EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Xiaojuan Pan,Junjie Fu,Xiaofan Gu,Meng Fan,Lixuan Pan,Yun Zhao,Xuan Liu,Xiongwen Zhang
Cancer cachexia-associated muscle atrophy represents a critical clinical challenge in advanced malignancies. Cancer cachexia is known as an inflammation-related disease, and the NoD-like receptor family pyrin domain-3 (NLRP3) inflammasome plays a significant role in cancer cachexia, especially in muscle atrophy. In the present study, the efficacy of MCC950, a selective NLRP3 inhibitor, on cancer cachexia-associated muscle atrophy was observed both in cultured C2C12 myotubes underwent various simulated cancer cachexia injuries and in cancer cachexia model mice bearing C26 colon tumor cells. In vitro , MCC950 alleviated C2C12 myotube atrophy induced by conditioned medium from tumor or tumor-macrophage co-cultures. In vivo , MCC950 markedly attenuated cachexia symptoms such as body weight loss and muscle atrophy in C26 tumor-bearing mice. Mechanistically, in tumor or tumor-macrophage co-culture, MCC950 suppresses NLRP3 inflammasome activation, reduces IL-1β and IL-18 release, subsequently decreases the potency of inducing NF-κB activation and Atrogin-1-mediated ubiquitin-proteasome degradation in myotubes, thereby attenuates C2C12 myotube atrophy. Furthermore, in muscle cells, MCC950 directly silences NLRP3 inflammasome signaling, inhibits pyroptosis and IL-1β/IL-18 secretion, suppresses muscle protein degradation to rescue cancer cachexia-driven muscle atrophy. These findings revealed the important role of NLRP3 inflammasome in cancer cachexia and also suggested the possibility of developing NLRP3 inflammasome inhibitors such as MCC950 to be novel therapeutic candidates for cancer cachexia treatment.
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高影响因子
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.
研究领域:
微生物学
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免疫学
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细胞生物学
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传染病学
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PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2021
·Vol. 47
·期 3
·713-722
·
IF 3.996
Zhang Haiju,Yu Shiqian,Xia Liping,Peng Xia,Wang Shun,Yao Baozhen
Epilepsy (SE) is a common and serious neurological disease. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome participates in the pathogenesis of SE, while its underlying mechanism is still unclear. Here, we attempted to explore the mechanism of action of NLRP3 inflammasome in SE. SE mouse model was constructed by administration of kainic acid (KA). Astrocytes were treated with KA to mimic SE cell model. MCC950 (NLRP3 inhibitor) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat astrocytes to inhibit the activity of NLRP3 and Caspase-1. Nissl staining was performed to examine the morphology of neuron. Western blot, enzyme-linked immunosorbent assay and immunofluorescence staining were performed to assess protein expression. SE mouse model exhibited an increase of neuronal loss, and an up-regulation of Cleaved-Caspase-1, IL-1β and IL-18 in hippocampus. The levels of GFAP + ADK + cells were significantly increased in SE mice. MCC950 or Z-YVAD-FMK abolished these impacts conferred by KA in SE mice. Moreover, KA treatment enhanced the expression of NLRP3, Cleaved-Caspase-1, IL-1β and IL-18 in astrocytes, which was rescued by knockdown of NLRP3 or Caspase-1. Additionally, CREB, p-CREB, REST were up-regulated, and SP1 was down-regulated in the KA-treated SE mice and KA-treated astrocytes. Inhibition of NLRP3 or Caspase-1 rescued these proteins expression in KA-treated astrocytes. CREB or REST silencing reduced adenosine kinase (ADK) expression, while SP1 knockdown enhanced ADK expression in KA-treated astrocytes. In conclusion, NLRP3 inflammasome activation enhances ADK expression to accelerate SE in mice through regulating CREB/REST/SP1 signaling pathway. Thus, inhibition of NLRP3 inflammasome may be a treatment for SE.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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高影响因子
MEDIATORS OF INFLAMMATION
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2018
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IF 3.549
Dacheng Wu,Keyan Wu,Qingtian Zhu,Weiming Xiao,Qing Shan,Zhigang Yan,Jian Wu,Bin Deng,Yan Xue,Weijuan Gong,Guotao Lu,Yanbing Ding
Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation.
研究领域:
药理学
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免疫学
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胃肠病学
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高影响因子
Biomedical Journal
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2023
·
IF 5.5
Shi-Le Wang,Man-Man Zhang,Han Zhou,Guo-Qiang Su,Yi Ding,Guang-Hui Xu,Xu Wang,Cheng-Fu Li,Wei-Feng Huang,Li-Tao Yi
Background Inflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory disease of gastrointestinal tissue characterized by inflammation of the gut. Recent studies have shown that gut microbiota is involved in the pathophysiology of IBD. However, it is unknown whether direct inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters gut microbiota. Methods Here, the NLRP3 expression was evaluated in the colon of IBD subjects. Then, we investigated the effects of NLRP3 inhibition by MCC950 on the gut microbiota and IBD-like symptoms induced by dextran sulfate sodium (DSS). Results Firstly, NLRP3 and IL-1β levels were increased in patients with IBD as compared with healthy individuals. Then, the animal experiment showed that NLRP3 inhibition by MCC950 significantly attenuated IBD-like symptoms such as diarrhea and colonic inflammation in DSS-induced mice. In addition, NLRP3 inhibition inhibited NLRP3/ASC/caspase-1/IL-1β signaling pathway in the colon, which was over-activated by DSS. Furthermore, MCC950 increased the abundance of phylum Firmicutes, decreased the abundance of phylum Bacteroidetes, and increased the Firmicutes/Bacteroidetes ratio, indicating that the inhibition of NLRP3 inflammasome could regulate the abundance of intestinal flora. According to correlation analysis, NLRP3 might produce its functional role in the regulation of oxidation indicators by changing the gut microbiota composition, especially the phylum Bacteroidota, genus Lactobacillus and species Lactobacillus reuteri . Conclusions This study suggests that NLRP3 inflammasome inhibition attenuates IBD-like symptoms by regulating gut microbiota, and provides a basis for the clinical application of NLRP3 as a target for the treatment of IBD.
研究领域:
免疫学
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胃肠病学
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微生物学
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高影响因子
MICROVASCULAR RESEARCH
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2021
·
IF 3.514
Keke Ge,Yatao Wang,Pan Li,Miao Li,Wenhua Zhang,Handong Dan,Xumeng Hu,Jiamu Zhou,Qixiang Yang,Jiaojiao Wang,Zongming Song
The investigation aimed to evaluate the effects of Mcc950, an inhibitor of the NLRP3 inflammasome , on diabetic retinopathy (DR) mice. The general physiological condition of each group of mice was recorded. Retinal blood vessels were stained for observation of the density of blood vessels, and retinas were used for further morphological examination and fluorescent staining after the intravitreal injection of Mcc950. Mcc950 partially reversed hyperglycemia-induced vascular damage and had reduced histological changes compared to DR mice. IL-1β production in mice retinas in the diabetic model (DM) group increased, but pretreatment with Mcc950 significantly reversed these changes. Additionally, Mcc950 engineered reduced FITC dextran extravasation and vascular leakage. Therefore, it played an apparent protective role in DR and could be a new treatment strategy for DR.
研究领域:
医学
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眼科
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免疫学
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药理学
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PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2023
·Vol. 64
·期 3
·16-16
·
IF 4.4
Lili Lian,Zhenmin Le,Zhenzhen Wang,Ying-ao Chen,Xiaodong Jiao,Hang Qi,J. Fielding Hejtmancik,Xiaoyin Ma,Qinxiang Zheng,Yueping Ren
Purpose:To determine whether SIRT1 regulates high glucose (HG)–induced inflammation and cataract formation through modulating TXNIP/NLRP3 inflammasome activation in human lens epithelial cells (HLECs) and rat lenses.Methods:HG stress from 25 to 150 mM was imposed on HLECs, with treatments using small interfering RNAs (siRNAs) targeting NLRP3, TXNIP, and SIRT1, as well as a lentiviral vector (LV) for SIRT1. Rat lenses were cultivated with HG media, with or without the addition of NLRP3 inhibitor MCC950 or SIRT1 agonist SRT1720. High mannitol groups were applied as the osmotic controls. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of SIRT1, TXNIP, NLRP3, ASC, and IL-1β. Reactive oxygen species (ROS) generation, cell viability, and death were also assessed.Results:HG stress induced a decline in SIRT1 expression and caused TXNIP/NLRP3 inflammasome activation in a concentration-dependent manner in HLECs, which was not observed in the high mannitol–treated groups. Knocking down NLRP3 or TXNIP inhibited NLRP3 inflammasome-induced IL-1β p17 secretion under HG stress. Transfections of si-SIRT1 and LV-SIRT1 exerted inverse effects on NLRP3 inflammasome activation, suggesting that SIRT1 acts as an upstream regulator of TXNIP/NLRP3 activity. HG stress induced lens opacity and cataract formation in cultivated rat lenses, which was prevented by MCC950 or SRT1720 treatment, with concomitant reductions in ROS production and TXNIP/NLRP3/IL-1β expression levels.Conclusions:The TXNIP/NLRP3 inflammasome pathway promotes HG-induced inflammation and HLEC pyroptosis, which is negatively regulated by SIRT1. This suggests viable strategies for treating diabetic cataract.
研究领域:
眼科学
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细胞生物学
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糖尿病
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炎症
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分子生物学
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高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2024
·
IF 8.2
Shanshan Li,Xuedie Gu,Muyue Zhang,Qihang Jiang,Tong Xu
Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n -acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.
研究领域:
毒理学
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环境科学
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免疫学
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细胞生物学
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Jinzhao Zhou,Yanwei Zhang,Ling Zeng,Xiaofei Wang,Wenpei Xiang,Ping Su
Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11–7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.
研究领域:
毒理学
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细胞生物学
·
生殖健康
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PubMed
高影响因子
Small Structures
·
2024
·
IF 13.9
Yuyao Liu,Jiayin Yan,Luxian Chen,Yuwei Liao,Lijia Huang,Jiali Tan
Alveolar bone resorption caused by bacteria-induced periodontitis remains challenging due to sustained inflammation. Periodontal pathogens like Porphyromonas gingivalis launch the primed signal of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in macrophages; consequent overproduction of proinflammatory cytokines and reactive oxygen species (ROS) leads to tissue destruction. This provides potential targets for a new therapeutic strategy. Herein, a multifunctionalized and dual-crosslinked hydrogel pGM/cPL@NI with NLRP3 inhibitor MCC950 loaded is prepared. Driven by the strategic functionalization of gelatin methacryloyl and ε -poly-lysine with phenylboronic acid and catechol, respectively, pGM/cPL@NI containing dynamic and photo-crosslinking networks demonstrates superior mechanical strength and stimuli-responsive behavior, as well as the overwhelmed performance in bacteria killing and ROS scavenging. Crucially, pGM/cPL@NI restores the compromised osteogenesis by specifically suppressing the proinflammatory cytokine cascade triggered by NLRP3 inflammasome activation and promoting anti-inflammatory polarization of macrophages. Collectively, pGM/cPL@NI presents robust potential as an effective “cocktail therapy” by combining antibacterial, antioxidant, inflammation resolution, and tissue regenerative functions. The present study reveals the underlying mechanism of the bacterial-immune-regeneration cascade and provides an extended approach for periodontal tissue engineering.
研究领域:
生物材料
·
组织工程
·
炎症
·
牙科科学
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再生医学
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高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-12
·
IF 3.8
Gao Kexin,Liu Yancui,Sun Cheng,Wang Ying,Bao Hongrong,Liu Guoyang,Ou Jinrui,Sun Ping
Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.
研究领域:
肿瘤学
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细胞生物学
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免疫学
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PubMed
高影响因子
TISSUE & CELL
·
2026
·
IF 3.1
Dayuan Zheng,Dongfan Yang,Tong Chu,Shaokui Liang,Kuanyun Zhang,Lu Yang,Yanchao Yang,Wenzhe Ma
YB overcomes chemoresistance in EBV-positive NPC. • YB induces ferroptosis rather than necroptosis in EBV-positive NPC. • YB activates ferritinophagy-dependent ferroptosis in EBV-positive NPC. • NCOA4 knockdown rescues YB-treated EBV-positive NPC. Background EBV-positive nasopharyngeal carcinoma frequently exhibits significant chemoresistance, posing a major challenge in clinical treatment. Yunnan Baiyao, a traditional Chinese patent medicine, has shown promise in antitumor research beyond its conventional hemostatic applications. This study investigated the efficacy of Yunnan Baiyao against EBV-positive nasopharyngeal carcinoma and explored the underlying molecular mechanisms of cell death. Methods Yunnan Baiyao-treated EBV-positive C666–1 and EBV-negative HK1/SUNE1 cells were subjected to Sulforhodamine B assay, colony formation assay, and C11-BODIPY/Fe²⁺ flow cytometry to verify antitumor activity and ferroptosis induction. Ferroptosis, autophagy, and ferritinophagy were confirmed via live-cell imaging, Transmission Electron Microscopy, and Western blotting. Specific inhibitors (Q-VD-Oph, Nec-1, etc.) validated the roles of apoptosis, necroptosis, and other pathways. Lentiviral NCOA4 knockdown verified its core function. Nude mouse xenograft models (with Liproxstatin-1 rescue and NCOA4-knockdown tumors) evaluated in vivo efficacy and dependence on ferroptosis/NCOA4. Results C666–1 cells (EBV-positive) are more resistant to cisplatin compared with SUNE1 and HK1 cells (both EBV-negative). Yunnan Baiyao exerted concentration- and time-dependent cytotoxicity on C666–1 cells. Notably, C666–1 cells were more sensitive to Yunnan Baiyao than SUNE1 cells. Yunnan Baiyao induced ferroptosis (not apoptosis/necroptosis/pyroptosis) with elevated lipid peroxidation, intracellular Fe²⁺ accumulation, and mitochondrial shrinkage. Yunnan Baiyao activated autophagic flux, and BAF (autophagy inhibitor) partially reversed ferroptosis. Yunnan Baiyao-induced cell death relied on NCOA4-mediated ferritinophagy; NCOA4 knockdown abrogated its effects in vitro. In vivo, Yunnan Baiyao significantly inhibited tumor growth, reversed by Lip-1 treatment or NCOA4 knockdown. Conclusions Yunnan Baiyao overcomes chemoresistance in EBV-positive nasopharyngeal carcinoma by triggering NCOA4-mediated ferritinophagy-dependent ferroptosis. These findings provide a mechanistic foundation for further preclinical evaluation of Yunnan Baiyao as a candidate therapeutic strategy for chemoresistant nasopharyngeal carcinoma. Download: Download high-res image (146KB) Download: Download full-size image
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