学
·
肝脏疾病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
·
2020
·
IF 4.133
Yan Wu,Yacheng Zhang,Jie Zhang,Tingting Zhai,Jingping Hu,Hairong Luo,Haiyan Zhou,Qinghai Zhang,Zhiguang Zhou,Feng Liu
Aims The antimicrobial peptide cathelicidin ( Camp ) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. Methods and results In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion . An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils . Knockout of Camp in mice reduced MI/R-induced myocardial inflammation , infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X 7 R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X 7 R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1β (a “first line” pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1β protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1β from human neutrophils via stimulating TLR4 signaling and P2X 7 R/NLRP3 inflammasome. Conclusions Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X 7 R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury .
研究领域:
心脏病学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Yulin Qi,Lu Liu,Dan Liang,Shiyun Tang,Xiaoyi Yu,Hejiang Ye,Nianzhi Chen
Background Retinitis pigmentosa (RP) refers to a group of progressive photoreceptor degenerative diseases . The activation of microglia has been reported to play an important role in the photoreceptor degeneration in RP retinal. Bujing Yishi tablets (BJYS), a Chinese herbal medicine , has been used to treat retinal diseases in China with desirable effect in improving visual function. However, the mechanisms underlying the efficacy of BJYS treatment in RP are not yet fully understood. Purpose Based on the preliminary experiments, this study aimed to investigate the therapeutic mechanism involved in treating N -Methyl- N -Nitrosourea (MNU)-induced retinal degeneration of RP with BJYS. Methods To explore the efficacy of BJYS, a rat experimental RP model was established through intraperitoneal injection of MNU (50 mg/kg). Two experiment was carried out. After the treatment, we conducted H&E, TUNEL , retinal cytokine levels and IBA-1 expression in microglia to confirm the impact on RP model. The specific mechanism of action of BJYS tablet was assessed by western blot , real-time polymerase chain reaction (RT-PCR), and immunofluorescence to determine the mRNA and protein expression levels involved in clarifying the effectiveness of BJYS exerted through P2X7R/CX3CL1/CX3CR1 pathway. Results Significant alleviation of retinal morphological structure and photoreceptor degeneration by BJYS treatment was observed in the retinal of MNU-induced RP rats, BJYS prevented the reduction of ONL thickness and decreased the level of apoptotic cells in ONL. It also inhibited microglia overactivation and reduced retinal levels of IL-1β, IL-6, TNF-α. In addition, BJYS decreased the protein expression and mRNA expression of P2X7, CX3CL1 and CX3CR1 and reduced the phosphorylation of p38 MAPK . Conclusion In summary, this study suggested that BJYS treatment could alleviate photoreceptors degeneration of RP by inhibiting microglia overactivation and inflammation through the P2X7R/CX3CL1/CX3CR1 pathway. These effects suggest that BJYS tablets may serve as a promising oral therapeutic agent for RP.
研究领域:
眼科学
·
药理学
·
神经科学
·
中医
✓ 已验证
产品关联
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
·
神经科学
·
糖尿病
·
炎症
✓ 已验证
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
INFLAMMATION
·
2025
·
IF 5
Chen Ru,Cheng Si-Min,Wang Hao-Chuan,Kun-Dong,Sun Hui-Li,Sun Meng-Mei,Gao Bo,Wu Wen-Ning
Epilepsy, a prevalent chronic brain disorder, remains inadequately controlled by current antiepileptic drugs. Neuroinflammation is considered a crucial component in the process of epileptogenesis. Vitexin (VT), primarily derived from medicinal plants, is a flavonoid monomer with significant biological activity that has demonstrated benefits in various neurological disorders by suppressing neuroinflammation. However, the role and underlying mechanism of VT in epileptic seizures are incompletely understood. We herein investigate VT’s antiseizure potential and the related mechanism utilizing a mouse model of status epilepticus induced by kainic acid (KA). Our findings indicate that VT pre-treatment exerts an antiseizure effect in a dose-dependent manner and attenuates KA-induced hippocampal neuronal damage in mice. Moreover, VT post-treatment (administration after the appearance of generalized seizures) can also alleviate KA-induced seizure and neuronal damage. Furthermore, VT suppresses the activity of hippocampal P2X7R and NLRP3 inflammasome in KA-treated mice. A438079, a specific P2X7R antagonist, inhibits NLRP3 inflammasome activation and reduces seizure severity and hippocampal neuronal damage. Conversely, the P2X7R activator BzATP negates the antiseizure and neuroprotective effects of VT. These findings demonstrate that VT can alleviate KA-induced seizure and neuronal damage by inhibiting P2X7R-NLRP3 inflammasome signaling in mice, potentially providing a novel strategy for prevention and treatment of acute seizures.
✓ 已验证
产品关联
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
·
生殖生物学
·
细胞生物学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 8.3
Jian Liu,Yeqing Liu,Changtie Liu,Jing Wang,Yuanyi Zhang,Yuxing Yang,Si Peng,Rongrong Xu,Lingxiang Xu,Xingchen Wang,Wei Xiong,Yun Gao
Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2×7 receptor (P2×7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2×7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2×7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2×7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl-2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2×7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Wenjie Zhong,Xinyan Wang,Lanxin Yang,Yue Wang,Qingyue Xiao,Simin Yu,Richard D. Cannon,Yan Bai,Chuangwei Zhang,Duanjing Chen,Ping Ji,Xiang Gao,Jinlin Song
Endoplasmic reticulum (ER) dysfunction is a potential contributor to the impaired repair capacity of periodontal tissue in diabetes mellitus (DM) patients. Restoring ER homeostasis is thus critical for successful regenerative therapy of diabetic periodontal tissue. Recent studies have shown that metformin can modulate DM-induced ER dysfunction, yet its mechanism remains unclear. Herein, we show that high glucose elevates the intracellular miR-129-3p level due to exocytosis-mediated release failure and subsequently perturbs ER calcium homeostasis via downregulating transmembrane and coiled-coil domain 1 (TMCO1), an ER Ca2+ leak channel, in periodontal ligament stem cells (PDLSCs). This results in the degradation of RUNX2 via the ubiquitination-dependent pathway, in turn leading to impaired PDLSCs osteogenesis. Interestingly, metformin could upregulate P2X7R-mediated exosome release and decrease intracellular miR-129-3p accumulation, which restores ER homeostasis and thereby rescues the impaired PDLSCs. To further demonstrate the in vivo effect of metformin, a nanocarrier for sustained local delivery of metformin (Met@HALL) in periodontal tissue is developed. Our results demonstrate that compared to controls, Met@HALL with enhanced cytocompatibility and pro-osteogenic activity could boost the remodeling of diabetic periodontal tissue in rats. Collectively, our findings unravel a mechanism of metformin in restoring cellular ER homeostasis, enabling the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue.
研究领域:
牙科学
·
药理学
·
分子生物学
·
细胞生物学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2021
·Vol. 18
·期 1
·1-19
·
IF 8.322
Jiang Li,Zhang Yixin,Jing Feng,Long Ting,Qin Guangcheng,Zhang Dunke,Chen Lixue,Zhou Jiying
Background Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation.Methods The CM model was established by repeated intraperitoneal injection of nitroglycerin (NTG) in mice. A Von Frey filament and radiant heat were used to assess the mechanical and thermal hypersensitivity. Western blotting and immunofluorescence assays were performed to detect the expression of P2X7R, autophagy-related proteins, and the cellular localization of P2X7R. To determine the role of P2X7R and autophagy in CM, we detected the effects of the autophagy inducer, rapamycin (RAPA) and P2X7R antagonist, Brilliant Blue G (BBG), on pain behavior and the expression of calcitonin gene-related peptide (CGRP) and c-fos. In addition, the effect of RAPA and BBG on microglial activation and subsequent inflammation were investigated.Results The expression of P2X7R was increased and was mainly colocalized with microglia in the TNC following recurrent NTG administration. The autophagic flux was blocked in CM, which was characterized by upregulated LC3-II, and accumulated autophagy substrate protein, p62. RAPA significantly improved the basal rather than acute hyperalgesia. BBG alleviated both basal and acute hyperalgesia. BBG activated the level of autophagic flux. RAPA and BBG inhibited the activation of microglia, limited the inflammatory response, and reduced the expression of CGRP and c-fos.Conclusion sOur results demonstrate the dysfunction of the autophagic process in CM. Activated autophagy may have a preventive effect on migraine chronification. P2X7R contributes to central sensitization through mediating autophagy regulation and might become a potential target for CM.
研究领域:
神经科学
·
药理学
·
分子生物学
·
疼痛研究
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Chunhui Shan,Qi Bing,Gang Qiu,Hui Zhang,Yingmin Chen
Galectin-3 disrupts microglial P2X7R/MerTK balance after stroke • ERK/ROS/BRD4 axis mediates Gal-3-induced P2X7R upregulation • Gal-3 promotes cGAS-STING inflammation and apoptosis via HIF1α/P2X7R • TD-139 restores P2X7R/MerTK balance and reduces cerebral infarction • Targeting Gal-3 improves motor, cognitive, and grip strength in MCAO rats This study demonstrates that Galectin-3 (Gal3) exacerbates cerebral infarction progression by modulating the P2X7R/MerTK equilibrium in microglia via the ERK/BRD4/HIF1α signaling axis, with reactive oxygen species (ROS) serving as a potential intermediate mediator linking ERK activation to BRD4 upregulation based on prior literature evidence. Single-cell transcriptomic analysis revealed that ischemia drives microglia from a homeostatic state to an activated disease phenotype, and virtual Gal3 knockout predicted corresponding downregulation of BRD4. Using a rat model of cerebral infarction, we found that the Gal3 inhibitor TD-139 significantly reduced infarct volume, promoted M2 polarization of microglia, and improved neurological function in behavioral assays. Mechanistic investigations in BV2 microglia revealed that Gal3 activates ERK1/2, leading to ROS accumulation, BRD4 upregulation, and subsequent HIF1α-mediated P2X7R transcription, while suppressing KLF4 and MerTK. This cascade increased P2X7R expression and suppressed MerTK/KLF4 expression, generating a pro-inflammatory and pro-apoptotic microenvironment. Notably, pharmacological inhibition of Gal3 enhanced efferocytosis and reduced apoptosis, whereas P2X7R blockade exerted similar neuroprotective effects. These findings identify Gal3 as a key regulator of microglial polarization via the experimentally validated ERK/BRD4/HIF1α-P2X7R signaling cascade, where P2X7R activation concurrently triggers cGAS-STING-mediated pro-inflammatory/pyroptotic responses and suppresses the KLF4/MerTK efferocytosis axis. Targeting this regulatory network could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Targeting this pathway could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Data were analysed using one-way ANOVA followed by Tukey's post-hoc test for multiple comparisons; P < 0.05 was considered statistically significant.
✓ 已验证
DOI
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
·
分子生物学
·
医学影像学
·
药理学
✓ 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）