CHEMOSPHERE
·
2018
·
IF 4.427
Feibo Xu,Qiang Ji,Jian Zhang,Wanyue Huang,Zheng Cao,Yanfei Li
Aluminum (Al), a common environmental pollutant, has been reported to inhibit the immune functions of macrophage. However, the mechanisms involved remain unclear. In this study, murine peritoneal macrophages were exposed to 0, 0.27, 0.54, and 1.08 mg/mL of aluminium chloride (AlCl 3 ) for 24 h, and then treated with 1 μg/mL lipopolysaccharide (LPS) for another 6 h. No addition of both AlCl 3 and LPS serviced as control group. We observed that AlCl 3 has cytotoxicity in murine peritoneal macrophages, showing a decrease in cell viability and an increase in lactate dehydrogenase release. Besides, AlCl 3 exposure restrained the LPS-induced NLR pyrin domain containing 3 (NLRP3) inflammasome activation presented as NLRP3 expressions reduction, caspase-1 cleavage inhibition and interleukin 1 beta (IL-1β) maturation lessened. Meanwhile, AlCl 3 exposure decreased LPS-induced IKKβ activity, IκBα phosphorylation, the phosphorylation and mRNA expression of NF-κB p65, as well the genes expression and concentration in medium supernatant of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). The results suggested that AlCl 3 inhibited the activation of NF-κB signaling pathway induced by LPS, which maybe one of the upstream signals involved in the inhibition of NLRP3 inflammasome activation by AlCl 3 . This research can provide theoretical basis for understanding the immune toxicity of Al, and deepening the cognition of Al exposure hazards to immune response.
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PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Zhenhui Chen,Huijuan Chen,Wanwen Huang,Xiaotong Guo,Lu Yu,Jiamin Shan,Xiaoshi Deng,Jiaxin Liu,Wendan Li,Wei Shen,Hongying Fan
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Pan Su,Liming Liu,Yuhang Gong,Shuaijun Peng,Xiangli Yan,Ming Bai,Erping Xu,Yucheng Li
Background The pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored. Methods In vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein–protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro . Results Our results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ antagonist T0070907 or overexpression with CA STAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CA STAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling. Conclusion Our results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.
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高影响因子
Biofabrication
·
2025
·
IF 8
Ruoyu Li,Wenfeng Li,Yungshan Teng,Runze Li,Siyi Kong,Xin Chen,Haotian Luo,Danying Chen,Yuqing Guo,Yangqiao Qing,Hio Cheng leong,Bingyan Guo,Meihan Chen,Zixin Pan,Shushuo Zheng,Yihong Deng,Yang Cao,Chen Zhou,Xuenong Zou,Weicai Wang
Craniofacial bone defect healing in periodontitis patients with diabetes background has long been difficult due to increased blood glucose levels which cause overproduction of reactive oxygen species (ROS) and a low pH environment. These conditions negatively affect the function of macrophages, worsen inflammation and oxidative stress, and ultimately, hinder osteoblasts' bone repair potential. In this study, we for the first time found that ANXA1 expression in macrophages was reduced in a diabetic periodontitis environment, with the activation of the NLRP3/Caspase-1/GSDMD signaling pathway, and, eventually, increased macrophage pyroptosis. Next, we have developed a new GPPG intelligent hydrogel system which was ROS and pH responsive, and loaded with Ac2-26, an ANXA1 bioactive peptide, and osteogenic peptide OGP as well. We found that Ac2-26/OGP/GPPG can effectively reduce ROS, mitigates macrophage pyroptosis via the ANXA1/NLRP3/Caspase-1/GSDMD pathway and enhanced osteogenic differentiation. The effect of Ac2-26/OGP/GPPG in regulation of pyroptosis and bone defect repair was also further validated by animal experiments on periodontitis-induced tooth loss model in diabetic rats. To conclude, our study unveils the effect of ANXA1 on macrophage pyroptosis in periodontitis patients with diabetes, based on which we introduced a promising innovative hydrogel system for improvement of bone defects repair in diabetic periodontitis patients via targeting macrophage pyroptosis and enhancing osteogenic potential.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Junjie Liu,Jingjing Liu,Yuxin Qiao,Hanxin Zhong,Jiaoxia Wei,Dongyang Han,Jin Peng,Yongzhou Feng,Danni Wang,Yujie Cheng,Haitao Lu,Li Yao
Ethnopharmacological relevance We previous study verified that decadienyl-L-carnitine (C10:2) biosynthesis has therapeutic-target capacity for RCE inhibiting pulmonary vascular remodeling to modulate experimental pulmonary hypertension(PH). However, the profound molecular mechanism remains incompletely elucidated. Aim of study This study aim to investigate whether C10:2 biosynthesis regulates pulmonary vascular remodeling by activating cell pyroptosis. Materials and methods Rats and pulmonary artery smooth musle cells (PASMCs) model with PH were successfully induced with monocrataline (MCT) and platelet-derived growth factor-BB (PDGF-BB) in present study. Following RCE treatment, cell targeted metabolomics assay combining biological information analysis and molecular biological methods were used to investigate the modulatory function of C10:2 on pulmonary vascular remodeling by activating cell pyroptosis and accordingly pharmacological mechanism of RCE against cell pyroptosis. Results We found that C10:2 activated NLRP3/Caspase-1/GSDMD signaling pathway to promote PASMCs pyroptosis, and decreased the level of azelaic acid in PASMCs. RCE can significantly upregulate miR-149-5p to targeting bind Cpt1a mRNA, thus, to decrease CPT1A expression, by which low level of C10:2 was maintained to further promote the biosynthesis of anti-inflammatory azelaic acid in vivo, along with this functional molecule is also one main compound of RCE. Our data further demonstrated that the biosynthesis of azelaic acid directly regulates NLRP3/Caspase1/GSDMD axis to inhibit pyroptosis by targeting NLRP3, we therefore argue that azelaic acid is a key functional compound of RCE for treating PH by inhibiting cell pyroptosis. Conclusion Collectively, our work characterized that azelaic acid is a key functional compound in RCE to express pharmacological efficacy against PH, which was observed to inhibit cell pyroptosis to ameliorate pulmonary vascular remodeling in rats through the regulation of decadienyl-L-carnitine/NLRP3/GSDMD axis. Such work will provide essentially molecular basis for developing anti-PH strategy and associated drug discovery.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Shan Meng,Xin Chen,Jikai Zhao,Xinyi Huang,Yuting Huang,Tao Huang,Zijun Zhou,Wenpu Ren,Tao Hong,Jinfeng Duan,Liming Yu,Huishan Wang
Fibronectin type III domain-containing protein 5 (FNDC5) exerts potential anti-arrhythmic effects. However, the function and mechanism of FNDC5 in diabetes-associated atrial fibrillation (AF) remain unknown. In this study, bioinformatics analysis, in vivo and in vitro experiments were conducted to explore the alteration and role of FNDC5 in diabetes-related atrial remodeling and AF susceptibility. RNA sequencing data from atrial samples of permanent AF patients and diabetic mice exhibited significantly decreased FNDC5 at the transcriptional level, which was in line with the protein expression in diabetic mice as well as high glucose and palmitic acid (HG+PA) injured atrial myocytes. Diabetic mice exhibited adverse atrial remodeling and increased AF inducibility. Moreover, reduced atrial FNDC5 was accompanied with exacerbated NOD-like receptor pyrin domain containing 3 (NLRP3) activation and disturbed mitochondrial fission and fusion processes, as evidenced by decreased expressions of optic atrophy 1 (OPA-1), mitofusin (MFN-1, MFN-2) and increased phosphorylation of dynamin-related protein 1 (Ser616). These effects were validated in HG+PA-treated atrial myocytes. Critically, FNDC5 overexpression remarkably enhanced cellular antioxidant capacity by upregulating the expressions of superoxide dismutase (SOD1, SOD2) level. In addition, HG+PA-induced mitochondrial dysfunction was ameliorated by FNDC5 overexpression as evidenced by improved mitochondrial dynamics and membrane potential. Moreover, NLRP3 inflammasome-mediated inflammation was reduced by FNDC5 overexpression, and AMPK signaling might serve as the key down-stream effector. The present study demonstrated that reduced atrial FNDC5-AMPK signaling contributed to the pathogenesis of diabetes- associated AF by impairing mitochondrial dynamics and activating the NLRP3 inflammasome. These findings provide promising therapeutic avenues for diabetes-associated AF.
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高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
·
2024
·Vol. 388
·期 3
·813-826
·
IF 3.1
Peter Thornton,Valérie Reader,Zsofia Digby,Pamela Smolak,Nicola Lindsay,David Harrison,Nick Clarke,Alan P. Watt
Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism.
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高影响因子
Journal of Functional Foods
·
2025
·
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.
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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.
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高影响因子
JOURNAL OF MOLECULAR MEDICINE-JMM
·
2024
·
IF 4.8
Wang Pengtao,Tao Wei,Li Qiujie,Ma Wanting,Jia Wei,Kang Yuting
Indole-3-aldehyde (I3A) is an intestinal microbial metabolite that regulates inflammation in various inflammatory diseases; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the anti-inflammatory effects and molecular mechanisms of I3A in COPD. We constructed in vivo models using cigarette smoke (CS)-stimulated mice and in vitro models using cigarette smoke extract (CSE)-stimulated MH-S cells. The results demonstrated that I3A significantly alleviated bronchial obstruction in mice with COPD and reduced the expression of inflammatory factors such as TNF-α, IL-1β, and IL-6. Additionally, I3A decreased the levels of matrix metalloproteinases MMP2, MMP12, and inhibited the NF-κB p65/NLRP3 pathways. Further investigation revealed that I3A inhibited NF-κB activity by suppressing p65 phosphorylation and nuclear translocation in CSE-stimulated MH-S cells. The activation of the NF-κB and NLRP3 signaling pathways is mediated by histone deacetylase 5 (HDAC5) and HDAC6, both of which are inhibited by I3A. Subsequent experiments indicated that aryl hydrocarbon receptor (AHR) knockdown attenuated the inhibitory effect of I3A on pro-inflammatory cytokines and the HDACs/NF-κB/NLRP3 signaling pathways, highlighting the dependence of I3A's anti-inflammatory effects on the AHR receptor. Key messages
I3A effectively reduced lung inflammation in COPD mice by inhibiting the NF-κB pathway.
In CSE-stimulated MH-S cells, I3A suppressed p65 phosphorylation and nuclear translocation, thereby inhibiting NF-κB activity.
The activation of the NF-κB/NLRP3 pathways by HDAC5 and HDAC6 was diminished by I3A.
Through the activation of the AHR receptor, I3A suppressed the activities of HDAC5/6, leading to a decrease in inflammatory factor levels.
Graphical abstract
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PubMed
高影响因子
MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-20
·
IF 6.4
Peng Shuaijun,Su Pan,Liu Liming,Li Zibo,Liu Yuan,Tian Lei,Bai Ming,Xu Erping,Li Yucheng
Background The dysregulation of neuroinflammation triggered by imbalance of microglia M1/M2 polarization is a key pathogenic factor and closely associated with occurrence of depression. Formononetin (FMN), a natural non-steroidal isoflavonoid, has been confirmed to exhibit remarkable anti-inflammatory efficacy, but the impact of FMN on depression and the underlying antidepressant mechanisms are still not fully understood. This study aimed to investigate whether the antidepressant effect of FMN is involved in modulating microglia polarization, and if so, what are the underlying mechanisms.Methods Lipopolysaccharide (LPS)-induced depressive mice were used to study antidepressant mechanisms of FMN. Microglia cell line BV2 stimulated by LPS was employed to investigate pharmacological mechanisms of FMN. Effects of FMN on neuronal damage were detected by H&E, Nissl and Golgi staining. The efficacy of FMN were evaluated by immunostaining and western blots in vivo and vitro. In addition, molecular docking, luciferase reporter assay, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to confirm the direct target of FMN.Results Our results showed that FMN significantly reverses depression-like behaviors, alleviates neuroinflammation and neuronal damage, rebalances M1/M2 polarization, inhibits NLRP3 inflammasome and enhances microglial autophagy level in prefrontal cortex of LPS-induced depressive mice. In vitro assays, results unraveled that autophagy inhibitor chloroquine (CQ) blocks effects of FMN on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization. Moreover, PPARα is identified as a direct target of FMN and FMN can activate PPARα-mediated autophagy. Furtherly, combination PPARα agonist (WY14643) with FMN had no significant additive effects on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization, whereas PPARα antagonist (GW6471) abrogated these pharmacologic effects of FMN in BV2. Importantly, GW6471 exhibited similar pharmacologic effects to abolish antidepressant effect of FMN in LPS-induced depressive mice.Conclusion Our study firstly demonstrated that FMN can rebalance microglia M1/M2 polarization and inhibit NLRP3 inflammasome, with the involvement of activating PPARα-mediated autophagy to ameliorate depression-like behaviors, which provides a novel view to elucidate antidepressant mechanisms of FMN and also offers a potential therapeutic target for depression.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Jie Zhao,Xiangyu Piao,Yue Wu,Shanshan Liang,Fang Han,Qian Liang,Shujuan Shao,Dewei Zhao
Cepharanthine (CEP) is a potential candidate for treatment of cerebral ischemia/reperfusion (I/R) injury, due to its anti-inflammatory and anti-oxidative properties. To investigate the effect of CEP on cerebral I/R injury, we established a mouse model of transient middle cerebral artery occlusion (tMCAO) and a microglia cell model of oxygen and glucose deprivation/reoxygenation (OGD/R). Administration of CEP attenuated neurological deficits, reduced infarct volume and edema, and decreased microglia activation in MCAO mice. Immunofluorescence staining showed an up-regulation in NLR Family Pyrin Domain Containing 3 (NLRP3) immunoreactivity in Iba1-labled microglia together with total Iba1 and NLRP3 expression in the brain following tMCAO, while down-regulated by CEP treatment. In both tMCAO-induced mice and OGD/R-treated BV-2 cells, CEP exhibited dose-dependent inhibition on the expression of NLRP3, ASC and cleaved caspase-1. Importantly, CEP attenuated tMCAO or OGD/R-induced overproduction of M1 microglia-regulated pro-inflammation cytokines IL-1β and IL-18, suggesting that CEP might involve in suppressing microglia polarization to M1 phenotype in vivo and in vitro . Moreover, CEP dose-dependently inhibited tMCAO-induced arachidonate 15 lipoxygenase (ALOX15) together with Iba1-labled microglia. The subsequent ALOX15-mediated oxidative stress was decreased by CEP treatment in vivo and in vitro , as evidenced by reduced ROS generation and MDA level, and increased SOD activity. Taken together, we demonstrate that CEP attenuates cerebral I/R injury probably by inhibiting microglia activation and NLRP3 inflammasome-induced inflammation and reducing oxidative stress via suppressing 12/15-LOX signaling.
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高影响因子
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