Animal Models and Experimental Medicine
·
2024
·
IF 3.8
Xue Wang,Chunyou Ning,Xingyi Cheng,Zhengzhong Wu,Dongbo Wu,Xuemei Ding,Cunxiang Ju,Zhihang Zhou,Lingfeng Wan,Wei Zhao,Peiliang Shi
Background The emerging incidence of pathogenic liver conditions is turning into a major concern for global health. Induction of pyroptosis in hepatocytes instigates cellular disintegration, which in turn liberates substantial quantities of pro-inflammatory intracellular substances, thereby accelerating the advancement of liver fibrosis. Consequently, directing therapeutic efforts towards inhibiting pyroptosis could potentially serve as an innovative approach in managing inflammation related chronic hepatic disorders. Methods GSDMD-NT ki/wt mice and Alb-cre ki/wt mice were generated using CRISPR/Cas9 technology. After crossing the two strains together, we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis. We analyzed differentially expressed genes by RNA sequencing and explored their biological functions. The efficacy of obeticholic acid (OCA) in the treatment of liver fibrosis was assessed. Results Doxycycline-treated GSDMD-NT ki/wt × Alb-cre ki/wt mice showed severe liver damage, vacuolation of hepatocytes, increased collagen fibers, and accumulation of lipid droplets. The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver. RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses, cell activation, and metabolic processes. Treatment with OCA alleviated the liver fibrosis, with reduced ALT and AST levels seen in the GSDMD-NT ki/wt × Alb-cre ki/wt mice. Conclusions We successfully constructed a novel mouse model for liver fibrosis. This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism. Our results demonstrated that we successfully constructed a mouse model of liver fibrosis, and GSDMD-NT induced fibrosis by mediating lipid metabolism.
研究领域:
肝病学
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分子生物学
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遗传学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Chuanqi Wan,Jiamin Lu,Lingyun Xu,Mei Jiang,Chen Zhu,Wen Zhang,Pingping Han,Jirong Zhang,Jing Wang,Weiwei Ren,Hui Chu,Bingzhi Zhou,Jiancheng Zhang,Guangjun Jin,Bangjiang Fang,Yuzhou He
Shenhuang Granules (SHG) attenuate sepsis-induced lung injury via the NLRP3/Caspase-1/GSDMD pathway. • (−)-Epicatechin gallate and gallic acid are the core bioactive monomers of SHG against PMVEC pyroptosis. • SHG inhibits pyroptosis by suppressing inflammasome assembly and pore formation. Ethnopharmacological relevance Shenhuang Granules (SHG) is a traditional Chinese medicine (TCM) formula composed of six medicinal materials: Panax ginseng C.A. Mey. (Ginseng Radix et Rhizoma), Rheum palmatum L. (Rhei Radix et Rhizoma), Sargentodoxa cuneata (Oliv.) Rehder & E.H. Wilson (Sargentodoxae Caulis), Taraxacum mongolicum Hand. -Mazz. (Taraxaci Herba), Aconitum carmichaelii Debeaux (Aconiti Lateralis Radix Praeparata), and Whitmania pigra Whitman (Hirudo). According to TCM theory, this formula is designed to replenish Qi and strengthen the body's resistance, clear heat and remove toxins, and promote blood circulation to eliminate blood stasis. In clinical practice, SHG has been used as an adjunctive therapy for sepsis, showing beneficial effects in ameliorating systemic inflammatory responses and microcirculatory disturbances. However, the underlying pharmacological mechanisms remain largely unclear. Aim of the study To validate that SHG and its active monomers alleviate sepsis-induced lung injury through targeted suppression of the NLRP3-driven PMVEC pyroptosis pathway. Materials and methods The chemical composition of SHG was analyzed by UHPLC-MS/MS. In vivo, SA-ARDS was induced in C57BL/6J mice by cecal ligation and puncture (CLP), with SHG (61.85 mg/mouse/d), its monomers, (−)-epicatechin gallate (ECG) and gallic acid (GA) (20 mg/kg/d), or the NLRP3 inhibitor MCC950 (10 mg/kg/d), were administered via intraperitoneal injection for 3 days prior to modeling. Lung injury severity and activation of the pyroptosis pathway were evaluated using histopathology, transmission electron microscopy, RT-qPCR, Western blotting, immunohistochemistry, immunofluorescence, and ELISA. In vitro, LPS-stimulated (1 μg/mL) PMVECs were used to screen 43 monomers, and the underlying mechanisms were subsequently verified. Results Compared with the Model group, SHG treatment significantly attenuated body weight loss in mice ( P < 0.001), reduced the lung wet-to-dry (W/D) weight ratio ( P < 0.05), and decreased Evans blue extravasation in lung tissues ( P < 0.01). SHG also significantly downregulated the mRNA expression levels of pyroptosis-related genes, including Twik2 , Nlrp3 , Asc , Caspase-1 , and Gsdmd , in lung tissues (all P < 0.01), and markedly reduced the protein expression of NLRP3, ASC, pro-Caspase-1, and Caspase-1 (all P < 0.05). ELISA results further demonstrated that SHG significantly decreased serum levels of the inflammatory cytokines TNF-α, IL-1β, IFN-γ, IL-18, pro-IL-1β, and pro-IL-18 in mice (all P < 0.05). In vitro, compared with the Model group, SHG significantly suppressed the transcriptional levels of Twik2 , Nlrp3 , Asc , Caspase-1 , and Gsdmd in PMVECs (all P < 0.05), and reduced the protein expression of NLRP3, ASC, GSDMD, GSDMD-NT, and IL-1β (all P < 0.05). Additionally, SHG markedly decreased lactate dehydrogenase (LDH) release ( P < 0.0001) and attenuated extracellular potassium ion (K + ) efflux ( P < 0.0001). Notably, ECG and GA individually exhibited potent inhibitory effects on PMVEC pyroptosis. Compared with the Model group, both ECG and GA significantly suppressed mRNA expression of Twik2, Nlrp3, Asc, Caspase-1, and Gsdmd (all P < 0.05) and reduced protein levels of NLRP3 , ASC , Caspase-1 , and GSDMD (all P < 0.05). Moreover, ECG significantly inhibited GSDMD-NT and IL-1β protein expression (all P < 0.05). Both ECG and GA markedly reduced TNF-α, IL-1β, and pro-IL-18 levels (all P < 0.05), and GA additionally suppressed IL-18 and pro-IL-1β expression (all P < 0.01). Furthermore, both ECG and GA significantly decreased LDH release ( P < 0.0001) and inhibited extracellular K + efflux ( P < 0.0001). However, this study has several limitations, including a small sample size, the absence of dose-gradient and time-course analyses, insufficient functional validation of the TWIK2 channel, and the lack of quantitative pharmacokinetic and synergy analyses, which should be addressed in future studies. Conclusion Shenhuang Granules attenuated PMVEC pyroptosis and ameliorated sepsis-induced lung injury by suppressing TWIK2 and the downstream NLRP3/Caspase-1/GSDMD pathway, with GA and ECG as the key active components. Download: Download high-res image (484KB) Download: Download full-size image
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PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2026
·
IF 11.2
Yuejia Lan,Qingrui Zhong,Hongkai Huang,Xiao Deng,Lu Yang,Jiayi Sun,Mingyang Liu,Xianli Meng,Jiasi Wu
Evidence indicates that nuclear receptor subfamily 1 group H member 3 (NR1H3) activation mitigates sepsis-induced acute lung injury (SALI) by reducing inflammatory response. Nevertheless, the mechanisms underlying NR1H3-inflammation interactions in addressing SALI remain unclear. Moreover, limited phytochemicals have been documented to ameliorate SALI via this pathway. Here, we discovered that NR1H3 activation directly suppresses the clustering of toll-like receptor 4 (TLR4) to lipid rafts, which acts as a part of the priming of NLR family pyrin domain containing 3 (NLRP3) inflammasome. This process results in the suppression of NLRP3 inflammasome assembly and activation, consequently alleviating gasdermin-D (GSDMD)-mediated pyroptosis. Furthermore, through dual-luciferase reporter gene testing, drug binding assays, gene expression analysis, and biochemical evaluation, we determined lappaconitine hydrobromide (LAH) as a novel NR1H3 agonist that effectively suppresses TLR4-NLRP3 signaling pathway. Our results showed LAH attenuates inflammatory lung injury in both lipopolysaccharide and cecal slurry-induced SALI mouse models. In vivo and in vitro experiments revealed that LAH suppresses NLRP3 signaling activation and pyroptosis. Additionally, RNA-seq and bioinformatics analysis demonstrated that the differentially expressed genes (DEGs) linked to interleukin-1 beta (IL-1β) production, modulation of inflammatory response, and control of innate immune response were markedly enriched in LAH, and core genes amongst the DEGs included NR1H3. Mechanistically, LAH reduces inflammation and pyroptosis through modulation of NR1H3-NLRP3-GSDMD axis in mice. This finding was further substantiated by the suppression of NR1H3 in vitro . Our findings offer novel perspectives on the NR1H3-inflammation interaction in SALI regulation and indicate the therapeutic promise of LAH as an NR1H3 agonist for SALI management via NLRP3 suppression.
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Jiajia Mu,Qiannan Sun,Nanyan Lin,Chenguang Yue,Jiaqiao Zhu,Hui Zou,Hongyan Zhao,Ruilong Song,Zongping Liu,Yonggang Ma
Ketosis in dairy cows is linked to endometritis, but the molecular mechanisms are unclear. We investigated whether P2X7R is crucial in ketosis-induced endometritis. Ketotic cows had higher levels of NLRP3, caspase-1, GSDMD, GSDME, and P2X7R in the uterine tissue. β-Hydroxybutyric acid (BHBA) exposure in bovine endometrial epithelial cells induced pyroptosis, increased pyroptosis protein and gene expression, and raised pyroptosis rates. P2X7R levels rose with BHBA, and BHBA also increased the level of extracellular ATP. Inhibitors of NLRP3, caspase-1, caspase-3, and P2X7R reduced BHBA-induced pyroptosis. P2X7R inhibition suppressed NLRP3, caspase-1, and caspase-3 activation, preventing pyroptosis. In P2rx7–/– mice with a ketosis model, blood BHBA was lower, and uterine tissue showed less pyroptosis-related protein expression compared to ketotic mice. P2X7R appears to regulate BHBA-induced pyroptosis through NLRP3 and caspase-3 signaling, suggesting it is a potential therapeutic target.
研究领域:
兽医学
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生殖生物学
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细胞生物学
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分子生物学
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免疫学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-24
·
IF 12.6
Tong Xin-Yi,Nong Wei-Jian,Tan Run-Min,Ouyang Jian-Ming
Objective This study aimed to compare the differences in pyroptosis and polarization of macrophages induced by different sizes of calcium oxalate monohydrate (COM) crystals and discuss the mechanism of kidney stone formation. Methods COM crystals with sizes of about 100 nm, 500 nm, 2.5 μm, and 10 μm were synthesized and characterized. THP-1 cells were induced to differentiate into macrophage-like cells. The damage of COM crystals to Mφs was evaluated by CCK-8 assay. The activation of the pyroptosis signaling pathway, cell morphology, and proportion of pyroptosis cells in Mφs induced by COM crystals were detected. Finally, the proportion of M1/M2 polarization was qualitatively and quantitatively assessed. Results COM-100 nm, COM-500 nm, COM-2.5 μm, and COM-10 μm all significantly induced the pyroptosis and polarization of Mφs. Among them, at the same cell viability, COM-10 μm induced the highest pyroptosis rate. The expression of NLRP3 and GSDMD-N induced by COM-10 μm increased by 81.43 ± 11.45% and 112.00 ± 9.87%, respectively, and the rate of caspase-1/PI double-positive pyroptosis cells was 22.2%. Meanwhile, COM-10 μm induced the highest proportion of M1 polarization (M1/M2 ratio was 209.90% ± 2.54%). Conclusion COM-10 μm significantly activates the classical caspase-1-mediated pyroptosis pathway and promotes M1 polarization in Mφs. Therefore, at the same cell viability, large-sized micro-COM is more capable of inducing inflammation than nano-COM. Graphical
研究领域:
纳米技术
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泌尿科学
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免疫学
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细胞生物学
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材料科学
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PubMed
高影响因子
FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
·
2023
·Vol. 61
·期 1
·47-55
·
IF 1.5
Weixing Mo Qingqing Yu Xiufeng Kuang Ting He Jun Lou Rongjun Tang Ke Zhang Lingdi Li Linfang Zhao
Introduction. Focused ultrasound (FUS) is a non-invasive tumor therapy technology emerging in recent years, which can treat various solid tumors. However, it is unclear whether FUS can affect the pyroptosis of colon cancer (CC) cells. Here, we analyzed the effect of FUS on pyroptosis in the orthotopic CC model. Material and methods. After an orthotopic CC mouse model was constructed by injecting CT26-Luc cells, BABL/C mice were allocated to the normal, tumor, FUS, and FUS + BAY11-7082 (pyroptosis inhibitor) groups. We monitored the tumor status of the mice through in vivo fluorescence image analysis. The histopathological injury of the intestinal tissue and the expression of IL-1β, IL-18, caspase-recruitment domain (ASC), cleaved caspase-1, gasdermin D (GSDMD), and NLRP3 of the CC tumors were examined utilizing hematoxylin and eosin staining, immunohistochemical assay, and Western blot. Results. FUS restrained the fluorescence intensity of the tumors in orthotopic CC mice, while FUS-mediated suppression of the bioluminescent signal of the tumors was alleviated by BAY11-7082. FUS was found to relieve the injury of the intestinal tissues in CC mice as revealed by morphology. Furthermore, the expressions of IL-1β, IL-18, GSDMD, ASC, cleaved caspase-1, and NLRP3 of the CC tumors in the FUS group were higher than those in the tumor group, while BAY11-7082 addition partly reversed the FUS’s effects on orthotopic CC model mice. Conclusions. Our results pointed out that FUS presented anti-tumor activity in experimental CC, and its mechanism was correlated with the promotion of pyroptosis.
研究领域:
肿瘤学
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生物医学工程
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分子生物学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
·
IF 3.8
Jiaxi Chen,Mengyue Pan,Jingjie Wang,Mengling Zhang,Mingmei Feng,Xiaoming Chai,Qi Zhang,Yang Sun
Hydroxysafflor yellow A (HSYA), a chalcone glycoside, is a component of Carthamus tinctorius L. and exerts anti-inflammatory and antioxidative effects. However, the therapeutic effect and the underlying mechanism of HSYA on ulcerative colitis is unclear. This study aimed to investigate the unexplored protective effects and underlying mechanisms of HSYA on UC. In vitro analyses showed that HSYA reduced the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 and inhibited nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD)-mediated pyroptosis in lipopolysaccharide/ adenosine-5′-triphosphate (LPS/ATP)-stimulated macrophages. Gas chromatography–mass spectrometry (GC–MS) profiling of intracellular metabolites showed that HSYA reduced the increased levels of glucose, glucose 6-phosphate, and lactic acid, and inhibited the increased hexokinase 1 (HK1) expression caused by LPS/ATP stimulation. HK1 shRNA transfection further confirmed that HSYA inhibited the NLRP3/GSDMD-mediated pyroptosis via HK1 downregulation. In vivo analyses showed that HSYA drastically attenuated UC symptoms by relieving body weight loss, a decline in colon length, and inflammatory infiltration in colonic tissues induced by dextran sulfate sodium (DSS). HSYA also reduced the secretion of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IL-18. Moreover, HSYA inhibited HK1/NLRP3/GSDMD-mediated pyroptosis in DSS-induced colitis mice. Finally, 16S rRNA sequencing analyses of gut microbiota revealed that HSYA reversed gut microbiota dysbiosis by reducing the abundance of Proteobacteria and increasing that of Bacteroidetes. This study demonstrated that HSYA not only exerted anti-inflammatory effects by inhibiting HK1/NLRP3/GSDMD and suppressing pyroptosis but also regulated gut microbiota in mice with DSS-induced colitis. Our findings provide new experimental evidence that HSYA might be a potential candidate for treating inflammatory bowel diseases.
研究领域:
药理学
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免疫学
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微生物学
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胃肠病学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 10
·1-10
·
IF 8.1
Li Ming-Qiao,He Yu-Qi,Zhang Meng-Ni,Tang Wan,Tan Ya,Cheng Yue,Yang Mei,Zhao Nan,Li Ling,Yu Si-Rui,Li Ruo-Lan,Pan Qiong,Wu Ming-Yue,Chai Jin
Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Bozhi Ye,Xudong Chen,Shanshan Dai,Jibo Han,Xiaohe Liang,Shuang Lin,Xueli Cai,Zhouqing Huang,Weijian Huang
Background Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes.Materials and methods Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes’ ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA.Results The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins.Conclusion This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Yiling Mei,Xudong Chen,Si Shi,Wante Lin,Zhenfeng Cheng,Xiaoxi Fan,Wenqi Wu,Jibo Han,Weijian Huang,Bozhi Ye,Shanshan Dai
Background and Purpose Myocardial dysfunction is a significant complication associated with sepsis. However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)-mediated pyroptosis has shown promise in mitigating sepsis-induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI-Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI-Y2 offers a cardioprotective effect in the context of sepsis-induced myocardial dysfunction. Experimental Approach A mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI-Y2 or macrophage membrane-encapsulated GI-Y2 nanoparticles (GI-Y2@MM-NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI-Y2 in treating septic cardiomyopathy. Key Results We observed that GI-Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI-Y2 reduced macrophage pyroptosis and attenuated macrophage-mediated cardiomyocyte injury induced by LPS/nigericin. Concurrently, we confirmed the protective effect of GI-Y2 against LPS-induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI-Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI-Y2@MM-NPs to enhance the targeting capability of GI-Y2 towards macrophages in heart tissues and demonstrated its protective effect in vivo . Conclusion and Implications These findings indicate that GI-Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD-mediated pyroptosis and mitochondrial damage. Both GI-Y2 and GI-Y2@MM-NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction. Graphical
研究领域:
免疫学
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心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Diabetology & Metabolic Syndrome
·
2023
·Vol. 15
·期 1
·1-13
·
IF 4.8
Li Tianrong,Yang Jingjing,Tan Anjun,Chen Hewen
Background Irisin plays a key role in metabolic diseases, including type 2 diabetes mellitus (T2DM). However, the mechanism underlying the link between irisin and the development of T2DM, particularly in pancreatic islet β-cells, remains unknown.Methods In vitro, Min6 cells were treated with high glucose (HG) to generate T2DM cell models. GSDMD-N staining, Western blotting assays, and ELISA were performed to measure the expression levels of GSDMD, caspase 1, IL-1β, and IL-18. Next, the NLRP3 stimulator, ATP, was used to assess the effect of irisin on NLRP3 inflammasome. To evaluate the function of the Nrf2-TrX/TXNIP signaling axis, the Nrf2 inhibitor ML385 was used. For in vivo assessment, we first established T2DM model mice. Then, hematoxylin and eosin (H&E) staining was performed to observe the islet morphology, and the immunofluorescence technique was used to examine the mass of α and β cells. To confirm the role of the Nrf2-TrX/TXNIP signaling axis, ML385 was injected into the mice. Immunofluorescence of Nrf2, caspase 1, and GSDMD was detected in the islet cells of the model mice to verify the results.Results We found that irisin treatment significantly decreased the expression of GSDMD-N (P31) and cleaved caspase-1 (p20), decreased caspase1 activity, and inhibited the secretion of IL-1β and IL-18 in HG-treated Min6 cells. We also found that irisin inhibited oxidative stress and NLRP3 expression by activating the Nrf2-TrX/TXNIP signaling axis. Additionally, in the T2DM model mice, irisin enhanced the function of islet cells, decreased insulin resistance, and preserved the morphology of pancreatic islets.Conclusion We showed in this study that irisin can be used for treating pyroptosis in HG-induced islet β-cells and T2DM model mice. We also found that irisin inhibits pyroptosis and oxidative stress by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis.
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PubMed
高影响因子
AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
·
2024
·Vol. 92
·期 1
·e13893
·
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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DOI
PubMed
高影响因子
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