BIOLOGICAL TRACE ELEMENT RESEARCH
·
2025
·
IF 3.6
Xu Hao,Yang Jingyi,Ye Ruiqi,Cao Mixia,Li Shenghe,Liu Chang,Li Lei
Acute cadmium (Cd) exposure induces hepatic toxicity in murine models, where oxidative stress and subsequent inflammatory responses are recognized as principal contributors to hepatocyte damage. The NLRP3 inflammasome, a pivotal member of the NOD-like receptor family, mediates pyroptotic cell death in diverse hepatic inflammatory pathologies. While murine liver exhibits heightened susceptibility to heavy metal toxicity, the mechanistic basis of Cd-induced hepatocyte injury remains incompletely characterized. This study aims to clarify the cytotoxic effects of Cd on murine hepatocyte line BNL CL.2 and systematically dissect the underlying molecular mechanisms. Via molecular and cellular assays, we evaluated mitochondrial function, reactive oxygen species (ROS) levels, NLRP3 inflammasome activation, and pyroptotic features in BNL CL.2 cells post Cd exposure; intervened with ROS scavengers N-acetylcysteine (NAC) and Mito-TEMPO, and detected transcriptional activity of the antioxidant regulator Nrf2. Experimental data demonstrate that Cd exposure triggers mitochondrial dysfunction coupled with excessive ROS production, concomitant NLRP3 inflammasome activation, and characteristic plasma membrane rupture confirming pyroptosis. Notably, NAC and Mito-TEMPO effectively attenuate these pathological responses, establishing ROS as critical regulators of Cd-induced NLRP3 inflammasome activation; mechanistically, Cd suppresses Nrf2 transcriptional activity and downstream antioxidant gene expression, thereby disrupting redox homeostasis. These findings collectively delineate a pathogenic cascade where Cd impairs mitochondrial integrity and disrupts Nrf2-dependent antioxidant defenses, synergistically driving ROS-mediated NLRP3 inflammasome activation and subsequent hepatocyte pyroptosis. This mechanism provides novel insights into heavy metal hepatotoxicity and identifies potential targets for treating Cd-induced liver injury.
研究领域:
毒理学
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分子生物学
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肝病学
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氧化应激
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炎症与免疫
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2025
·
IF 5.1
Yizhang Chen,Chenxiang Wang,Yuna Wu,Yuhan Zeng,Shangjing Xie,Jialu Weng,Lei Guo,Jing Fu,Tao Zhou,Xiuhua Zhang,Ziye Zhou
Introduction Alectinib is a widely used first-line ALK inhibitor for fusion-positive non-small cell lung cancer. However, its clinical use is limited by hepatotoxicity, and its mechanism remains unclear. This study aims to elucidate how alectinib induces liver injury and to explore a potential protective strategy.Methods In vitro, AML-12 hepatocytes were incubated with alectinib to determine cell viability and morphology by using CCK-8 assay and optical microscopy, respectively. Necrosis was assessed by flow cytometry after Annexin V-FITC/PI staining. Mitochondrial damage was analyzed by measuring membrane potential, ultrastructure, and respiratory chain complex activities using JC-1 staining under fluorescence microscopy, transmission electron microscopy, and assay kits, respectively. Intracellular reactive oxygen species (ROS) levels were detected using DCFH-DA staining and flow cytometry. Pyroptosis- and oxidative stress-related proteins (NLRP3, GSDMD-N, P20, cleaved IL-1β, Nrf2, HO-1) were quantified by Western blot. In vivo, C57BL/6J mice were divided into control, alectinib treatment, and alectinib plus magnesium isoglycyrrhizinate (MgIG) treatment groups. Serum ALT and AST were measured to assess liver function. Hepatic oxidative stress was evaluated by SOD and MDA levels. Inflammatory cytokines including IL-1β and TNF-α were measured by corresponding kits. Liver histopathology was examined by hematoxylin-eosin staining.Results We found alectinib could induce the death of AML-12 hepatocytes. Alectinib impaired both the function and structure of mitochondria and caused a significant increase in ROS levels. The excessive accumulation of ROS triggered oxidative stress and finally resulted in cell pyroptosis in AML-12 cells. MgIG was found to alleviate mitochondrial damage and reduce ROS levels, restore the Nrf2/HO-1 signaling pathway, thereby inhibiting oxidative stress and pyroptosis caused by alectinib.Conclusion Alectinib induces elevated ROS levels in hepatocytes by damaging mitochondria and causing oxidative stress in hepatocytes, which results in cell pyroptosis and ultimately hepatotoxicity, whereas MgIG can treat alectinib-induced hepatic injury by restoring mitochondrial function and structure.
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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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
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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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
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IF 19
Jiali Deng,Yi Zhu,Jingyi Wang,Xinyi Ding,Sunxian Dai,Jiajing Guo,An Chen,Rong Cao,Li Zhang,Haiyu Liu,Xiance Zhao,Xinyang Wu,Hongwei Lu,Zhongling Wang
The accurate non-invasive monitoring of pyroptosis-based immunotherapy is hindered by the lack of sensitive imaging strategies. Here, a self-amplifying chemical exchange saturation transfer (CEST) imaging-guided pyroptosis therapy (pyropCEST) strategy for activating and highly sensitive visualizing pyroptosis-induced immune response is reported. The biocompatible nanoplatform, composed of human serum albumin loaded with gemcitabine, can induce pyroptosis in the tumor microenvironment, promoting dendritic cell maturation and T cell activation. Meanwhile, nanoprobe dissociation enhances chemical exchange between the NH 2 groups within gemcitabine/albumin and bulk water, yielding self-amplified CEST signals and boosting imaging sensitivity to 435% compared to normal physiological conditions. In the subcutaneous tumor mouse model, the long-term accumulation of nanoprobes in the tumor leads to a 2.5-fold increase in CEST signal over free gemcitabine. Changes in CEST signal serve as an indicator for evaluating CD8 + T cell infiltration and tumor growth, exhibiting an excellent “theranostic correlation.” Moreover, integration with multiparametric MRI enables comprehensive tracking of therapeutic outcomes, including suppression of distant metastases. Collectively, this pyropCEST strategy introduces a clinically translatable imaging paradigm for non-invasive, dynamic visualization of pyroptosis and immune microenvironment remodeling.
研究领域:
肿瘤学
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分子影像学
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免疫治疗
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纳米医学
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生物医学工程
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产品关联
DOI
高影响因子
Advanced Science
·
2024
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IF 14.3
Lin Liu,Junpeng Shi,Jinyuan Wang,Linping He,Yan Gao,Peng Lin,Yutong Han,Ping'an Ma,Jun Lin,Yun Zhang
Pyroptosis possesses potent antitumor immune activity, making pyroptosis inducer development a promising direction for tumor immunotherapy. Persistent luminescence nanoparticles (PLNPs) are highly sensitive optical probes extensively employed in tumor diagnosis and therapy. However, a pyroptosis inducer based on PLNPs has not been reported yet. Herein, polyethylene glycol–poly lactic acid-co-glycolic acid (PEG–PLGA: PP) modified biodegradable CaS:Eu 2+ (CSE@PP) PLNPs are synthesized as a pyroptosis inducer for tumor immunotherapy for the first time. The synthesized CSE@PP possesses biowindow persistent luminescence (PersL) and pH-responsive degradation properties, allowing it to remain stable under neutral pH but degrade when exposed to weak acid (pH < 6.5). During degradation within the tumor, CSE@PP constantly releases H 2 S and Ca 2+ while its PersL gradually fades away. Thus, the PersL signal can self-monitor H 2 S and Ca 2+ release. Furthermore, the released H 2 S and Ca 2+ result in mitochondrial dysfunction and the inactivation of reactive oxygen species scavenging enzymes, synergistic facilitating intracellular oxidative stress, which induces caspase-1/GSDM-D dependent pyroptosis and subsequent antitumor immune responses. In a word, it is confirmed that CSE@PP can self-monitor H 2 S and Ca 2+ release and pyroptosis-mediated tumor Immunotherapy. This work will facilitate biomedical applications of PLNPs and inspire pyroptosis-induced tumor immunotherapy.
研究领域:
纳米技术
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生物医学工程
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癌症研究
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免疫治疗
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材料科学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 7
·3710
·
IF 6.208
Qiaoqiao Luo,Ruoyu Shi,Yutong Liu,Libo Huang,Wei Chen,Chengtao Wang
Huangjiu usually caused rapid-drunkenness and components such as β-benzyl ethanol (β-be), isopentanol (Iso), histamine (His), and phenethylamine (PEA) have been reported linked with intoxication. However, the destructive effect of these components on gut microbiota and liver is unclear. In this study, we found oral treatment of these components, especially His, stimulated the level of oxidative stress and inflammatory cytokines in liver and serum of mice. The gut microbiota community was changed and the level of lipopolysaccharide (LPS) increased significantly. Additionally, cellular pyroptosis pathway has been assessed and correlation analysis revealed a possible relationship between gut microbiota and liver pyroptosis. We speculated oral His treatment caused the reprogramming of gut microbiota metabolism, and increased LPS modulated the gut-liver interaction, resulting in liver pyroptosis, which might cause health risks. This study provided a theoretical basis for the effect of Huangjiu, facilitating the development of therapeutic and preventive strategies for related inflammatory disorders.Keywords:gut microbiota;food ingredients;metabolic disease;health;metabolism;molecular mechanism
研究领域:
免疫学
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微生物学
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分子生物学
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胃肠病学
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肝病学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2020
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IF 2.985
Feng Yang,Wen Zhu,Xiaofang Cai,Wen Zhang,Zhonghai Yu,Xiangting Li,Jingsi Zhang,Min Cai,Jun Xiang,Dingfang Cai
Background Inflammasome activation and followed by the release of proinflammatory cytokines play a pivotal role in the development and progression of depression. However, the involvement of gasdermin D (GSDMD)-mediated pyroptosis in inflammasome-associated depression has not been studied. The present study aimed to determine the involvement of pyroptosis in the development of depression. Methods The rat depressive model was established by the administration of monosodium glutamate (MSG) in postnatal rats. Minocycline (an anti-inflammatory agent) and VX-765 (a specific inhibitor of caspase-1) were given as intervention treatments when rats were two-month-old. Rat depressive behaviors were evaluated by behavioral tests, including open field test, sucrose preference test , and forced swim test . Rat hippocampi were collected for western blotting and immunofluorescence examination. Results MSG administration induced depressive-like behavior in rats. MSG upregulated protein presences of caspase-1, GSDMD, interleukin-1β (IL-1β), interleukin-18 (IL-18), NLR pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), high mobility group box 1 protein (HMGB1), and the receptor for advanced glycation end products (RAGE) in the hippocampus. Protein presences of HMGB1, NLRP3 and GSDMD were upregulated in Olig2+ oligodendrocytes in the hippocampus. The data suggest that both HMGB1/RAGE/NLRP3 signalings and GSDMD-dependent pyroptosis were activated. Both minocycline and VX-765 treatments improved depressive-like behaviors. Minocycline treatment significantly reduced both HMGB1/RAGE/NLRP3 inflammasome signalings and GSDMD-dependent pyroptosis. VX-765 downregulated GSDMD-dependent pyroptosis, but not HMGB1/RAGE signalings, indicating that GSDMD-dependent pyroptosis is a key player in the progress of depression. Conclusion In rats hippocampus, NLRP3 inflammasome activates GSDMD mediated-pyroptosis in the hippocampus of MSG-induced depressive rats.
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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抑郁症
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DOI
PubMed
高影响因子
ACS Nano
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2026
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IF 17.3
Ping Li,Qianying Li,Lu Ding,Shiyu Peng,Hui Wei,Tingtao Chen,Yonghua Xiong,Ben Zhong Tang,Xiaolin Huang
Interleukin-2 (IL-2) immunotherapy offers considerable potential for metastatic cancers; however, its efficacy is limited by low response rates, dose-dependent toxicity, short half-life, poor tumor accumulation, and off-target immune activation. In this work, we present a biohybrid microrobot (IL-2@Z/C/A) engineered through biomimetic mineralization of IL-2 variant-secreting Escherichia coli Nissle 1917 (EcN) with a zeolitic imidazolate framework-8 (ZIF-8) shell coloaded with an aggregation-induced emission photosensitizer and catalase. The ZIF-8 coating preserves bacterial viability tumor-homing capability while preventing premature drug leakage and systemic exposure, thus minimizing off-target effects. Upon accumulation in the acidic tumor microenvironment (TME), the framework degrades to release engineered bacteria and therapeutic cargo. Locally delivered zinc ion release, light-triggered reactive oxygen species and EcN derived pathogen-associated molecular patterns act synergistically to induce Cle-caspase/GSDMD mediated pyroptosis, resulting in immunogenic cell death accompanied by damage-associated molecular pattern release and pro-inflammatory cytokine production. Simultaneously, catalase-driven oxygen generation alleviates hypoxia and suppresses HIF-1α-induced immunosuppression. In combination with PD-L1 blockade, IL-2@Z/C/A achieves near-complete tumor regression in a B16F10 melanoma model via a coordinated immune cascade: pyroptosis-mediated antigen exposure primes adaptive immunity, hypoxia reversal counteracts immunosuppression, and sustained local IL-2 release reverses T cell exhaustion, collectively reprogramming the immunosuppressive TME and eliciting strong antitumor immunity. This work establishes a distinct paradigm for spatially controlled immunotherapy and highlights the potential of this biohybrid microrobot in converting immunologically “cold” tumors into responsive niches.
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PubMed
高影响因子
Toxics
·
2026
·Vol. 14
·期 6
·461
·
IF 4.9
Xiangyu Yu,Jiawen Ren,Ying Kang,Shizhi Wang,Jianrui Dou,Yongquan Yu
Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013–2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans.
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2025
·
IF 8
Yiming Sun,Ruili Zhang,Jiali Li,Yihan Hu,Haolin Zhang,Xiangjie Wang,Yi Yang,Haibin Wang,Ming Ge
2-Ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer easily released into the environment. Its biological toxicity is of great concern. The lung is considered a possible target organ for EHDPHP, but currently, there are limited studies on the biotoxicity of EHDPHP in poultry lungs. Therefore, the lungs were selected as the target organ to study the toxic effects of EHDPHP on chicks and their mechanisms of action. In this study, 7-day-old chicks were gavaged with different concentrations of EHDPHP, and lung samples were collected at 14, 28, and 42 days after intragastric administration. Lung histopathological and ultrapathological changes were examined by paraffin section-HE staining and transmission electron microscopy. The levels of lung damage markers (LDH) and oxidative stress markers (GSH-Px, SOD, and MDA) were detected by applying the kit. In contrast, lung cell pyroptosis-related factors (NLRP3, ASC, NF-κB, Pro-Caspase-1, IL-18, and IL-1β) and inflammatory factors (IL-6 and TNF-α) were assessed by using the qRT-PCR, Western blot and ELISA techniques. The results showed that EHDPHP induced pathological morphological changes and elevated LDH content in chick lungs, decreased lung antioxidant enzymes (GSH-Px and SOD) activities, increased peroxidation product MDA content and up-regulated the expression levels of cellular pyroptosis factors (NLRP3, ASC, NF-κB, Pro-Caspase-1, IL-18, and IL-1β), and the synthesis and secretion of inflammatory factors (IL-6 and TNF-α) were promoted. The above changes were EHDPHP dose-dependent. The results indicated that EHDPHP induced oxidative stress in chick lungs, resulting in oxidative damage to the lungs, and, intriguingly, the cellular pyroptosis pathway was activated, which was also involved in the process of EHDPHP-induced inflammatory damage in chick lungs. The results of this study revealed for the first time the damaging effects and mechanisms of EHDPHP on chick lungs. Also, they provided a scientific basis for further exploring the mechanisms of toxicity damage, safe use, and pollution control of EHDPHP.
研究领域:
毒理学
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环境科学
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兽医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Lei Li,Hailong Tian,Zhe Zhang,Ning Ding,Kai He,Shuaijun Lu,Ruolan Liu,Peijie Wu,Yu Wang,Bo He,Maochao Luo,Peilan Peng,Mao Yang,Edouard C. Nice,Canhua Huang,Na Xie,Dong Wang,Wei Gao
Pyroptosis, as a novel mode of cell death, has been proven to have impressive antitumor effects. Dying cells undergoing pyroptosis can elicit antitumor immunity by the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Accordingly, developing an effective, stable, and controllable nanoplatform that can promote these two side effects is a promising option for cancer therapy. In this study, we designed a carrier-free chemo-photodynamic nanoplatform (A-C/NPs) using a co-assembly strategy with cytarabine (Ara-C) and chlorin e6 (Ce6) to induce pyroptosis and a subsequent immune response against breast cancer. Mechanistically, A-C/NPs can trigger GSDME-mediated pyroptosis in a controllable manner through reactive oxygen species (ROS) accumulation, causing immunogenic cell death (ICD), in which dying cells release high-mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and calcitonin (CRT). Additionally, Ara-C can stimulate the maturation of cytotoxic T lymphocytes to act synergistically with Ce6-mediated immunogenic cell death (ICD), collectively augmenting the anticancer effect of A-C/NPs. The A-C/NPs showed excellent suppressive effects on the growth of orthotopic, abscopal, and recurrent tumors in a breast cancer mouse model. The chemo-photodynamic therapy (PDT) using the proposed nanomedicine strategy could be a novel strategy for triggering pyroptosis and improving the global anticancer immune response.
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高影响因子
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