Journal of Hepatocellular Carcinoma
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2025
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IF 3.4
Jiayuan Zhang,Tian Tian,Shanshan Tian,Jinhai Yao,Yingwan Zhang,Rujia Xie,Ting Yang,Bing Han
Purpose This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment.Methods Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region.Results NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects.Conclusion NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.
研究领域:
分子生物学
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肿瘤学
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药理学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2024
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IF 8.3
Xiujie Zhao,Yan Ma,Jianhao Di,Yanqi Qiao,Jie Yu,Yongmei Yin,Rimo Xi,Meng Meng
Pyroptosis has been reported to improve the antitumor effect by evoking a more intense immune response and a therapeutic effect. For phototherapy, several photosensitizers have been found to initiate pyroptosis. However, the effect of pyroptosis associated with apoptosis in enhancing the antitumor therapy needs sufficient characterization, especially under long-term treatment. As a NIR photosensitizer, heptamethine cyanines have been discovered for anticancer phototherapy for deep tissue penetration and inherent tumor-targeted capability. However, they are not quite stable for long-term performance. To investigate the effect of pyroptosis along with apoptosis on the anticancer immune responses and phototherapy, here, we chemically modulate the cyanine IR780 to regulate hydrophobicity, stability, and intracellular targeting. Two photosensitizers, T780T-TPP and T780T-TPP-C12, were finally optimized and showed excellent photostability with high photothermal conversion efficiency. Although the cellular uptake of the two molecules was both mediated by OATP transporters, T780T-TPP induced tumor cell death via pyroptosis and apoptosis and accumulated in tumor accumulation, while T780T-TPP-C12 was prone to accumulate in the liver. Ultimately, via one injection-multiple irradiation treatment protocol, T780T-TPP displayed a significant antitumor effect, even against the growth of large tumors (200 mm3).
研究领域:
肿瘤学
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免疫学
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药理学
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PubMed
高影响因子
Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-11
·
IF 9.6
Chu Xiufeng,Zhang Ting,Bukhari Ihtisham,Hu Mei,Xu Jixuan,Xing Yamin,Liang Xinfeng,Zhang Zisen,Zheng Pengyuan
Gasdermin D (GSDMD) is a critical pyroptosis mediator, consisting of one N-terminal pore-forming domain and one C-terminal auto-inhibitory domain. The free N-terminal domain (GD-NT), which is released through caspase-1/11 cleavage, exhibits distinct features from the full-length GSDMD (GD-FL), including oligomerization, membrane translocation, and pore-formation. However, the underlying mechanisms are not well elucidated. Here, we found that GD-NT, but not GD-FL, was massively ubiquitinated in cells. The K63-linked polyubiquitination of GD-NT at Lys236/237 (human/mouse), catalyzed by TRAF1, directly prompted its membrane translocation and pore-formation during pyroptosis. Inhibition of GD-NT ubiquitination via site-directed mutations or the UBA1 inhibitor PYR-41 suppressed cell death in several pyroptosis cell models. Additionally, applying PYR-41 in septic mice efficiently suppressed the release of IL-18 and TNFα. Thus, GD-NT ubiquitination is a key regulatory mechanism controlling its membrane localization and activation, which may provide a novel target for modulating immune activity in pyroptosis-related diseases.
研究领域:
免疫学
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细胞生物学
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PubMed
高影响因子
Genes
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2022
·Vol. 13
·期 11
·2133
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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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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Liang Hang-fei,Yang Xiao,Li Hui-lin,Li Xuan,Tian Jia-ning,Su Hai-guo,Huang Min,Fang Jian-hong,Bi Hui-chang
Our previous study shows that activation of pregnane X receptor (PXR) exerts hepatoprotection against lithocholic acid (LCA)-induced cholestatic liver injury. In this study we investigated whether PXR activation could inhibit hepatocyte pyroptosis, as well as the underlying mechanisms. Male mice were treated with mouse PXR agonist pregnenolone 16α-carbonitrile (PCN, 50 mg·kg −1 ·d −1 , i.p.) for 7 days, and received LCA (125 mg/kg, i.p., bid) from D4, then sacrificed 12 h after the last LCA injection. We showed that LCA injection resulted in severe cholestatic liver injury characterized by significant increases in gallbladder size, hepatocellular necrosis, and neutrophil infiltration with a mortality rate of 68%; PCN treatment significantly inhibited hepatocyte pyroptosis during LCA-induced cholestatic liver injury, as evidenced by reduced serum lactic dehydrogenase (LDH) levels, TUNEL-positive cells and hepatocyte membrane damage. Furthermore, PXR activation suppressed both the NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical pyroptosis and the apoptosis protease activating factor-1 (APAF-1) pyroptosome-induced non-canonical pyroptosis. Inhibition of the nuclear factor kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways was also observed following PXR activation. Notably, dual luciferase reporter assay showed that PXR activation inhibited the transcriptional effects of NF-κB on NLRP3, as well as FOXO1 on APAF-1. Our results demonstrate that PXR activation protects against cholestatic liver injury by inhibiting the canonical pyroptosis through the NF-κB-NLRP3 axis and the non-canonical pyroptosis through the FOXO1-APAF-1 axis, providing new evidence for PXR as a prospective anti-cholestatic target.
研究领域:
肝病学
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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
FASEB JOURNAL
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2025
·Vol. 39
·期 5
·e70420
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IF 4.2
Min Zhu,Xiaofang Fan,Nan Zhang,Hui Wang,Jianshe Ma,Xianghong Yin,Junyan Cai,Linjing Cong,Ran Chen,Junming Fan,Xiaoxia Kong,Bin Geng,Yongsheng Gong,Congkuo Du
Endothelial pyroptosis, a pro-inflammatory programmed cell death, promotes endothelial inflammation and is a pivotal process in the initial stage of acute lung injury (ALI). Hydrogen sulfide (H 2 S), a gasotransmitter primarily dependent on cystathionine γ-lyase (CSE) in the cardiovascular and respiratory systems, plays a protective role during ALI. Nonetheless, the modulatory role and precise molecular mechanism of endothelial endogenous CSE/H 2 S in the pathogenesis of ALI remain elusive. Herein, we prepared an ALI mouse model using intratracheal administration of LPS (5 mg/kg), and lung injury was assessed by evaluating pulmonary edema, inflammatory response, and endothelial pyroptosis. In this model, H 2 S production from pulmonary tissues declined in a time-dependent manner, accompanied by a compensatory elevation of CSE protein levels. Treatment with the H 2 S donor (NaHS) attenuated pulmonary edema, inflammatory cell infiltration, endothelial pyroptosis, and reduced serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Meanwhile, the inducible deletion of CSE in endothelial cells exacerbated these changes. The blocking effect of CSE/H 2 S on endothelial pyroptosis (evidenced by caspase-11 activation and GSDMD-NT formation) was also confirmed in cultured pulmonary microvascular endothelial cells (PMECs). Mechanistically, H 2 S-mediated regulation of sirtuin-1 (SIRT1) expression and activation (via sulfhydration) contributed to the modulatory process. Collectively, we uncovered that endothelial endogenous CSE/H 2 S alleviates endothelial pyroptosis by activating SIRT1, thereby preventing LPS-induced acute lung injury. Graphical In the LPS-induced ALI model, caspase-1-independent pyroptosis was activated. The expression of activated caspase-11 and GSDMD-NT was increased, accompanied by pulmonary edema and inflammatory infiltration. Endothelial CSE/H 2 S deficiency aggravated endothelial pyroptosis and acute lung injury. Mechanistically, endothelial endogenous CSE/H 2 S mediated the expression and activation of sirtuin-1 (SIRT1) via sulfhydration, one of the post-translational modifications. Activated SIRT1 inhibited the activation of caspase-11 and GSDMD-NT to inhibit endothelial pyroptosis, thereby alleviating acute lung injury.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Zong-hui Xu,Man Li,Lin Liu,Shu-jing Wu,Ruo-an Wei,Mpofu Uphakeme Inobubele Sitholumusa,Xiao-ping Zhao,Jun-qiu Liu,Guo-yin Kai
Astragaloside IV (AS-IV), derived from Astragalus membranaceus , exhibits significant anti-inflammatory properties in a variety of diseases. However, the specific anti-inflammatory mechanism of AS-IV depends on the different organs and doses. Its protective effect is still unknown in acute lung injury (ALI). This study aims to investigate the potential anti-inflammatory mechanism of AS-IV in ALI. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were utilized to form pyroptosis models in MH-S and RAW264.7 cells. Mouse model of ALI was induced by intranasal LPS administration. In addition, the anti-pyroptosis effect of AS-IV was evaluated by using the C5aR1 agonists BM-213, the C5aR1 overexpression plasmids and C5aR1 siRNA. AS-IV significantly reduced pulmonary edema, improved histopathological injury, and decreased inflammatory factors. Meanwhile, AS-IV reduced ROS level and the amount of NLRP3 and GSDMD-N in vitro and in vivo . Inhibiting C5aR1 can effectively and significantly alleviate the pyroptosis of alveolar macrophages. Further studies found that BM-213 and C5aR1 overexpression plasmids partially reversed the anti-pyroptosis effect of AS-IV. The anti-pyroptosis effect of AS-IV was significantly inhibited when C5aR1 was knocked down. Our study demonstrate that AS-IV has anti-inflammatory protective effects on LPS-induced ALI, indicating that AS-IV may be a potential therapeutic agent for the treatment of ALI. This effect may be achieved by reducing the content of C5a, lowering the expression of C5aR1, and inhibiting cell pyroptosis.
研究领域:
药理学
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免疫学
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分子生物学
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PubMed
高影响因子
Scientific Reports
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2022
·Vol. 12
·期 1
·1-13
·
IF 4.996
Zhou Bin,Sha Shanshan,Tao Juan,Li Jun,Shen Chen,Zhu Jinjin,Tan Lulu,Dong Liyun,Huang Changzheng
Cutaneous melanoma (CM, hereafter referred to as melanoma) is a highly malignant tumor that typically undergoes early metastasis. Pyroptosis, as a special programmed cell death process that releases inflammatory factors and has been widely studied in tumors, but its role in melanoma has not been fully elucidated. In this study, we examined the relationship between pyroptosis and the prognosis of melanoma through bioinformatic analysis of RNA-sequencing data. Our results demonstrated that pyroptosis is a protective factor associated with melanoma prognosis. A higher pyroptosis score was associated with a more favorable overall survival. We used weighted gene co-expression networks analysis (WGCNA) to establish an effective prognosis model based on 12 pyroptosis-related genes. We then validated it in two independent cohorts. Furthermore, a nomogram combining clinicopathological characteristics and a pyroptosis-related gene signature (PGS) score was designed to effectively evaluate the prognosis of melanoma. Additionally, we analyzed the potential roles of pyroptosis in the tumor immune microenvironment and drug response. Interestingly, we found that the elevated infiltration of multiple immune cells, such as CD4 + T cells, CD8 + T cells, dendritic cells, and M1 macrophages, may be associated with the occurrence of pyroptosis. Pyroptosis was also related to a better response of melanoma to interferon-α, paclitaxel, cisplatin and imatinib. Through Spearman correlation analysis of the 12 pyroptosis-related genes and 135 chemotherapeutic agents in the Genomics of Drug Sensitivity in Cancer database, we identified solute carrier family 31 member 2 ( SLC31A2 ) and collagen type 4 alpha 5 chain ( COL4A5 ) as being associated with resistance to most of these drugs. In conclusion, this PGS is an effective and novelty prognostic indicator in melanoma, and also has an association with the melanoma immune microenvironment and melanoma treatment decision-making.
研究领域:
肿瘤学
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生物信息学
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免疫学
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DOI
PubMed
高影响因子
CELL RESEARCH
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2023
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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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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Shuo Zhang,Shuang Guo,Pengyu Wang,Yan Song,Leiming Yang,Qiyu Sun,Qi Huang,Youzhi Zhang
Background Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear. Methods The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits. Results Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin. Conclusion Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
Guoqiang Fan,Yaxin Liu,Limei Tao,Danping Wang,Yizhu Huang,Xiaojing Yang
Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unclear causes and limited treatment options. Sodium butyrate (NaB), a byproduct of dietary fiber in the intestine, has demonstrated efficacy in treating inflammation. However, the precise anti-inflammatory mechanisms of NaB in colon inflammation remain largely unexplored. This study aims to investigate the effects of NaB on dextran sulfate sodium (DSS)-induced colitis in rats. The findings indicate that oral administration of NaB effectively prevent colitis and reduce levels of serum or colon inflammatory factors. Additionally, NaB demonstrated in vitro inhibition of RAW264.7 inflammation cytokines induced by LPS, along with suppression of the ERK and NF-κB signaling pathway activation. Moreover, NaB mitigated LPS and Nigericin-induced RAW264.7 pyroptosis by reducing indicators of mitochondrial damage, including increased mitochondrial membrane potential (JC-1) levels and decreased Mito-ROS production. NaB increases ZO-1 and Occludin expression in CaCo2 cells by inhibiting RAW264.7 pyroptosis. These results suggest that NaB could be utilized as a therapeutic agent or dietary supplement to alleviate colitis.
研究领域:
免疫学
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消化病学
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药理学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-18
·
IF 12.6
Li Xiaoyan,Wang Ying,Cao Xinyue,Song Xinran,Chen Liang,Chang Meiqi,Chen Yu,Huang Bingcang
Background Reactive oxygen species (ROS)-mediated pyroptosis provides a robust strategy for overcoming apoptosis resistance in breast cancer therapy. Nevertheless, the low efficiency of pyroptosis remains an undeniable challenge. Overcoming this obstacle necessitates the creation of innovative approaches and nanocatalysts to boost ROS generation. Herein, the distinct lanthanum-doped BiFeO 3 (La-BFO) piezoelectric nanozymes are rationally designed and engineered for the specific cell pyroptosis of breast cancer through inducing the amplified production of ROS and releasing La ions. Results The introduction of La reduces the recombination rate of electron-hole pairs through narrowing the bandgap and creating the oxygen vacancy of BFO, improving the harmful ROS generation efficiency. Importantly, the released La ions robustly disrupt the lysosomal membrane, ultimately inducing cell pyroptosis, in combination with ROS-induced biological effect. Conclusion In vitro and in vivo antineoplastic results confirm the desirable therapeutic effect on combating tumor. Especially, the iron and bismuth elemental components endow the nanocomposites with dual-mode computed tomography/magnetic resonance imaging ability, guaranteeing the potential therapeutic guidance and monitoring. Graphical
研究领域:
生物医学工程
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肿瘤学
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材料科学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）