Genes
·
2022
·Vol. 13
·期 11
·2133
·
IF 4.141
Jiahui Lin,Xianhui Lai,Xiaoxi Fan,Bozhi Ye,Lingfeng Zhong,Yucong Zhang,Ruiyin Shao,Si Shi,Weijian Huang,Lan Su,Miaomiao Ying
Pyroptosis serves a crucial function in various types of ischemia and reperfusion injuries. Oridonin, a tetracycline diterpene derived fromRabdosia rubescens, can significantly inhibit the aggregation of NLRP3-mediated inflammasome. This experiment is aimed at investigating the effect of oridonin on pyroptosis in mice cardiomyocytes. Based on the models of myocardial ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R), Evans Blue/TTC double staining, TUNEL staining, and Western blotting were applied to determine the effects of oridonin on myocardial damage, cellular activity and signaling pathways involved in pyroptosis. During I/R and H/R treatments, the extent of gasdermin D-N domains was upregulated in cardiomyocytes. Apart from that, oridonin improved cell survival in vitro and decreased the myocardial infarct size in vivo by also downregulating the activation of pyroptosis. Finally, the expression levels of ASC, NLRP3 and p-p65 were markedly upregulated in cardiomyocytes after H/R treatment, whereas oridonin suppressed the expression of these proteins. The present experiment revealed that myocardial I/R injury and pyroptosis can be alleviated and inhibited by oridonin pretreatment via NF-κB/NLRP3 signaling pathway, both in vivo and in vitro. Therefore, oridonin may serve as a potentially novel agent for the clinical treatment of myocardial ischemia-reperfusion injuries.Keywords:oridonin;cardiac ischemia/reperfusion injury;pyroptosis;GSDMD
研究领域:
心脏病学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2025
·
IF 3.1
You Xujun,Li Honghan,Li Qixin,Zhang Qing,Cao Yiguo,Fu Wei,Wang Bin
Prostate cancer (PCa) is an epithelial malignancy affecting the prostate gland. Astragaloside IV combined with polypeptide extract from scorpion venom (PESV) has been reported to inhibit the growth of PCa. This study aimed to investigate the mechanisms by which this combination mitigates the progression of PCa. Bioinformatic analysis was utilized to investigate the correlation between zinc finger DHHC-type containing 1 (ZDHHC1) expression and PCa progression. The extent of pyroptosis in PCa cells was assessed by measuring cell viability, IL-1β and IL-18 secretion, LDH release, and HMGB1 content. PCa mouse models were constructed by subcutaneous injection of DU145 or PC-3 cells into nude mice, with subsequent monitoring of tumor weight and volume. ZDHHC1 expression was significantly lower in PCa patient tissues, which correlated with a poor prognosis. ZDHHC1 overexpression inhibited PC-3 and DU145 cell viability and increased IL-1β, IL-18, LDH, and HMGB1 levels in cell supernatants. Notably, the pyroptosis inhibitor LDC7559 partially reversed these effects. Co-IP assay demonstrated an interaction between ZDHHC1 and GSDMD. ZDHHC1 overexpression significantly enhanced GSDMD palmitoylation-mediated membrane translocation and pyroptosis; however, this effect was partially reversed by the palmitoylation inhibitor 2-BP. The combination of Astragaloside IV and PESV promoted GSDMD membrane translocation and pyroptosis in PCa cells, with ZDHHC1 knockdown partially reversing the effects of Astragaloside IV-PESV. Furthermore, treatment with Astragaloside IV-PESV significantly inhibited tumor tissue growth in tumor-bearing nude mouse models. Astragaloside IV-PESV enhances palmitoylation-mediated membrane translocation of GSDMD-N by upregulating ZDHHC1 expression, thereby facilitating pyroptosis in PCa cells and attenuating PCa progression.
研究领域:
肿瘤学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Shanshan Dai,Yunxuan Chen,Xiaoxi Fan,Jibo Han,Lingfeng Zhong,Yucong Zhang,Qingran Liu,Jiahui Lin,Weijian Huang,Lan Su,Zhouqing Huang,Bozhi Ye
Background Doxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown. Hypothesis/Purpose We aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect. Methods The model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD −/− mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation. Results Emodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD −/− mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1β and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane. Conclusion Emodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Hao Zhang,Jia-Gen Cui,Ming-Shan Chen,Jia-Xin Wang,Xiao-Han Sun,Yi Zhao,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.
研究领域:
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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产品关联
DOI
PubMed
高影响因子
CARDIOVASCULAR DRUGS AND THERAPY
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2024
·
IF 3.1
Ye Bozhi,Cai Xueli,Liang Xiaohe,Chen Yunxuan,Dai Shanshan,Huang Zhuqi,Huang Weijian,Zhang Lei,Wang Zixuan,Xing Jincheng,Lai Xianhui,Huang Zhouqing,Jia Zhuyin
Purpose Inflammatory responses induced by NLRP3 inflammasome contribute to the progression of atherosclerosis. This study seeks to investigate the effect of emodin on the NLRP3 inflammasome in atherogenesis and to probe the underlying mechanism. Methods ApoE-knockout (ApoE −/− ) mice were treated with a high-fat diet (HFD) for 12 weeks and intragastrically with emodin for 6 weeks. Human mononuclear cell line THP-1 was pretreated with emodin or signaling pathway inhibitors and induced into macrophages using phorbol 12-myristate 13-acetate (PMA) for 48 h. The NLRP3-mediated inflammatory response was studied both in vivo and in vitro. The level of the inflammation was detected by western blot, real-time PCR analysis, and ELISA. Results Emodin attenuated atherosclerotic lesions in HFD-treated ApoE −/− mice. Emodin dramatically decreased the expression of NLRP3, GSDMD, IL-1β, and IL-18 in HFD-treated ApoE −/− mice and PMA-induced macrophages. Moreover, emodin significantly hindered the activation of nuclear factor kappa-B (NF-κB) by inhibiting the formation of the TLR4/MyD88 complex in PMA-induced macrophages. Conclusion Our data demonstrate that emodin can inhibit the development of atherosclerotic plaques by alleviating NLRP3/GSDMD-induced inflammation through repressing the TLR4/MyD88/NF-κB signaling pathway in macrophages. This finding suggests that emodin can be a potential candidate for the treatment of atherosclerosis.
研究领域:
免疫学
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心血管疾病
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药理学
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DOI
PubMed
高影响因子
Scientific Reports
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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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 19
·14771
·
IF 5.6
Pan Lei,Zhiyang Li,Qiuwei Hua,Ping Song,Lun Gao,Long Zhou,Qiang Cai
The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1β, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage.Keywords:ursolic acid;neuroinflammation;cerebral hemorrhage;microglial;pyroptosis
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
·
IF 4.7
Guosong Xin,Yanxiu Hou,Yuhan Liu,Hairu Li
Purpose This study examined the effects and underlying mechanisms of tetrandrine (TET) combined with adriamycin (ADR) in reversing multidrug resistance (MDR) in breast cancer cells. Methods Cell viability, proliferation, and drug resistance were assessed via the MTT assay. Small interfering RNA (siRNA) transfection was used to knock down GSDMD expression in MCF-7/ADR cells. Pyroptosis induction by the combined TET and ADR treatment was evaluated through morphological observations, cytotoxicity assays, and flow cytometry. The expression levels of mRNA and proteins were analyzed using qRT-PCR and western blotting, respectively. Results At non-cytotoxic concentrations, the combined treatment of TET and ADR significantly inhibited the growth of MCF-7/ADR cells, demonstrating a synergistic effect in reversing MDR. This combination effectively reduced MDR protein expression in MCF-7/ADR cells via GSDMD modulation, which diminished efflux activity and promoted ADR accumulation. The increased accumulation of ADR subsequently activated the NLRP3/Caspase-1/GSDMD signaling pathway, leading to elevated LDH release and enhanced pyroptosis rates. Conclusion The combined use of TET and ADR not only suppresses MCF-7/ADR cell growth but also reverses MDR by targeting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These findings propose a promising therapeutic strategy for combatting MDR in breast cancer and highlight the potential for further clinical application of this combination therapy.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Rongrong Huang,Ranran Chen,Lijuan Xing,Lianhao Wu,Wenwen Zhu,Junsong Jing,Ting Zhou,Yueguo Wu,Sheng Zhang,Zhenqiang You
Background Viral pneumonia is the most common and lethal pandemic disease, but there are no broad-spectrum antiviral drugs with high genetic barriers to resistance. To elucidate the mechanisms of viral pneumonia progression and potential targets for its treatment. Methods Viral pneumonia models were induced by the PR8 virus strain in wild-type (WT) and STING knockout (STING-KO) mice. Series of molecular biology techniques were used to evaluate the severity of pneumonia and cytokine levels. Results In this study, STING (stimulator of interferon genes) was activated in the lungs of virus-infected mice, leading to cytokine production and amplification of the immune response, thereby causing rapid deterioration of symptoms. Furthermore, excessive activation of innate immune response via STING was prevented by a STING inhibitor (C-176), which significantly reduced viral lung inflammation. The formation of neutrophil extracellular traps (NETs) was similarly suppressed during viral pneumonia treatment with STING inhibitors (C-176), and NETs formation and STING expression were positively correlated, indicating that STING plays an important role in NETs formation. Symptoms of pneumonia in STING-KO mice infected with PR8 were significantly milder than those in WT mice, and NETs were less likely to form in the lung tissue of STING-KO mice. Additionally, transcriptomic analysis revealed that STING-mediated regulation of NETs may be associated with gasdermin D (GSDMD), and immunoprecipitation experiments revealed that STING, GSDMD, and NETs-related proteins interact with each other. Immunofluorescence assays revealed that in neutrophils from WT mice, STING and GSDMD were colocalized on the membrane after viral infection, whereas in neutrophils from STING-KO mice, GSDMD expression was decreased after exposure to the virus. Conclusions Our study demonstrated that targeted intervention with STING alleviated pneumonia by inhibiting inflammation and NETs formation. The study also revealed that blocking STING could inhibit the activation of GSDMD to inhibit NETs formation, slowing the progression of viral pneumonia.
研究领域:
免疫学
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病毒学
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分子生物学
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呼吸病学
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2023
·Vol. 42
·期 9
·554-562
·
IF 3.1
Liangliang Yang,Yang Gao,Jinlong Huang,Hantao Yang,Puyuan Zhao,Chen Li,Zhigang Yang
Inhibition of the inflammatory response triggered by microglial pyroptosis inflammatory activation may be one of the effective ways to alleviate cerebral ischemia–reperfusion injury, the specific mechanism of which remains unclear. In this study, BV-2 microglia with or without oxygen–glucose deprivation/reoxygenation (OGD/R) or long noncoding RNA (lncRNA) Gm44206 knockdown were used as cell models to conduct an in vitro study. Detection of lactate dehydrogenase release and pyroptosis-related protein levels was performed using a corresponding kit and western blotting, respectively. Proliferation of microglia was evaluated by CCK8 assay. Enzyme-linked immunosorbent assay was applied for measuring levels of proinflammatory cytokines. This study verified the involvement of microglial pyroptosis as well as upregulation of NLRP3, Caspase-1, GSDMD, and Apoptosis-associated Speck-like protein containing a C-terminal caspase-recruitment domain (ASC) in cerebral ischemia–reperfusion injury. Moreover, knockdown of lncRNA Gm44206 could alleviate OGD/R-induced microglial pyroptosis and cell proliferation inhibition through the NLRP3/Caspase-1/GSDMD pathway, thus decreasing the release of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor-alpha. In conclusion, this study established a correlation between microglial pyroptosis and cerebral ischemia–reperfusion injury and identified lncRNA Gm44206 as a potential regulator of NLRP3/Caspase-1/GSDMD axis-mediated microglial pyroptosis, which could be considered a promising therapeutic target.
研究领域:
神经科学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
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2022
·
IF 8.786
Gu Lingui,Sun Mingjiang,Li Ruihao,Zhang Xingyu,Tao Yihao,Yuan Ye,Luo Xu,Xie Zongyi
Neuroinflammation has been proven to exert an important effect on brain injury after intracerebral hemorrhage (ICH). Previous studies reported that Didymin possessed anti-inflammatory properties after acute hepatic injury, hyperglycemia-induced endothelial dysfunction, and death. However, the role of Didymin in microglial pyroptosis and neuroinflammation after ICH is unclear. The current study aimed to investigate the effect of Didymin on neuroinflammation mediated by microglial pyroptosis in mouse models of ICH and shed some light on the underlying mechanisms. In this study, we observed that Didymin treatment remarkably improved neurobehavioral performance and decreased BBB disruption and brain water content. Microglial activation and neutrophil infiltration in the peri-hematoma tissue after ICH were strikingly mitigated by Didymin as well. At the molecular level, administration of Didymin significantly unregulated the expression of Rkip and downregulated the expression of pyroptotic molecules and inflammatory cytokines such as Nlrp3 inflammasome, GSDMD, caspase-1, and mature IL-1β, TNF-α, and MPO after ICH. Besides, Didymin treatment decreased the number of Caspase-1-positive microglia and GSDMD-positive microglia after ICH. Inversely, Locostatin, an Rkip-specific inhibitor, significantly abolished the anti-pyroptosis and anti-neuroinflammation effects of Didymin. Moreover, Rkip binding with Asc could interrupt the activation and assembly of the inflammasome. Mechanistically, inhibition of Caspase-1 by VX-765 attenuated brain injury and suppressed microglial pyroptosis and neuroinflammation by downregulation of GSDMD, mature IL-1β, TNF-α, and MPO based on Locostatin-treated ICH. Taken together, Didymin alleviated microglial pyroptosis and neuroinflammation, at least in part through the Asc/Caspase-1/GSDMD pathway via upregulating Rkip expression after ICH. Therefore, Didymin may be a potential agent to attenuate neuroinflammation via its anti-pyroptosis effect after ICH.
研究领域:
神经科学
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药理学
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炎症
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神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Xi Ma,YuZheng Yang,Hao Li,ZeHong Luo,QiuYi Wang,XueMing Yao,Fang Tang,Ying Huang,Yi Ling,WuKai Ma
Although the pathogenesis of rheumatoid arthritis (RA) remains unclear, an increasing number of studies have confirmed that pyroptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) is an important factor affecting the progression of RA. Periplogenin (PPN) is a natural cardiac glycoside; reportedly, it exerts anti-inflammatory and analgesic effects in diseases by inhibiting cell growth and migration. This study aimed to determine the effect of PPN on the growth, migration, and invasion of RA-FLS and the potential mechanism of pyroptosis regulation. We discovered that PPN could inhibit the migration and invasion abilities of RA-FLS and block their growth cycle, down-regulate the secretion and activation of NLRP3, Caspase-1, GSDMD, IL-1β, and IL-18, and reduce the number of pyroptosis. In summary, PPN inhibited pyroptosis, reduced the release of inflammatory factors, and improved RA-FLS inflammation by regulating the NLRP3/Caspase-1/GSDMD signaling pathway.
研究领域:
药理学
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免疫学
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风湿病学
✓ 已验证
DOI
PubMed
高影响因子
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