BRAIN RESEARCH BULLETIN
·
2024
·
IF 3.5
Zhijuan Cheng,Jianglong Tu,Kai Wang,Fang Li,Yuan He,Wei Wu
Cerebral ischemia-reperfusion (IR) is the main pathophysiological process after stroke and can seriously impair neurological function. Wogonin, a natural flavonoid extracted from the roots of Scutellaria baicalensis, has potent anti-inflammatory properties. In this study, we investigated the protective mechanism of wogonin against middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) model-induced cerebral IR injury through adenosine 5‘-monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome axis. Our results showed that wogonin (20 mg/kg, intraperitoneal injection) effectively reduced infarct size, attenuated brain edema, improved neurological deficits, and alleviated histopathological damage. In addition, wogonin reduced microglial cell activation and inflammatory factors, including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-10, in brain tissue and serum after cerebral IR injury. Wogonin also effectively activated the AMPK/SIRT1 signaling pathway and inhibited NLPR3 inflammasome-related molecules upregulation in cerebral IR injury as well as in OGD/R-stimulated HT-22 cells. Furthermore, inhibition of the AMPK/SIRT1 signaling pathway by Compound C, an AMPK inhibitor, significantly reversed the protective effect of wogonin on OGD/R-induced NLRP3 inflammasome. Meanwhile, the protective effect of wogonin against brain IR injury was also reversed in the presence of compound C. These results suggest that wogonin ameliorates cerebral IR injruy-induced inflammation by inhibiting NLRP3 inflammasome through the AMPK/SIRT1 signaling pathway.
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AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
·
2024
·Vol. 92
·期 1
·e13893
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IF 2.5
Yongmei Peng,Yanan Xu,Sainan Li,Mingkun Shao,Zijia Shen,Wenjin Qi
Problem Vulvovaginal candidiasis (VVC) is a common mucosal fungal infection, and Candida albicans is the main causative agent. The NLRP3 inflammasome plays an important role in VVC, but the underlying mechanism is unknown. Method of Study Vaginal epithelial cells were divided into three groups: control, C. albicans strain SC5314 (wild-type, WT), and WT+ Matt Cooper Compound 950 (MCC950, a specific NLRP3 inhibitor). After human vaginal epithelial cells were pretreated with 1 µmol/L MCC950 for 2 h, C. albicans (MOI = 1) was cocultured with the human vaginal epithelial cells for 12 h. The cell supernatants were collected, LDH was detected, and the IL-1β and IL-18 levels were determined by ELISA. The expression of the pyroptosis-related proteins NLRP3, Caspase-1 p20 and GSDMD was measured by Western blotting analysis. The protein expression of the pyroptosis-related N-terminus of GSDMD (GSDMD-N) was detected by immunofluorescence. Results In this study, we showed that the WT C. albicans strain induced pyroptosis in vaginal epithelial cells, as indicated by the LDH and proinflammatory cytokine levels and the upregulated levels of the pyroptosis-related proteins NLRP3, Caspase-1 p20, and GSDMD-N. MCC950 reversed the changes in the expression of these proteins and proinflammatory cytokines in vaginal epithelial cells. Conclusion C. albicans activated the NLRP3 inflammasome to induce vaginal epithelial cell pyroptosis. MCC950 inhibited the NLRP3 inflammasome, reduced vaginal epithelial cell pyroptosis, and decreased the release of inflammatory cytokines.
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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 .
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JOURNAL OF APPLIED TOXICOLOGY
·
2025
·
IF 2.8
Shuge Shu,Xinting Chen,Jiawen Ren,Xiangyu Yu,Hao Zhang,Yongquan Yu
Glyphosate is reported to compromise the central nervous system and induce behavioral disorders in mammals. However, evidence is deficient with respect to the potential mechanisms involved. In this study, C57BL/6 mice were orally exposed to glyphosate at doses ranging from 0 to 200 mg/kg/day for 16 weeks. The results of behavioral tests showed that glyphosate decreased time spent and distance traveled within the central area of open field test, decreased the retention time and number of entries into the open arms, and increased the retention time and number of entries into the close arms of elevated plus maze test. The expressions of anxiety-related genes htr5 , htr6 , and tmem132d were also significantly upregulated by glyphosate. This behavioral phenotype was linked to the permeation of glyphosate into the brain via disrupting the functional tight junctions of blood–brain barrier (BBB). As a result, glyphosate directly compromised the morphological structure of neurons, increased the number of IBA-1 microglia, and activated the expression of NLRP3-mediated pyroptosis pathway (NLRP3, Caspase-1, GSDMD, and IL-18) in the hippocampus of mice. Moreover, the glyphosate-induced activation of NLRP3 pathway in microglia was markedly reversed by NLRP3 inhibitor MCC950. The conditional mediums from glyphosate-treated BV2 cells aggravated the cytotoxicity of HT-22 neurons, which was also rescued by MCC950. In conclusion, this work demonstrated that microglia-mediated activation of NLRP3 pyroptosis pathway plays a detrimental role in glyphosate-behavioral disorders and neuron damage. These findings provide novel evidence for glyphosate-induced neurotoxicity and support the growing association between glyphosate exposure and neurobehavioral disorders in humans.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Shan Liu,Yue Zhang,Hao Zhou,Yating Ma,Fangzhou Huang,Tianyuan Lei,Qingbin Wang,Shangmin Yu
Ginsenoside Re (Re) was proved effective in improving depressive-like behaviors. However, the potential antidepressant mechanism of Re remains unrevealed. In this study, we investigated whether PINK1-mediated mitophagy and NLRP3 inflammasomes were linked to the antidepressant mechanism of Re in chronic unpredictable mild stress (CUMS) mice and lipopolysaccharide (LPS)-stimulated astrocytes. RNA sequencing and bioinformatics analyses were performed to discover the targets and pathways associated with Re. PTEN-induced putative kinase 1 (PINK1) knockdown was conducted to clarify the role of PINK1-mediated mitophagy in the antidepressant mechanism of Re. The outcomes showed that Re ameliorated depressive-like behaviors, activated PINK1-mediated mitophagy, and inhibited NLRP3 inflammasome activation. PINK1 knockdown attenuated the antidepressant effect of Re. The promotion of mitophagy and the decline of NLRP3 inflammasome activation caused by Re were reversed by PINK1 knockdown. In conclusion, Re inhibited NLRP3 inflammasome activation by promoting PINK1-mediated mitophagy to exert its antidepressant effect.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Wei Zhang,Wenting Zhu,Xiao Liu,Silong Yuan,Da Li,He Huang,Xiaoming Huang,Lei Wang,Honggang Zhang
Background The pathogenesis of sepsis-induced cardiomyopathy (SIC) remains unclear, presenting a complex challenge in both clinical practice and research. Gypenoside XLIX (Gyp-XLIX) has garnered significant attention for its anti-inflammatory, antioxidant, and various other pharmacological activities; however, its protective effect on SIC has not been thoroughly investigated. Purpose This study aims to explore the effect of Gyp-XLIX on SIC and its potential therapeutic mechanisms. Methods A sepsis mouse model was established through cecal ligation and puncture surgery and treated with Gyp-XLIX. The modeling was evaluated through sepsis model scoring, survival analysis, weight changes, wet-to-dry weight ratio, H&E staining, biochemical assays and cardiac ultrasound. The mechanism exploration was deteced using proteomics sequencing, Western blotting, qPCR, biochemical analysis, and reactive oxygen species assays. Additionally, target proteins of Gyp-XLIX were identified through LC-MS/MS proteomics analysis, molecular docking, CESTA, DARTS, SPR with SIRT1 being a primary focus. Bioinformatics and Immunoprecipitation mass spectrometry analysis, and immunohistochemistry were employed to further elucidate the downstream target of SIRT1, specifically the YAP-NLRP3 pathway. The degradation mechanisms of YAP-NLRP3 were explored using MG132, chloroquine, cycloheximide, and co-immunoprecipitation. Corresponding rescue experiments were conducted in H9C2 cells for further validation. Results Gyp-XLIX effectively mitigates SIC, reduces cardiac inflammation, and restores cardiac structural, left ventricular functional abnormalities, and oxidative stress balance. Proteomics results showed that Gyp-XLIX binded to SIRT1 and alleviates inflammation and oxidative stress. Whereas, SIRT1 is low expressed and alleviated oxidative stress and NLRP3 inflammasome activation in SIC. Mechanically, Gyp-XLIX binded to SIRT1 improved its stability and promoted the deacetylation and phosphorylation of downstream YAP, which in turn regulated YAP degradation. This process subsequently affects the ubiquitination of NLRP3, downstream of YAP, at the K27 site, leading to its degradation and, consequently, alleviating inflammation and oxidative stress during SIC. Conclusion Gyp-XLIX targets SIRT1 to block YAP-NLRP3 activation and improve SIC, suggesting that Gyp-XLIX is an effective protective agent against SIC and represents a promising therapeutic strategy.
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Food Science & Nutrition
·
2025
·Vol. 13
·期 11
·e71074
·
IF 3.8
Tingting Chen,Xiaoqin Wu,Danna Wang,Tianqi Cui,Jiayu Li,Ziyi Zhang,Min Qiu,Chenlu Ma,Hengrui Liu,Yong Gao,Jiangtao Zeng,Hang Li,Jiawen Huang
Exocarpium Citri Grandis (ECG, known as Huajuhong in Chinese), as the fruit that can be used both as medicine and food, has gained attention for its hypolipidemic and anti‐obesity effects. However, its lipid‐lowering potential and ability to alleviate metabolic syndrome (MS) remain unexplored. This study aimed to confirm the therapeutic effects of ECG on postmenopausal MS and investigate its underlying mechanisms. An animal model of female postmenopausal MS was established using 8‐week‐old ovariectomized (OVX) mice. Starting from the third week after model establishment, the mice were orally administered at the doses of 25, 50, and 100 mg/kg for 12 consecutive weeks. HepG2 cells co‐induced by oleic acid and palmitic acid (OA&PA) were used as an in vitro model. Ultra‐high‐performance liquid chromatography‐Q‐Exactive (UHPLC‐Q‐Exactive) analysis, histological examination, immunofluorescence, network pharmacology, molecular docking, molecular dynamics simulations, and other methods were employed for further analysis. ECG contains ingredients such as naringin and narirutin. In vitro experiments showed that ECG intervention significantly reduced reactive oxygen species (ROS) accumulation and downregulated the mRNA expression of Srebp1, G6, Fas, Pgc1α, Acc, Casp1, Nfkb, IL1β, IL6, Txnip, Nlrp3 , and ASC . Additionally, ECG inhibited the protein expression of NF‐κB, Txnip, NLRP3, ASC, and Caspase‐1, while enhancing the expression of Trx‐1. In vivo, ECG alleviated metabolic disorders in OVX mice by reducing lipid accumulation, attenuating inflammatory responses, and inhibiting NLRP3 inflammasome activation. Network pharmacology analysis and molecular dynamics identified the PI3K/AKT1 signaling pathway as a crucial target mediating the functional effects of ECG. ECG exerts therapeutic benefits in ameliorating postmenopausal MS‐related metabolic disorders by inhibiting inflammatory responses, suppressing NLRP3 inflammasome activation, and modulating the PI3K/AKT1 signaling pathway, providing new insights into the application of ECG for managing postmenopausal MS. Exocarpium Citri Grandis (ECG, Huajuhong in Chinese), as the fruit of a plant that can be used both as medicine and food, has gained attention for hypolipidemic and anti‐obesity effects. To our knowledge, this is an innovative study based on in vivo and in vitro experiments aimed at exploring the pharmacological mechanisms of ECG in ameliorating MS after menopause. Our findings provide new insights into the application of foods that are homologous to medicine and food in managing menopausal MS.
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ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 43
·期 8
·2016-2025
·
IF 7.169
Wang Jin-cheng,Shi Qi,Zhou Qian,Zhang Lu-lu,Qiu Yue-ping,Lou Da-yong,Zhou Li-qin,Yang Bo,He Qiao-jun,Weng Qin-jie,Wang Jia-jia
Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5–20 μM) suppressed the phosphorylated activation of NF-κB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 μM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients.
研究领域:
药理学
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免疫学
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肝病学
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细胞生物学
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Cheng Fu,Tianyi Hu,Xiangli Zhao,Yahui Huang,Jiang zhang,Lan Zhu,Jun Yang,Gang Chen
Rhein, an anthraquinone-derivative monomer isolated from the rhubarb plant, is the active ingredient of the drug Diacerein® (generic name: diacetylrhein), which possesses anti-inflammatory and antioxidant properties. It has been reported that rhein is effective in protecting against cerebral and retinal ischemia–reperfusion injury (IRI), but whether it can protect against renal IRI remains unknown. Here, a lethal renal IRI model was established with a 100 % mortality rate in untreated mice. Treatment with 100 mg/kg of rhein for 5 consecutive days before ischemia resulted in 100 % survival, maximal preservation of renal function, and a significant reduction in pathological damage, apoptosis and inflammation. In addition, rhein pretreatment significantly inhibited the upregulation of NLRP3, caspase-1, IL-1β and NGAL seen in the IRI control group. Through a series of experiments (including Co-Immunoprecipitation (Co-IP), pull-down, molecular dynamics simulation and surface plasmon resonance (SPR)), we confirmed that rhein has a strong binding affinity with PPARγ. By using the specific inhibitor T0070907 to block PPARγ, the protective effect of rhein on renal IRI in vivo and the protective effect on cell damage in the NLRP3 inflammasome activation model induced by (LPS + Nig) in vitro can be largely eliminated. We demonstrate here that rhein can potently protect against lethal renal IRI in mice. This protection is mainly achieved by targeting and enhancing the expression of PPARγ, thereby inhibiting the activation of the NLRP3 inflammasome. Thus, rhein may be therapeutically useful for the clinical prevention and treatment of renal IRI.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2026
·Vol. 60
·期 32
·22274-22286
·
IF 12.2
Liu Xinwei,Zhao Jiayi,Zhang Yinqing,Zhu Lingyan
Microplastics are ubiquitous in the
atmosphere and may be inhaled
into the respiratory system to cause adverse health effects. Photoaging
of microplastics in the atmosphere is inevitable, which changes their
toxic effects greatly, yet the impacts and underlying mechanisms remain
poorly understood. In this study, poly(vinyl chloride) microplastics
(PVC-MPs), commonly detected in the atmosphere, were selected to investigate
the effects of photoaging on pulmonary toxicological responses at
7 days after a single intratracheal instillation in a mouse model.
Photoaging enhanced the abundance of oxygen-containing functional
groups on the particle surface, surface hydrophilicity, and oxidative
potential. Upon a short-term intratracheal exposure, photoaged PVC-MPs
(A-PVC) induced more severe pulmonary inflammation and epithelial
barrier dysfunction than the virgin PVC-MPs (V-PVC), as evidenced
by increased protein leakage and lactate dehydrogenase release in
bronchoalveolar lavage fluid and disruption of tight junction proteins.
Transcriptomic analysis revealed enrichment of the NOD-like receptor
signaling pathway and activated TXNIP–NLRP3 inflammasome axis. In vitro tests with BEAS-2B cells indicated that more A-PVC
was adsorbed on the cell membrane, likely due to increased membrane
affinity than V-PVC, thus triggering excessive ROS generation and
leading to TXNIP-dependent NLRP3 activation and tight junction disruption.
Inhibition of ROS, TXNIP, or NLRP3 attenuated inflammasome activation
and preserved barrier integrity. These findings demonstrate that environmental
photoaging exacerbated short-term pulmonary toxicity of PVC-MPs through
a ROS–TXNIP–NLRP3-mediated inflammatory amplification
axis.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Songtao Zheng,Yefei He,Xiaoying Cui,Xinran Xu,Ruonan Tang,Shuhui Liu,Wenkai Xie,Wenhui Yu,Xiaowen Jiang
Melatonin (MT), a neurohormone secreted by the mammalian pineal gland, has been demonstrated to exert hepatoprotective effects. In this study, we employed exogenous MT intervention in both in vivo and in vitro models of chronic liver injury induced by D-galactose (D-gal) in mice to investigate the specific mechanisms underlying its hepatoprotective action, aiming to provide a reference for the prevention of liver injury by MT. Preliminary network toxicology and network pharmacology analyses revealed that D-gal possesses potential hepatotoxicity, whereas MT exerts hepatoprotective effects through modulating oxidative damage and inflammation. Further analysis indicated that the targets of MT and D-gal are highly enriched in the PI3K/AKT signaling pathway. We therefore examined the PI3K/AKT pathway and downstream proteins associated with NLRP3 inflammasome activation. Our results demonstrated that exogenous MT improves hepatic physiological function and alleviates liver injury by activating the PI3K/AKT signaling pathway, which in turn inhibits NLRP3 inflammasome activation. Download: Download high-res image (273KB) Download: Download full-size image
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Kaixin Ping,Panpan Zhao,Jingyuan Zhou,Yue Xin,Boran Hu,Baihao Zhang,Dong Xu,Aimin Li,Yong Sun
Background Subarachnoid hemorrhage (SAH) is a lethal stroke subtype with high mortality. Microglia-driven neuroinflammation plays a pivotal role in early brain injury (EBI) after SAH. Xanthotoxol (Xol), a natural furanocoumarin, exhibits anti-inflammatory properties and neuroprotective potential, yet its role in SAH remains unclear. This study investigates whether Xol alleviates SAH-induced neuroinflammation and its underlying mechanisms. Methods SAH was induced in male SD rats and Balb/c mice via endovascular perforation. Three weeks prior to the SAH surgery, AAV2/9-CX3CR1-ZsGreen-miR30-Fyn virus was injected into the medial prefrontal cortex for in vivo mechanistic investigations. In vitro SAH models were established using oxyhemoglobin-stimulated microglia and microglia-neuron co-cultures. Finally, the efficacy of Xol was investigated both in vivo and in vitro following SAH. Assessments included neurological and cognitive function evaluation, brain water content measurement, detection of apoptosis, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, immunohistochemistry, and Nissl staining. Results Fyn was upregulated in microglia post-SAH and associated with neuroinflammatory and apoptotic pathways via proteomics. Its knockdown ameliorated neurological deficits, edema, neuronal injury, and NLRP3 activation. Mechanistically, Fyn promoted K48-linked ubiquitination and degradation of Sirt1 via E3 ligase C-cbl. Xol directly bound Fyn, inhibiting its kinase activity and NLRP3 activation, thereby mitigating brain injury. Conclusion This study revealed Fyn recruits E3 ligase C-cbl to mediate Sirt1-K48 ubiquitination/degradation, activating NLRP3 inflammasome to drive SAH-induced neuroinflammation and brain injury. Xol inhibits Fyn activation, thereby attenuating inflammatory injury. The Fyn/Sirt1 axis represents a novel therapeutic target, and Xol offers a promising natural strategy for SAH treatment.
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