TOXICOLOGY AND APPLIED PHARMACOLOGY
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2026
·
IF 3.6
Shangxiang Feng,Kun Song,Hao Zhang,Zhuoqun Wang,Yuchi Zhao,Zhongyuan Zhao,Chao Wan
This study investigated the effects of Aureusidin on extracellular matrix (ECM) degradation and pyroptosis of chondrocytes in osteoarthritis. Network pharmacology, molecular docking, and pull-down assays were initially conducted to explore the target of Aureusidin. Subsequently, Sprague-Dawley rats underwent anterior cruciate ligament transection (ACLT) received oral administration of Aureusidin. Cartilage damage was evaluated histopathologically by H&E and Safranin O-fast green staining. Primary rat chondrocytes were treated with Aureusidin under IL-1β stimulation. Pyroptotic morphology was observed under light microscopy. Propidium iodide staining and flow cytometry were conducted to evaluate membrane rupture. The expression of markers associated with ECM degradation and pyroptosis was analyzed by qRT-PCR, Western blot, immunohistochemistry, and ELISA. Caspase-3 was identified as a target for Aureusidin. Aureusidin (5, 10, 20 mg/kg) alleviated ACLT-induced cartilage damage and ECM degradation. It reduced the OARSI score and serum levels of CTX-II and COMP, while upregulating the expression of Col2a1 and Acan , and downregulating Adamts5 , Mmp13 , and Mmp3 . Aureusidin also mitigated atypical pyroptosis, evidenced by inhibited expression of GSDME-N, Caspase-3, and Cleaved-Caspase-3, and decreased levels of IL-1β and IL-18. In IL-1β-stimulated primary chondrocytes, Aureusidin (5, 10, 20 μM) attenuated ECM degradation and Caspase-3/GSDME-mediated pyroptosis. Treating chondrocytes with the Caspase-3 inhibitor Z -DEVD-FMK under IL-1β-stimulated conditions alleviated ECM degradation and pyroptosis, but the additional application of Aureusidin did not provide further inhibition. Aureusidin has the potential to inhibit ECM degradation and Caspase-3/GSDME-mediated chondrocyte pyroptosis during osteoarthritis progression. Its therapeutic effects are dependent on binding to and modulating the Caspase-3.
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高影响因子
LIFE SCIENCES
·
2026
·
IF 6.4
Zhaoxu Qiu,Huaxing Zhang,Bo Tan,Qian Chen,Huizi Gao,Yuhan Yao,Yangxuan Peng,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xu Teng,Yanzhuo Ma,Yuming Wu,Sheng Jin
Aims The present study was aimed to investigate whether trimethylamine N-oxide (TMAO) contributed to cardiac aging and to explore the underlying mechanism. Materials and methods Male C57BL/6 J mice were randomly divided into four age groups (3, 12, 18, and 24 months) to assess the cardiac function. Markers of senescence, oxidative stress, and the protein expression of pyroptosis were also measured. To test the hypothesis that TMAO promoted cardiac aging, 8-week-old mice were intraperitoneally injected with TMAO for 1–3 months and 3,3-dimethyl-1-butanol was administered in drinking water starting from 15 months of age for three months to inhibit TMAO production. Gasdermin D (GSDMD) knockout mice were also used. Key findings Plasma TMAO levels increased with age and correlated with upregulation of cardiac senescence markers, diastolic dysfunction, cardiac fibrosis, and elevated plasma brain natriuretic peptide levels. Starting from 2 months of TMAO treatment, impairment of cardiac diastolic function and progression of cardiac fibrosis were observed alongside the upregulation of senescence marker proteins expression. Mechanistically, TMAO promoted cardiac oxidative stress and activated the NLRP3-mediated pyroptosis pathway. Genetic ablation of GSDMD abolished TMAO-associated cardiac aging. Furthermore, pharmacological inhibition of TMAO production in aged mice attenuated oxidative stress, suppressed NLRP3-mediated pyroptosis activation, and alleviated cardiac aging. Significance This study revealed that plasma TMAO levels progressively increase with age in mice and TMAO contributed to cardiac aging in a time-dependent manner through NLRP3-mediated pyroptosis driven by oxidative stress. Moreover, the inhibition of TMAO generation might offer a basis for future therapeutic strategies. Download: Download high-res image (146KB) Download: Download full-size image
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Liver Research
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2026
·
IF 4.3
Hang-Fei Liang,Chuo-Ying Mai,Xuan Li,Jia-Ning Tian,Hai-Guo Su,Min Huang,Jian-Hong Fang,Hai-Tao Wang,Xiao Yang,Hui-Chang Bi
Background and aims The mechanism of cholestatic liver injury (CLI) is unclear, and effective therapies are lacking. While peroxisome proliferator-activated receptor alpha (PPARα) agonists show potential hepatoprotective effect and pyroptosis is implicated in hepatocellular damage, how PPARα activation mitigates lithocholic acid (LCA)-induced pyroptosis remains unknown. Methods The hepatoprotective effect of PPARα agonists was evaluated in a mouse model of intrahepatic cholestasis induced by LCA. Liver injury was assessed via serum biochemistry, hematoxylin and eosin and TUNEL staining, and electron microscopy. Pyroptosis pathways were analyzed using real-time quantitative polymerase chain reaction, Western blot, and co-immunoprecipitation. Results Combined morphological, histopathological, and biochemical analyses confirmed that PPARα activation protects against CLI. Compared with LCA treatment alone, PPARα activation significantly attenuated the elevation of serum lactate dehydrogenase (LDH), the increased TUNEL-positive cells, and the formation of hepatocyte membrane pores. Mechanistically, PPARα activation suppressed both NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis and apoptosis protease-activating factor-1 (APAF-1)/CASPASE-3/GSDME-mediated pyroptosis. Furthermore, PPARα agonist pretreatment inhibited activation of the nuclear factor-kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways. Conclusions PPARα protects against LCA-induced CLI by inhibiting both NLRP3 inflammasome-mediated pyroptosis associated with NF-κB and APAF-1/CASPASE-3/GSDME-mediated pyroptosis associated with the FOXO1 signaling pathway.
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BIOMACROMOLECULES
·
2025
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IF 5.4
Xiaoxi Zhao,Qinjie Zhong,Naibijiang Abudouaini,Yan Zhao,Jibin Zhang,Guozhu Tan,Guifeng Miao,Xiaowu Wang,Jianqiang Liu,Ying Pan,Xiaorui Wang
Photodynamic therapy (PDT) has emerged as a promising modality for cancer treatment, but its clinical application is constrained by unexpected phototoxicity arising from nonspecific photosensitizer activation and their “always-on” nature. Herein, we developed a switchable nanophotosensitizer, poly(cation−π) nanoparticles (NP), which achieves supramolecular assembly through cation−π interactions. By coupling choline cationic moieties with aromatic photosensitizers (ZnPc), the polymer facilitates self-assembly driven by cation−π interactions for NP engineering. Surprisingly, the photoactivity of ZnPc was completely quenched upon complexation via cation−π interactions, thereby significantly avoiding skin phototoxicity. Upon targeting tumor cells, NP undergoes a GSH-responsive degradation process that weakens cation−π interactions, leading to spontaneous restoration of photoactivity and amplifying tumor immunogenic pyroptosis. In vivo studies demonstrated that NP achieved a high tumor inhibition rate of 84% while effectively avoiding skin phototoxicity. This work provides a novel perspective for enhancing the safety and efficacy of PDT-based tumor treatment.
研究领域:
生物医学工程
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肿瘤学
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药理学
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高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Qinglin Wei,Xuejiao Song,Xiaorui Wang,Yawen Chen,Wenjun Wang,Ping Sun,Xiaochen Dong
Based on their distinctive manners of driving cell death, cuproptosis and pyroptosis exhibit significant potential in overcoming the apoptosis resistance of cancer cells. Nevertheless, limited copper concentrations and complex tumor microenvironment (TME) severely constrain the therapeutic efficacy. Herein, DSPE-PEG 2000 modified copper-nitrogen-doped carbon-based photocatalysts (Cu-NC@PEG) are developed as photo-activated reactive oxygen species (ROS) amplification systems to trigger pyroptosis and cuproptosis in a synergistic manner. Cu-NC@PEG enriches in tumor cells and generates a large amount of superoxide anions under the second near-infrared region (NIR-II) laser irradiation, followed by further induction of cell pyroptosis through caspase-mediated cleavage of Gasdermin D (GSDMD). The copper ions released from Cu-NC@PEG in the acidic TME can not only generate ·OH and consume the antioxidants to enhance ROS-induced pyroptosis, but also effectively activate cuproptosis through Cu + -mediated dihydrolipoamide S-acetyltransferase aggregation and Fe-S cluster protein loss. Simultaneously, the mitochondrial damage induced by pyroptosis leads to a considerable efflux of ATP and the restricted ATP availability could enhance the disruption of copper metabolic homeostasis, thereby potentiating cuproptosis. The increased tumor-inhibiting effects of the combined induction of cuproptosis and pyroptosis could be achieved. Statement of significance 1. NIR-II photo-activated copper-nitrogen-doped carbon-based photocatalysts (Cu-NC@PEG) were developed. 2. ROS amplification was achieved based on the photo catalytic properties and Fenton-like reaction of Cu-NC@PEG. 3. Therapeutic efficacy was enhanced via ROS-induced pyroptosis and Cu + -mediated cuproptosis.
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高影响因子
Advanced Science
·
2024
·
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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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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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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高影响因子
Cells
·
2022
·Vol. 11
·期 22
·3579
·
IF 7.666
Yan Liu,Xuehua Kong,Yan You,Linwei Xiang,Yan Zhang,Rui Wu,Lan Zhou,Liang Duan
NLRP3 inflammasome-dependent pyroptosis has been implicated in liver fibrosis progression. However, the definite intrahepatic cell types that undergo pyroptosis and the underlying mechanism as well as the clinical importance remain unclear. Here, augmented levels of pyroptosis-related indicators GSDMD, IL-1β, and IL-18 were verified in both liver fibrosis patients and CCl4-induced fibrotic mouse model. Confocal imaging of NLRP3 with albumin, F4/80 or α-SMA revealed that enhanced NLRP3 was mainly localized to kupffer cells (KCs), indicating that KCs are major cell types that undergo pyroptosis. Targeting pyroptosis by inhibitor MCC950 attenuated the severity and ameliorated liver function in fibrosis models. In addition, elevated S100A8 in liver fibrosis patients was correlated with pyroptosis-related indicators. S100A8 stimulated pyroptotic death of macrophages, which resulted in activation of human hepatic stellate cell line LX-2 cells and increased collagen deposition. Mechanistically, S100A8 activated TLR4/NF-κB signaling and upregulated its target genes NLRP3, pro-IL-1β, and pro-IL-18 expression, and induced reactive oxygen (ROS) abundance to activate NLRP3 inflammasome, finally leading to pyroptotic cell death in macrophages. More importantly, circulating GSDMD had the optimal predicting value for liver fibrosis progression. In conclusion, S100A8-mediated NLRP3 inflammasome-dependent pyroptosis by TLR4/NF-κB activation and ROS production in macrophages facilitates liver fibrosis progression. The identified GSDMD has the potential to be a biomarker for liver fibrosis evaluation.Keywords:NLRP3;S100A8;GSDMD;liver fibrosis
研究领域:
免疫学
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肝病学
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细胞生物学
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病理学
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高影响因子
MOLECULAR BIOLOGY
·
2022
·Vol. 57
·期 1
·105-112
·
IF 1.54
Zeng H. B.,Zhang L. H.,Yuan D. P.,Wang W.,Su X. M.,Weng W. X.,Miao R.,Xu J. Y.,Long J.,Song Y. H.
Abstract As a byproduct of mitochondrial respiration or metabolism, reactive oxygen species (ROS) can act as a signaling molecule to activate NLR family pyrin domain containing 3 (NLRP3) inflammasome, thereby triggering immune response. NLRP3 inflammasome acts as a sensor of various danger signals and is central to the control of pyroptosis occurrence. Macrophage pyroptosis is closely related to atherosclerosis, arthritis, pulmonary fibrosis and other inflammatory diseases. Methylophiopogonanone A (MO-A) is a main homoisoflavonoid in Chinese herb Ophiopogonis Radix, which has antioxidant effect. However, it is not clear whether MO-A can alleviate macrophage pyroptosis by inhibiting oxidative stress. Here we have shown that MO-A increases the activities of superoxide dismutase (SOD) and catalase (CAT), inhibits the production of ROS, reduces the activation of NLRP3 inflammasome and the release of lactate dehydrogenase (LDH), and inhibits pyroptosis in macrophages induced by lipopolysaccharides (LPS) and adenosine triphosphate (ATP). These effects can be reversed by the ROS promoter H 2 O 2 . Therefore, MO-A can inhibit macrophage pyroptosis through the ROS/NLRP3 pathway and may be considered as a candidate drug for the treatment of inflammatory diseases.
研究领域:
免疫学
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药理学
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炎症
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高影响因子
Advanced Science
·
2026
·
IF 14.1
Yabing Gan,Yuling Xu,Ting Yu,Yang Li,Xin Jiang,Haoyu Jin,Haitao Li,Youyu Zhang,Peng Yin,Jong Seung Kim
Real-time visualization of oxidative stress in living systems poses a formidable challenge in epilepsy research, primarily due to the scarcity of tools capable of selectively distinguishing structurally similar reactive oxygen species (ROS) with high specificity. Here, we present a dual-functional fluorescent probe, HH , capable of independently detecting hydrogen peroxide (H 2 O 2 ) and hydroxyl radicals (•OH) through distinct recognition mechanisms, yielding spectrally resolved signals with high sensitivity, selectivity, and biocompatibility. HH enables high-resolution, interference-free imaging of redox dynamics in both gasdermin-mediated pyroptosis and pentylenetetrazol (PTZ)-induced epileptic cell models. Furthermore, HH was successfully employed in PTZ-induced zebrafish and kainic acid (KA)-induced mouse epilepsy models, revealing elevated ROS levels under seizure-like conditions. Notably, ROS-targeted therapeutic interventions significantly modulated oxidative profiles, demonstrating HH ’s potential for therapeutic evaluation. This work not only fills a critical methodological gap in ROS biology and epilepsy research but also provides a versatile platform for studying redox regulation in neurological and inflammatory diseases and enabling mechanistic and therapeutic investigations.
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高影响因子
MOLECULAR REPRODUCTION AND DEVELOPMENT
·
2026
·Vol. 93
·期 7
·e70135
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IF 2.6
Yang Sun,Haipeng Pei,Xing Zhang,Yi Jing,Ziheng Zhang,Xinghao Zhang,Huaying Qian,Fengjuan Chang,Yuhang Geng,Ziyang Han,Yun Chen
Pyroptosis, a proinflammatory form of programmed cell death mediated by the NLRP3 inflammasome, has recently been implicated in Sertoli cell inflammatory injury. Crocin, a water-soluble carotenoid glycoside derived from Crocus sativus L. and Gardenia jasminoides Ellis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties, yet its role in Sertoli cell pyroptosis remains unclear. Here, we investigated the pharmacological effects and mechanisms of crocin in regulating TM4 Sertoli cell viability and pyroptosis. Network pharmacology based on oligoasthenospermia (OA)-related candidate targets, together with molecular docking, identified HSP90AA1 as a candidate molecular target associated with crocin-mediated regulation of Sertoli cell pyroptosis. MST analysis further provided target-engagement evidence supporting a direct interaction between crocin and HSP90AA1. In TM4 Sertoli cells, crocin improved cell viability, enhanced Ki-67 expression, and protected against lipopolysaccharide/nigericin-induced pyroptosis, as evidenced by reduced lactate dehydrogenase release, decreased PI-positive cells, and downregulated expression of IL-1β, IL-18, NLRP3, Caspase-1, and GSDMD. Moreover, under HSP90AA1-overexpressing conditions, crocin partially reduced pyroptosis-related injury and inflammatory mediator expression, supporting the involvement of HSP90AA1 in crocin-mediated regulation of Sertoli cell pyroptosis. Collectively, these findings indicate that crocin enhances Sertoli cell proliferation and mitigates inflammasome-driven pyroptosis through an HSP90AA1-associated mechanism. These findings should be interpreted as preliminary in vitro evidence for crocin-mediated regulation of Sertoli cell proliferation and pyroptosis, and further validation in animal models and clinical samples is required.
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高影响因子
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