Oncotarget
·
2017
·
IF 5.168
Zhen-Huan Lv,Trinh Anh Phuong,Shi-Jie Jin,Xiao-Xue Li,Ming Xu
Recent studies have demonstrated that NLRP3 inflammasome complex acts as pivotal elements to initiate inflammatory responses and plays an important role in the dysfunction of cardiovascular complications. Meanwhile, simvastatin prevents vascular endothelial dysfunction from inflammasome invasion contributing to reduce cardiovascular risk. However, Whether or not the simvastatin improves vascular endothelial barrier function through inhibiting the activation of NLRP3 inflammasome pathway remains unknown. Here, we explored the role and mechanisms of simvastatin in the activation of NLRP3 inflammasome which are involved in vascular endothelial hyperpermeability causing by the disruption of tight junction protein ZO-1 and adherens junction protein VE-Cadherin, an early initiation of cardiovascular complication. Our results found that high glucose significantly induced the formation and activation of NLRP3 inflammasome through NADPH oxidase-dependent reactive oxygen species (ROS) formation, associated with vascular endothelial hyperpermeability causing by ZO-1 and VE-Cadherin disruption in the rat aortic endothelial cells (RAECs). Simvastatin treatment remarkably abolished vascular endothelial hyperpermeability and enhanced the protein expression of ZO-1 and VE-Cadherin through NLRP3 inflammasome. Mechanistically, the inhibitory role of simvastatin endothelial hyperpermeability is attributed to the decreased release of cytoplasmic high mobility group box protein-1 (HMGB1) derived from endothelial NLRP3 inflammasome activation. We further confirm the protective role of simvastatin on vascular leakage in the heart of diabetic rats injected with Evans blue dye, which was associated with HMGB1 release in the serum. Collectively, the mechanism of simvastatin treatment alleviating vascular endothelial permeability dysfunction may be through inhibiting the NLRP3 inflammasome-dependent HMGB1 release in RAECs.
研究领域:
心血管疾病
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药理学
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分子生物学
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糖尿病
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2024
·
IF 3.8
Zhaoqing Xi,Ling Shu,Lingling Xiao,Xuesheng Fang,Mingyan Dai,Jing Wang,Yuan Wu,Junxia Zhang,Mingwei Bao
Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to the normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68 + NLRP3 + macrophages infiltration in hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of nuclear factor-kappa B (NF-κB) pathway. This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity.
研究领域:
心脏病学
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免疫学
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神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Xi Ma,YuZheng Yang,Hao Li,ZeHong Luo,QiuYi Wang,XueMing Yao,Fang Tang,Ying Huang,Yi Ling,WuKai Ma
Although the pathogenesis of rheumatoid arthritis (RA) remains unclear, an increasing number of studies have confirmed that pyroptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) is an important factor affecting the progression of RA. Periplogenin (PPN) is a natural cardiac glycoside; reportedly, it exerts anti-inflammatory and analgesic effects in diseases by inhibiting cell growth and migration. This study aimed to determine the effect of PPN on the growth, migration, and invasion of RA-FLS and the potential mechanism of pyroptosis regulation. We discovered that PPN could inhibit the migration and invasion abilities of RA-FLS and block their growth cycle, down-regulate the secretion and activation of NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18, and reduce the number of pyroptosis. In summary, PPN inhibited pyroptosis, reduced the release of inflammatory factors, and improved RA-FLS inflammation by regulating the NLRP3/Caspase-1/GSDMD signaling pathway.
研究领域:
药理学
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免疫学
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风湿病学
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2025
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IF 4
Peng Chen,Wenhao Xiao,Fanzhao Zou,Jiexin Lei,Fuchao Chen,Ruhong Zhang
This study explored the effects of methylated urolithin A (mUro A), on lipopolysaccharide (LPS)-induced cognitive impairment and anxiety- and depression-like behaviors, and their molecular mechanism. mUro A significantly mitigated cognitive dysfunction, anxiety- and depression-like behaviors. Furthermore, mUro A improved activities of antioxidative enzymes, regulated the release of inflammatory factors, inhibited the LPS-induced generation of Aβ 1 – 42 and restored the cholinergic system balance in the AD mouse brain. Additionally, mUro A markedly attenuated microglial activation by inhibiting the Drp1/HK1/NLRP3 pathway, thereby suppressing mitochondrial inflammation. This was evidenced by the downregulation of p-Drp1 (s616), VDACs, NLRP3, ASC, cleaved caspase 1, IL-18, and IL-1β, alongside the upregulation of HK1 expression. In conclusion, mUro A mitigates AD-associated cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation.
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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产品关联
DOI
高影响因子
BRAIN RESEARCH
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2024
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IF 2.7
Zhu Wang,Bowen Li,Jingrui Yang,Ying Gao,Liu Gao,Qiang Jia,Li Yu,Yunzhi Ling
The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1β expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1β expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus.
研究领域:
神经科学
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药理学
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外科手术
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炎症
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认知障碍
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
·
2025
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IF 2.7
Yarong Yan,Shulei Xing,Jinghua Liu,Xinlin Yan,Yi Guan,Zhixin Jiang,Wei Zhang,Xuan Li
Lycium barbarum glycopeptide (LbGp), derived from the Chinese medicinal plant Lycium barbarum, has demonstrated anti-inflammatory properties; however, its precise role and mechanism in corneal repair following injury remain elusive. The present research investigated the mechanisms and effects of LbGp on corneal repair following alkali burn injury using in vivo mouse models of corneal alkali burn and in vitro human keratocyte fibrosis models. Corneal inflammation, opacity, and epithelial defects were assessed via a slit lamp microscope. Results showed that LbGp-treated mice exhibited reduced edema, accelerated re-epithelialization, and decreased corneal opacity compared to the phosphate-buffered saline (PBS)-treated controls. Proteomic analysis revealed altered proteins enriched in the extracellular matrix among the control, injury, and LbGp treatment groups. Moreover, LbGp significantly attenuated TGFβ-1-induced myofibroblasts transdifferentiation from keratocytes. Consistently, LbGp treatment inhibited the upregulation of fibrosis markers (αSMA, fibronectin, and collagen III) at both the protein and mRNA levels after corneal alkali burns. LbGp also effectively suppressed the activation of the NF-κB/NLRP3/IL-1β signaling pathway and neutrophil infiltration following corneal alkali burn injury. Additionally, miR-21 was upregulated in TGFβ-1-stimulated keratocytes and in the alkali-burned mouse cornea. LbGp decreased miR-21 expression, while increasing expression of its target, Smad7, thereby dampening the TGFβ/Smad2/3 signaling pathway. This research demonstrates that LbGp promotes corneal healing by inhibiting inflammation and fibrosis after alkali burns, suggesting its potential as a supplementary therapy for corneal injury repair.
研究领域:
药理学
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眼科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 18
·3279
·
IF 5.1
Xiaoyan Feng,Hongbin Yuan,Tao You,Hengyi Xu
Secondary liver injury (SLI) is the most common complication in the development of inflammatory bowel disease (IBD), and it is susceptible to environmental factors, including diet patterns. As a food-brightening agent, titanium dioxide nanoparticles (TiO2NPs) are inevitably consumed by IBD patients. Currently, there are a few studies on TiO2NPs exposure to SLI in colitis mice. In this study, a SLI model was built using dextran sodium sulfate (DSS) free-drinking for 7 days after pre-exposure to TiO2NPs. The changes in the pathological results and liver function indicators suggested that high-dose TiO2NPs only exhibited a slight injury in the liver. With further analysis, we found that pre-exposure to high-dose TiO2NPs in mice with SLI led to an increase in intestinal permeability and hepatic LPS content, along with increased inflammatory cytokines and an anti-oxidative system imbalance. Subsequently, accumulated LPS and ROS overproduction activated the NOD-like receptor family pyrin-containing 3 (NLRP3) inflammasome, inducing hepatic cell pyroptosis. To provide compelling evidence, NLRP3 gene-deficient mice were used, and the results showed that the absence of NLRP3 improved liver function, alleviated hepatic inflammation, and reduced hepatic oxidative injury in SLI mice with TiO2NPs exposure. In summary, these results confirmed the critical role of the NLRP3 inflammasome in the TiO2NP-aggravated progression of SLI. Our study provided a comprehensive evaluation of foodborne nanoparticles on IBD complications, hoping that more studies can focus on IBD complications affected by environmental factors.
研究领域:
消化病学
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纳米毒理学
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免疫学
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分子生物学
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肝脏病学
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炎症性肠病
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环境与健康
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Shengchen Ding,Jun Chen,Guangming Chen,Weiyi Tian,Junping Zheng,Haiming Hu,Lu Cao,Xiaowei Yao,Baifei Hu,Hongtao Liu
This study aimed to isolate oligosaccharides from P. sibiricum , analyze its structure, and elucidate the pharmacological mechanism for colitis improvement. First, a homogeneous oligosaccharide PSO-A was isolated and its structure was characterized. Then, the colitis model was induced with 3 % dextran sulfate sodium (DSS) and intervened with PSO-A. The results show that PSO-A was an agavin-type acetylated fructooligosaccharide with a molecular weight of 2.12 kDa. PSO-A consisted of (2 → 6)-β-D-Fru f residue backbone with an internal α-D-Glc p residue and (2 → 1)-β-D-Fru f residue side chains. Further, PSO-A increased mucin content, protected intestinal barrier integrity of colitis mice, and significantly inhibited the levels of inflammatory factors. Moreover, the protein expressions of NLRP3, ASC, and Caspase-1 in colitis mice was statistically inhibited by PSO-A. In summary, PSO-A could alleviate colitis by inhibiting NLRP3 inflammasome pathway, which provides a basis for the development and application of P. sibiricum oligosaccharides as drug or functional food to relieve colitis.
研究领域:
药理学
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生物化学
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分子生物学
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免疫学
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胃肠病学
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产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Xueming Xu,Yuanfeng Han,Jiali Deng,Shengfeng Wang,Shijie Zhuo,Kai Zhao,Wenhu Zhou
Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs. Recently, disulfiram (DSF), a drug primarily used for alcohol addiction treatment, has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis, a form of programmed cell death. The therapeutic activity of DSF can be further enhanced by the presence of Cu 2+ , although the underlying mechanism of this enhancement remains unclear. In this study, we investigated the mechanistic basis of Cu 2+ -induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate (CuET) complex. CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action. However, despite its potent activity, CuET suffered from poor solubility and limited permeability, as revealed by our druggability studies. To overcome these intrinsic limitations, we developed a scalable method to prepare CuET nanocrystals (CuET NCs) using a metal coordination-driven self-assembly approach. Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability. Notably, CuET NCs exhibited high biodistribution in the intestine, suggesting their potential application for the treatment of inflammatory bowel diseases (IBDs). To evaluate their therapeutic efficacy in vivo , we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms. Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent, and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.
研究领域:
药理学
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纳米技术
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炎症
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胃肠病学
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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
·
炎症
·
神经病学
✓ 已验证
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2018
·
IF 2.064
Yinji Liang,Yupei Zhang,Yuanjun Deng,Shu Liang,Yifang He,Yanning Chen,Chan Liu,Chenli Lin,Li Han,Guifang Tu,Qinhe Yang
We evaluate the effects of the Chaihu-Shugan-San decoction on intestinal microbe dysbiosis and chronic metabolic inflammation via the NLRP3 pathway in NAFLD rats that were fed a high-fat diet. Twenty-four SD rats (male, six weeks old, 200 ± 20 g) were randomly divided into three groups: normal control group (NC group), high-fat diet-fed group (HFD group), and Chaihu-Shugan-San decoction intervention group (CH group). The NC group rats were given standard feed, the HFD group rats were all fed a high-fat diet (83% standard feed + 10% lard oil + 5% sucrose + 1.5% cholesterol + 0.5% cholate), and the CH group rats were given a HFD plus Chaihu-Shugan-San at 9.6 g•kg−1•d−1. Body composition, serum and liver lipids, inflammatory markers, intestinal microbial population, and the NLRP3 pathway-associated protein were assessed. The results showed that Chaihu-Shugan-San decoction significantly reduced body weight and total fat mass and the levels of serum LPS, TG, TNF-α, IL-1β, and IL-18, as well as liver TC, TG, TNF-α, IL-1β, and IL-18 (P < 0.05). The abundance of Enterobacteriaceae (0.375% versus 0.064%, P < 0.05), Staphylococcaceae families (0.049% versus 0.016%, P < 0.05) and Veillonella genus (0.096% versus 0.009%, P < 0.01) significantly decreased, whereas the abundance of Anaeroplasma genus (0.0005% versus 0.0178%, P < 0.01) significantly increased. The expression levels of NLRP3, ASC, and Caspase-1 were changed significantly (P < 0.05). In summary, the Chaihu-Shugan-San decoction modulated intestinal microbe dysbiosis, reduced fat accumulation, and alleviated inflammatory factor expression, which are all processes related to the NLRP3 inflammasome pathway in NAFLD rats.
研究领域:
药理学
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微生物学
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炎症研究
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DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Danliangmin Song,Jingqi Cheng,Kai Dong,Shiyu Liu,Chaoxin Man,Shiqian Fu,Xinyan Yang,Qianyu Zhao,Yujun Jiang
Cronobacter sakazakii is a facultative anaerobic gram-negative pathogen that has attracted widespread attention for causing necrotizing enterocolitis in infants (premature and low-weight newborns) by contaminating powdered infant formula. Several studies have found that the antibiotic tolerance of Cronobacter sakazakii isolated from food sources is increasing, thereby markedly increasing the difficulty of clinical treatment of Cronobacter sakazakii infection. At present, most studies are focused on clarifying the pathogenicity of Cronobacter sakazakii , but there is still a gap in the study of necrotizing enterocolitis in neonatal rats caused by Cronobacter sakazakii with different antibiotic tolerance. To fill this gap, we analyzed and compared the ability of Cronobacter sakazakii induced by different classes of antibiotics to induce necrotizing enterocolitis in neonatal rats by mediating TLR4-NLRP3-IL-1β pathway. In the results, Cronobacter sakazakii acquired tolerance to aminoglycosides, quinolones and cephalosporins, and caused more inflammatory damage in neonatal rats, improved the ability of mediating TLR4-NLRP3-IL-1β pathway to induce necrotizing enterocolitis. Compared with the XS001 group, the NEC scores of neonatal rats in XS001-Amp, XS001-Ami, XS001-Ofl and XS001-Ceo groups were increased by 8.3%, 58.3%, 50.0% and 58.3%. The acquisition of penicillin and tetracycline tolerance had little effect on the ability of Cronobacter sakazakii to induce necrotizing enterocolitis in neonatal rats. The ability of Cronobacter sakazakii to induce necrotizing enterocolitis in neonatal rats was significantly different due to the type and tolerance of antibiotics.
研究领域:
微生物学
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免疫学
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儿科
·
分子生物学
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DOI
高影响因子
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