FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
·
2023
·Vol. 61
·期 1
·47-55
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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
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Meitong Liu,Jing Lu,Qingbin Liu,Yuelin Chen,Guang Wang,Qian Zhang,Shuang Guan
Sodium metabisulphite (SMB) is the most used foods and drugs antioxidant among sulfites . So far, there were few studies about its harm, especially in mast cells. Our study was to investigate the effects of SMB on mitophagy and pyroptosis in mast cells. The results revealed that SMB dose-dependently promoted the expressions of NLRP3, GSDMD-N and other marker proteins of pyroptosis. Knockdown of GSDMD, NLRP3 inhibitor, mitophagy activator and mtROS inhibitor all reversed the changes in pyroptosis indicators caused by SMB. Considering the degranulation characteristics of mast cells and the sensitization of sulfite, we examined the effects of the above inhibitors on the degranulation of mast cells caused by SMB. The results showed that SMB-mediated mast cell degranulation was significantly inhibited by the above inhibitors. Meanwhile, we used immunofluorescence co-localization experiments and found that GSDMD pore-forming protein and histamine co-localized near the cell membrane. Overall, evidence suggested that SMB caused pyroptosis by inhibiting mitophagy, leading to mast cell degranulation. These findings are of great significance to the sensitization mechanism of SMB and provide a new insight into SMB toxicology and mast cell degranulation.
研究领域:
毒理学
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免疫学
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细胞生物学
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PubMed
高影响因子
CELL RESEARCH
·
2023
·
IF 44.1
Ai Yuan-li,Wang Wei-jia,Liu Fan-jian,Fang Wei,Chen Hang-zi,Wu Liu-zheng,Hong Xuehui,Zhu Yuekun,Zhang Ci-xiong,Liu Long-yu,Hong Wen-bin,Zhou Bo,Chen Qi-tao,Wu Qiao
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N -acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME T6E or GSDME T6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.
研究领域:
癌症生物学
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细胞生物学
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药理学
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分子生物学
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PubMed
高影响因子
Frontiers in Veterinary Science
·
2023
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IF 3.2
Juyu Wang,Jieyan Yang,Kai Liu,Weijie Qu,Kuan Wang,Yu Zhao,Yaxiong Zhou,Xiang Liu,Limei Zhang,Xiaolong Gu
The toxic heavy metal cadmium (Cd) has a significant impact on kidney health. Documents manifested that non-toxic flavonoid quercetin can reduce Cd-induced kidney damage by reducing oxidative stress and inhibiting apoptosis, while the effect of quercetin on Cd-induced renal cell pyroptosis has not been elucidated. In this study, we established a model of Cd poisoning treated with quercetin both in vitro and in vivo . Results revealed that quercetin effectively reversed the decrease in Cd-induced cell viability. Furthermore, Cd increased blood urea nitrogen while reducing GPX and SOD levels, caused histopathological injuries in kidney with a significantly elevated cell pyroptosis characterized by enhanced levels of proteins representing assembly (NLRP3) and activation (pro IL-1β, cleaved IL-1β, and IL-18) of NLRP3 inflammasome as well as pyroptosis executor (pro caspase-1, cleaved caspase-1). However, quercetin administration alleviated kidney injuries above by decreasing cell pyroptosis. Overall, it suggests that kidney cells are susceptible to pyroptotic cell death due to Cd exposure; while quercetin exhibits protective effects through cell pyroptosis inhibition.
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Small
·
2023
·
IF 13.3
Jiahao Hu,Yuchan You,Luwen Zhu,Jucong Zhang,Yanling Song,Jingyi Lu,Xinyi Xu,Xiaochuan Wu,Xiajie Huang,Xiaoling Xu,Yongzhong Du
The efficacy of immune checkpoint blockade (ICB) in promoting an immune response against tumors still encounters challenges such as low response rates and off-target effects. Pyroptosis, an immunogenic cell death (ICD) mechanism, holds the potential to overcome the limitations of ICB by activating and recruiting immune cells. However, the expression of the pyroptosis-related protein Gasdermin-E(GSDME) in some tumors is limited due to mRNA methylation. To overcome this obstacle, sialic acid-functionalized liposomes coloaded with decitabine, a demethylation drug, and triclabendazole, a pyroptosis-inducing drug are developed. This nanosystem primarily accumulates at tumor sites via sialic acid and the Siglec receptor, elevating liposome accumulation in tumors up to 3.84-fold at 24 h and leading to the upregulation of pyroptosis-related proteins and caspase-3/GSDME-dependent pyroptosis. Consequently, it facilitates the infiltration of CD8 + T cells into the tumor microenvironment and enhances the efficacy of ICB therapy. The tumor inhibition rate of the treatment group is 89.1% at 21 days. This study highlights the potential of sialic acid-functionalized pyroptosis nanotuners as a promising approach for improving the efficacy of ICB therapy in tumors with low GSDME expression through epigenetic alteration and ICD.
研究领域:
肿瘤学
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免疫学
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药学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Bo Zhang,Mengru Shu,Chenwen Shao,Yingqi Deng,Haitang Chen,Zhihui Zhang,Xiubo Zhao
Pyroptosis immunotherapy has shown great potential in cancer treatment, but its clinical application is often hindered by insufficient immune activation and low bioavailability. Here, we report a bimetallic MOF-based nanoplatform (At10@CoZn-MOF) constructed via a microfluidic device to encapsulate the anticancer peptide (ACP) At10 within a Co/Zn-MOF framework. The nanosystem exhibits excellent physicochemical stability, pH-responsive drug release, and efficient cellular uptake. Notably, At10@CoZn-MOF possesses Fenton-like catalytic activity and, in combination with At10-induced mitochondrial damage, efficiently generates reactive oxygen species (ROS), which ultimately activates the caspase-1/GSDMD pathway, mediating pyroptosis and inducing immunogenic cell death. Importantly, At10@CoZn-MOF evokes robust pyroptotic responses in vivo, leading to tumor cell death and strong antitumor immunity. Taken together, the robust microfluidic synthesis of At10@CoZn-MOF provides an effective strategy for pyroptosis-mediated cancer therapy.
研究领域:
纳米医学
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癌症免疫治疗
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材料科学
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生物工程
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制药纳米技术
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高影响因子
Frontiers in Immunology
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2025
·
IF 5.9
Yang Yuexiang,Rong Zhiwei,Baitian Li,Wang Qing,Liu Chunzheng,Wang Zetian,Liao Lijun
Introduction Sepsis-related acute liver injury (SALI) is a severe and life-threatening complication in septic patients, for which current therapeutic options are limited. This study aimed to investigate the potential protective role of taurochenodeoxycholic acid (TCDCA) against SALI and to elucidate the underlying mechanisms. Methods A cecal ligation and puncture (CLP) mouse model was employed to induce SALI. The effects of TCDCA treatment were assessed by measuring serum liver injury markers (AST, ALT) and pro-inflammatory cytokines (IL-6, TNF-α, IL-1β). Liver histology, hepatocyte apoptosis, and the macrophage response were evaluated. Molecular docking was used to predict the interaction between TCDCA and the receptor TGR5, which was functionally validated using the TGR5 antagonist SBI-115. Transcriptomic analysis and Western blotting were performed to identify the key signaling pathways involved. Results TCDCA treatment significantly reduced serum levels of AST and ALT, suppressed the production of IL-6, TNF-α, and IL-1β, and alleviated histological liver damage, including lobular disruption, inflammation, and hemorrhage. TCDCA also decreased hepatocyte apoptosis and modulated the liver macrophage response. Molecular docking confirmed a strong interaction between TCDCA and TGR5, and the protective effects of TCDCA were abolished by the TGR5 antagonist SBI-115. Transcriptomic analysis identified 430 differentially expressed genes after TCDCA treatment, with significant enrichment in pyroptosis-related pathways. Accordingly, Western blot analysis demonstrated that TCDCA inhibited the activation of the NLRP3 inflammasome and its downstream pyroptotic proteins, an effect that was also reversed by SBI-115. Discussion Our findings demonstrate that TCDCA confers a protective effect against SALI by suppressing hepatocyte pyroptosis, and this action is mediated through the TGR5 receptor. These results highlight TCDCA as a promising therapeutic candidate for SALI. However, further research, including clinical trials, is necessary to address potential species-specific differences and to fully elucidate its comprehensive mechanisms of action.
研究领域:
肝病学
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免疫学
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分子医学
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炎症研究
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重症医学
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PubMed
高影响因子
Frontiers in Immunology
·
2021
·
IF 7.561
Wang Yue,Zhao Yan,Wang Zhecheng,Sun Ruimin,Zou Boyang,Li Ruixi,Liu Deshun,Lin Musen,Zhou Junjun,Ning Shili,Tian Xiaofeng,Yao Jihong
Pyroptosis is a newly discovered form of cell death. Peroxiredoxin 3 (PRX3) plays a crucial role in scavenging reactive oxygen species (ROS), but its hepatoprotective capacity in acetaminophen (APAP)-induced liver disease remains unclear. The aim of this study was to assess the role of PRX3 in the regulation of pyroptosis during APAP-mediated hepatotoxicity. We demonstrated that pyroptosis occurs in APAP-induced liver injury accompanied by intense oxidative stress and inflammation, and liver specific PRX3 silencing aggravated the initiation of pyroptosis and liver injury after APAP intervention. Notably, excessive mitochondrial ROS (mtROS) was observed to trigger pyroptosis by activating the NLRP3 inflammasome, which was ameliorated by Mito-TEMPO treatment, indicating that the anti-pyroptotic role of PRX3 relies on its powerful ability to regulate mtROS. Overall, PRX3 regulates NLRP3-dependent pyroptosis in APAP-induced liver injury by targeting mitochondrial oxidative stress.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
iScience
·
2025
·Vol. 29
·期 1
·
IF 4.1
Xue-Wu Chen,Xin-Yi Tong,Run-Min Tan,Jian-Ming Ouyang
This article explored the differences in pyroptosis mediated by calcium oxalate monohydrate (COM) crystals with sizes of 100 nm, 1 μm, 3 μm, 5 μm, and 10 μm and were used to induce pyroptosis of HK-2 cells. The proportion of pyroptosis cells was detected by caspase-1/PI double staining. Three small-sized COM crystals (0.1–3 μm) could be endocytosis by HK-2 cells and increased intracellular oxidative stress, which further promoted the activation of NLRP3 inflammasome and pyroptosis. The two COM crystals with large sizes (3–10 μm) were difficult to endocytose, and the main mechanism was the crystal adhesion, leading to pyroptosis. Crystal endocytosis leads to higher pyroptosis. The pyroptosis rates mediated by COM with different sizes were as follows: COM-100nm (17.81%) > COM-1μm (17.28%) > COM-3μm (17.25%) > COM-5μm (12.44%) > COM-10μm (9.05%). The smaller the COM crystal size, the higher the pyroptosis rate, which is related to the stronger oxidative stress.
研究领域:
肾脏病学
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细胞生物学
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泌尿系结石研究
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炎症与免疫
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PubMed
高影响因子
EUROPEAN JOURNAL OF CELL BIOLOGY
·
2021
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IF 4.492
Jian Zhao,Zhaoyu Liu,Zhihui Chang
Endothelial cell pyroptosis is a novel cause of endothelial dysfunction in sepsis. Reticulocalbin-2 (RCN2) is involved in regulating vascular inflammation and plays an important role in the cardiovascular system. However, the role of RCN2 in inflammation-induced endothelial cell pyroptosis remains to be explored. Here, we found that RCN2 was upregulated after lipopolysaccharide (LPS) treatment in a concentration‐ and time-dependent manner. RCN2 knockdown resulted in a significant decrease in pyroptosis, reduced LDH and IL-1β release and ROS production and inhibited the expression of pyroptosis‐related proteins (NLRP3, cleaved caspase-1, and cleaved GSDMD) (all p < 0.05). N‐acetyl‐L‐cysteine (NAC) counteracted the effects of RCN2 on pyroptosis (all p < 0.01). The silencing of RCN2 antagonized the inhibitory effect of LPS on the phosphorylation of eNOS (p < 0.05). We predicted and confirmed that specificity protein-1(SP1) could directly bind to the RCN2 promoter and regulate RCN2. RCN2 overexpression rescued the inhibitory effect of SP1 inhibitor on HUVEC pyroptosis induced by LPS (all p < 0.05). These findings suggested that the activation of the SP1/RCN2/ROS signaling pathway could promote LPS-induced endothelial cell pyroptosis.
研究领域:
免疫学
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心血管生物学
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细胞信号传导
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炎症
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DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2022
·Vol. 41
·期 12
·1038-1052
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IF 3.55
Qianyu Tang,Wenhui Liu,Xuefeng Yang,Yaying Tian,Jiacheng Chen,Yang Hu,Nian Fu
Despite activated autophagy ameliorating hepatocyte steatosis and metabolic associated fatty liver disease (MAFLD), mechanisms underlying the beneficial roles of autophagy in hepatic deregulation of lipid metabolism remain undefined. We explored whether autophagy can ameliorate oleic acid (OA)-induced hepatic steatosis by suppressing pyroptosis. Pyroptosis is involved in hepatocyte steatosis induced by OA. In addition, autophagy flux was blocked in OA-treated hepatocytes. Treatment with OA induced lipid accumulation in liver cell line L-02, which was attenuated by rapamycin (Rap), an autophagy agonist, while aggravated by autophagy inhibitor bafilomycin A1 (Baf A1). Inversely, treatment with pyroptotic agonist Nigericin aggravated OA-induced hepatic steatosis, while pyroptosis antagonist disulfiram ameliorated this effect. Mechanistically, treatment with Rap downregulated the expression of pyroptosis-related proteins, including NLRP3, Caspase-1, IL-18, GSDMD expression evoked by OA, thus improving pyroptosis in hepatic steatosis. Significantly, overexpression of ATG5 obviously downregulated cleaved caspase-1 expressions without altering the total caspase1 expressions in hepatic cell steatosis. Taken together, our studies strongly demonstrated that the activation of ATG5 inhibits pyroptosis to improve hepatic steatosis and suggest autophagy activation as a potential therapeutic strategy for pyroptosis-mediated MAFLD.
研究领域:
肝脏病学
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细胞生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
PLoS One
·
2026
·Vol. 21
·期 1
·e0339020
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IF 2.6
Weihua Nong,Qiumei Huang,Sheng Dou,Yanhong Wei,Yanlun Song,Junli Wang,Xiaocan Lei,Fenglian Yang,Liqiao He
This study investigates the protective effects of nicotinamide mononucleotide (NMN) against aluminum-induced testicular dysfunction in mice. While previous research has demonstrated the general protective role of NMN in testicular function and highlighted the interaction between aluminum and the NLRP3 inflammasome, the precise mechanisms through which NMN mitigates aluminum-induced reproductive toxicity remain unclear. Our findings show that NMN protects Sertoli cells by inhibiting NLRP3-mediated pyroptosis, which subsequently improves spermatogenesis and testosterone synthesis. We also identify WT1 and GATA4 as key regulators involved in maintaining Sertoli cell integrity and function under aluminum-induced stress. This work provides new insights into the molecular mechanisms of aluminum-induced male infertility and underscores NMN’s potential as a therapeutic strategy for preventing reproductive dysfunction caused by environmental toxicants, such as aluminum. Aluminum exposure disrupts spermatogenesis, yet no effective pharmacological interventions exist to treat aluminum-induced male infertility. In this study, we established an aluminum toxicity model in C57BL/6J mice through intragastric administration of AlCl 3 . We assessed the therapeutic effects of NMN by evaluating testicular histopathology, sperm quality, and serum reproductive hormone levels. Hematoxylin and eosin (H&E) staining revealed significant damage, including reduced seminiferous tubule diameter, disorganized germ cell layers, and a decreased number of germ cells and sperm. Sperm motility was significantly reduced, while the proportion of abnormal sperm increased. However, NMN treatment partially reversed these impairments. Transcriptomic analysis revealed significant upregulation of genes involved in the NLRP3 inflammasome and apoptosis pathways (e.g., NLRP3, GSDMD, caspase-1, and IL-1β) in the AlCl 3 -exposed group. NMN treatment mitigated testicular damage, suppressed NLRP3-mediated pyroptosis in Sertoli cells, and restored serum testosterone levels. Additionally, NMN treatment preserved the expression of key testicular proteins, including WT-1 GATA4, and vimentin. In summary, our study uncovers a novel mechanism by which aluminum exposure impairs spermatogenesis via NLRP3-mediated pyroptosis in testicular cells. We also demonstrate for the first time that NMN can ameliorate aluminum-induced reproductive dysfunction by inhibiting this pathway, offering a potential therapeutic strategy for aluminum-associated male infertility.
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高影响因子
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