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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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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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Haitao Yang,Xinyu Zhou,Baihao Zhang,Yuzhen Shan,Yichen Jin,Enzhuang Pan,Dong Xu,Liwen Fan,Panpan Zhao,Yong Sun,Jingquan Dong
Sepsis-associated encephalopathy (SAE) is a common and serious complication of sepsis, characterized by neuroinflammation and cognitive dysfunction, yet its molecular mechanisms remain unclear. This study aimed to investigate the role of heat shock protein 90α (HSP90α) in microglial NLRP3 inflammasome activation and cognitive impairment in SAE, and to explore the therapeutic potential of a small molecule compound, nicotinamide N-oxide (NAMO). SAE models were established using cecal ligation and puncture (CLP) in mice and LPS/ATP stimulated primary microglial cells/BV-2 cells. A combination of H&E/Nissl/TUNEL staining, transcriptomics, immunoblotting, qPCR, immunofluorescence, ELISA, mtDNA release, co-immunoprecipitation, molecular docking, AAV stereotaxic delivery, and pharmacological/siRNA interventions were utilized. Results showed that HSP90α expression was significantly upregulated in microglia during SAE. HSP90α facilitated NLRP3 inflammasome activation and exacerbated cognitive dysfunction in SAE by inducing mitochondrial dysfunction and promoting the release of mitochondrial DNA (mtDNA). Mechanistically, HSP90α interacted with PPP3CA, which facilitated Drp1 dephosphorylation at Ser637, triggering mitochondrial fragmentation and mtDNA release. Importantly, we identified that NAMO binds directly to HSP90α, inhibits the HSP90α–PPP3CA–Drp1 axis, reduces mtDNA release, and suppresses NLRP3 inflammasome activation. Administration of NAMO significantly alleviated cognitive impairment in SAE mice. Collectively, our findings reveal a novel HSP90α–PPP3CA–Drp1–mtDNA–NLRP3 signaling pathway in microglial activation and cognitive injury during SAE, and propose NAMO as a promising therapeutic candidate for SAE intervention.
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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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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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FOOD RESEARCH INTERNATIONAL
·
2025
·
IF 8
Mengqiong Wang,Baifei Hu,Jimin Ni,Kun Liu,Shuanggui Tian,Junping Zheng,Songlin Liu,Hongtao Liu
Functional constipation (FC) has become a prevalent gastrointestinal disorder worldwide. Arctii Fructus , a plant used for both food and medicine, contains oils, dietary fiber and arctiin as its core components, which have been demonstrated to alleviate constipation. However, its underlying mechanisms remain unclear. This study evaluated the interventive effects of the water extract of Arctii Fructus (WAF) in constipated mice induced by loperamide. Integrated metabolomics and 16S rDNA sequencing revealed that WAF significantly reshaped the gut microbiota structure, regulated the plasma metabolic profile, and inhibited the glycerophospholipid metabolism pathway in constipated mice. MetOrigin analysis further indicated that microbiota-host interactions play a critical role in WAF-mediated constipation relief. Serum pharmacochemical analysis identified five WAF-dependent active components that were absorbed into the bloodstream following microbial transformation. Based on network pharmacology predictions, we proposed that WAF alleviates constipation by suppressing the NLRP3 inflammasome pathway. This mechanism was subsequently validated through assessment of the spleen index, histopathological examination of intestinal tissues, and detection of key protein expression in the NLRP3 signaling pathway. In conclusion, this study systematically elucidates the multi-dimensional mechanisms by which WAF alleviates functional constipation through the gut microbiota-metabolism-inflammation axis. These findings provide a solid scientific foundation for its development as a functional food to improve intestinal health.
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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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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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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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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.
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Journal of Integrative Agriculture
·
2023
·
IF 4.8
Ke-da SHI,Yan LI,Min-sheng XU,Kun-li ZHANG,Hong-chao GOU,Shao-lun ZHAI,Chun-ling LI
Streptococcus suis serotype 2 ( S. suis 2) is a zoonotic pathogen that clinically causes severe swine and human infections (such as meningitis, endocarditis, and septicemia). In order to cause widespread diseases in different organs, S. suis 2 must colonize the host, break the blood barrier, and cause exaggerated inflammation. In the last few years, most studies have focused on a single virulence factor and its influences on the host. Membrane vesicles (MVs) can be actively secreted into the extracellular environment contributing to bacteria-host interactions. Gram-negative bacteria-derived outer membrane vesicles (OMVs) were recently shown to activate host caspase-11-mediated non-canonical inflammasome pathway via deliverance of OMV-bound lipopolysaccharide (LPS), causing host cell pyroptosis. However, little is known about the effect of the MVs from S. suis 2 (Gram-positive bacteria without LPS) on cell pyroptosis. Thus, we investigated the molecular mechanism by which S. suis 2 MVs participate in endothelial cell pyroptosis. In this study, we used proteomics, electron scanning microscopy, fluorescence microscope, western blotting, and bioassays, to investigate the MVs secreted by S. suis 2. First, we demonstrated that S. suis 2 secreted MVs with an average diameter of 72.04 nm, and 200 proteins in MVs were identified. Then, we showed that MVs were transported to cells via and dynamin-dependent endocytosis. The S. suis 2 MVs activated NLRP3/Caspase-1/GSDMD canonical inflammasome signaling pathway, resulting in cell pyroptosis, but it did not activate the caspase-4/-5 pathway. More importantly, endothelial cells produce large amounts of reactive oxygen species (ROS) and lost their mitochondrial membrane potential under induction by S. suis 2 MVs. The results in this study suggest for the first time that MVs from S. suis 2 were internalized by endothelial cells via mainly dynamin-dependent endocytosis and might promote NLRP3/caspase-1/GSDMD pathway by mitochondrial damage, which under induction produced mtDNA and ROS, leading to the pyroptosis of endothelial cells.
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Scientific Reports
·
2025
·Vol. 15
·期 1
·40525
·
IF 3.9
Ma Chunli,Wang Linghong,Cao Lili,Zhao Linyun,Zhang Xin,Ma Chengyou,Lian Hua,Bao Xiufang,Eerde Mutu,Buren Qiqige,Tong He,Dai Lili,Amu Guleng,Bao Yulong,Hong Mei,Wang Li
Acute liver injury (ALI) is a prevalent hepatic condition that poses significant risks to both life and overall health. Traditional Mongolian medicine utilizes Honghua Qinggan Thirteen-Flavor Pills (HHQG) as a primary formula for dispelling liver heat, illustrating both an extensive application in clinical settings and notable therapeutic effectiveness for treating liver ailments such as hepatitis and liver failure. Nevertheless, the molecular mechanisms underpinning the hepatoprotective properties of HHQG remain inadequately understood.We employed a CCl 4 -induced mouse model of liver injury alongside network pharmacology analysis, molecular docking studies, and cellular assays to dissect the effects and mechanisms of action of HHQG. Our findings demonstrated that HHQG significantly improved CCl 4 -induced liver injury in mice, reducing pathological damage and inflammatory factors. Network pharmacology identified 184 overlapping targets, 6 key genes, and 5 key active components in HHQG. Molecular docking confirmed the binding affinity of these components to RASD1. Gene expression analysis in liver tissue revealed a positive correlation between mRNA expression of RASD1 and NLRP3. Cell experiments demonstrated the role of RASD1 in regulating NLRP3 inflammasome and inflammatory factors. Pretreatment of HHQG attenuated LPS-induced inflammatory response and the activation of PKCδ-NF-κB signaling pathway. In the CCl 4 -induced liver injury model, HHQG significantly reduced NLRP3, RASD1, and PKCδ-NF-κB expression.This study revealed that HHQG effectively mitigates CCl 4 -induced liver injury by inhibiting the activation of NLRP3 inflammasome by regulating the PKCδ-NF-κB signaling pathway via RASD1. These findings provide novel theoretical support for the rational application of HHQG as a potential hepatoprotective agent.
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