Small
·
2025
·
IF 12.1
Xu Zhang,Zhichao Dou,Huayang Fan,Tu Huang,Zhuohao Zhang,Yaling Tang,Xin-hua Liang
Reactive oxygen species (ROS) can catalyze the palmitoylation of Gasdermin D (GSDMD), thereby promoting pyroptosis. However, tumor cells frequently exhibit elevated expression of heat shock proteins (HSPs), which attenuate pyroptosis through the inhibition of key pyroptotic mediators. To solve these problems, a folate-acid-modified polydopamine nanoparticle loaded with copper peroxide (PDCF nanoparticles) is developed to simultaneously trigger and amplify pyroptosis while suppressing HSPs-mediated defensive mechanisms. PDCF nanoparticles efficiently elevated intracellular ROS, thereby directly promoting the palmitoylation and subsequent cleavage of GSDMD to its active N-terminal GSDMD (GSDMD-N). This process created a positive feedback loop that enhanced pyroptosis, characterized by pore formation in the plasma membrane and the release of interleukin 1β (IL-1β) and interleukin 18 (IL-18). Concurrently, the elevated ROS significantly downregulated HSPs expression to achieve a mild photothermal therapy (MPTT). This combined strategy of pyroptosis amplification and HSPs inhibition potently suppressed tumor growth in oral squamous cell carcinoma (OSCC). The novel multifunctional therapeutic strategy provides a new view for the treatment of OSCC through ROS-mediated downregulation of HSPs and improving pyroptosis.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Liangwei Wang,Zhongpan Li,Zhilang Xie,Xianghan Hou,Rongzhu Li,Yulin Xiang,Xiaohui Chen,Fulan Zhao,Jiaqi Wu,Guoyou Wang,Rui Huang
Injectable nanohydrogel enabled localized and sustained intra-articular delivery. • GLP hydrogel prolonged joint retention and enabled sustained local drug exposure. • GLP hydrogel alleviated synovial inflammation and cartilage damage in CIA rats. • GLP hydrogel suppressed NF-κB/NLRP3-driven pyroptosis with good in vivo safety. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation. To overcome the limitations of conventional therapies, including poor bioavailability, insufficient target specificity, and cumulative systemic toxicity, this investigation delineates the design and fabrication of an enzymatically cross-linked hydrogel scaffold derived from a gelatin-gallic acid (GGA) graft copolymer, designated as GGA@Lipo@EMO (GLP), for the encapsulation of emodin (EMO)-loaded liposomal nanoparticles. This advanced delivery platform facilitates localized sustained release and precise intra-articular drug delivery. Rheological analysis, scanning electron microscopy (SEM), and proton nuclear magnetic resonance ( 1 H NMR) confirmed its injectability, interconnected porous structure, and controlled release behavior. The Network pharmacology analyses, in vitro cellular experiments, and in vivo studies using collagen-induced arthritis (CIA) rat models collectively demonstrate that the GLP hydrogel effectively inhibits the nuclear factor-κB (NF-κB) signaling pathway and NOD-like receptor protein 3 (NLRP3) inflammasome activation, thereby blocking cysteine–aspartic acid protease-1 (caspase-1)/gasdermin D (GSDMD)-mediated pyroptosis. This results in significant downregulation of key inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18), thereby mitigating inflammatory cell infiltration and cartilage degradation. The GLP hydrogel exhibits substantial therapeutic efficacy and favorable biosafety, offering a new approach for localized therapy of RA. Download: Download high-res image (211KB) Download: Download full-size image
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
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IF 6.8
Jiani Sun,Lei Gan,Siji Lv,Tao Wang,Chaoqun Dai,Jing Sun
Endocrine-disrupting chemicals (EDCs) have been reported to affect populations by disrupting the human endocrine system. Di-(2-ethylhexyl) phthalate (DEHP) is an EDC that is present in various consumer products. Exposure to DEHP could contribute to reproductive system dysfunction, with subsequent adverse female reproductive outcomes. Granulosa cells (GCs) play essential roles in ovarian function and fertility. To further reveal the underlying mechanism by which DEHP impairs female fertility and affects the normal function of GCs, in vivo and in vitro experiments were performed. Transcript sequencing was used to identify genes that were differentially expressed in GCs after DEHP treatment. SLC39A5 was shown to be overexpressed in the DEHP group compared to the normal control group. DEHP treatment and overexpression of SLC39A5 activated NF-κB-related factors, followed by an increase in the transcript expression level of NLRP3. NLRP3 inflammasomes play crucial roles in pyroptosis by acting as sensors. Pyroptosis is a type of inflammation-related cell death associated with various diseases, including ovarian cancer and polycystic ovary syndrome. Activation of NF-κB contributed to the upregulation of pyroptosis in GCs, while pyroptosis factors were downregulated after the inhibition of NF-κB with JSH-23. The same phenomenon was also observed in a mouse model in which DEHP-treated mice had higher expression levels of NF-κB and pyroptosis markers in GCs. Moreover, this phenomenon could be partially reversed by the NF-κB inhibitor JSH-23. DEHP treatment also disrupted the normal expression of ovarian function-related genes and inhibited the proliferation of GCs. Reproductive system impairment was observed in mice exposed to DEHP. DEHP-treated mice had a lower body weight, smaller reproductive organs, fewer healthy follicles, and diminished ovarian reserve. Thus, DEHP contributes to ovarian dysfunction by inducing pyroptosis via the SLC39A5/NF-κB/NLRP3 axis in GCs.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
·
IF 3.8
Hao Zhao,Xin Lin,Qingfeng Chen,Xiaoyue Wang,Yongya Wu,Xiaoxia Zhao
Sepsis-induced cardiomyopathy (SIC) has high morbidity and mortality. Quercetin (QUE) has been used to treat many inflammatory diseases related to pyroptosis . However, its effect on SIC has not been reported before. We aimed to explore the therapeutic mechanism of QUE on SIC. We found that the expression levels of NOX2, markers of myocardial injury and inflammatory factors related to pyroptosis were upregulated in the serum of SIC patients. QUE improved the viability and reduced the death rate of LPS-treated H9C2 cells. It could downregulate the expression level of NOX2 and alleviate NOX2-induced mitochondrial damage to inhibit the ROS-mediated NF-κB/TXNIP pathway thus ameliorating cell pyroptosis. Overexpression of NOX2 partially attenuated the anti-pyroptotic effects of QUE on LPS-treated H9C2 cells in vitro. Besides, the results of animal experiments reported that the mitochondrial damage was reduced by QUE treatment, which subsequently inhibited the ROS-mediated NF-κB/TXNIP pathway to ameliorate cell pyroptosis to further alleviate myocardial injury in CLP-induced rats in vivo. To conclude, QUE suppressed the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve SIC.
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高影响因子
FASEB JOURNAL
·
2023
·Vol. 37
·期 6
·e22964
·
IF 4.8
Fei Sun,Cheng An,Can Liu,Ying Hu,Yue Su,Zhixiang Guo,Hong Che,Shenglin Ge
Cardiac ischemia/reperfusion (I/R) injury is a complicated pathological event, which has close association with pyroptosis. This study uncovered the regulatory mechanisms of fat mass and obesity-associated protein (FTO) in NLRP3-mediated pyroptosis during cardiac I/R injury. H9c2 cells were stimulated with oxygen–glucose deprivation/reoxygenation (OGD/R). Cell viability and pyroptosis were detected by CCK-8 and flow cytometry. Western blotting or RT-qPCR was performed to analyze target molecule expression. NLRP3 and Caspase-1 expression was observed by immunofluorescence staining. IL-18 and IL-1β production was detected by ELISA. The total m6A and m6A level of CBL was determined by dot blot assay and methylated RNA immunoprecipitation-qPCR, respectively. The interaction between IGF2BP3 and CBL mRNA was confirmed by RNA pull-down and RIP assays. The protein interaction between CBL and β-catenin and β-catenin ubiquitination were evaluated by Co-IP. Myocardial I/R model was established in rats. We determined infarct size by TTC staining and pathological changes by H&E staining. LDH, CK-MB, LVFS, and LVEF were also assessed. FTO and β-catenin were down-regulated, while CBL was up-regulated by OGD/R stimulation. FTO/β-catenin overexpression or CBL silencing restrained OGD/R-induced NLRP3 inflammasome-mediated pyroptosis. CBL repressed β-catenin expression via ubiquitination and degradation. FTO reduced the mRNA stability of CBL by inhibiting m6A modification. CBL-mediated ubiquitination and degradation of β-catenin were involved in FTO-induced pyroptosis inhibition during myocardial I/R injury. FTO inhibits NLRP3-mediated pyroptosis to attenuate myocardial I/R injury via repressing CBL-induced ubiquitination degradation of β-catenin.
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ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2021
·
IF 4.86
Jie Tang,Mingrong Bei,Jia Zhu,Guangtao Xu,Deqing Chen,Xin Jin,Jianzhong Huang,Jingjian Dong,Lili Shi,Long Xu,Bo Hu
Cadmium (Cd) exposure can exert an impact on carcinogenicity of breast cancer, however, the mechanism is not fully understood in triple-negative breast cancer (TNBC). We performed a TNBC MDA-MB-231 cell model and assessed the toxic effect of Cd exposure (0, 10, 20, 50, 60, 80 μM). Cd reduced cell viability in a time- and dose-dependent manner, followed by cell cycle arrest in S phase with alterations of cyclin 1A1, cyclin 1D1 and CDK2. Lactate dehydrogenase (LDH) release, apoptosis and pyroptosis were increased, which were relieved by z-VAD. Elevated ROS and NLRP3, caspase-1, IL-1β and IL-18 were detected, which was attenuated by N-acetylcysteine. Increased bax and decreased caspase-8, caspase-9 and caspase-3 were found. gasdermin E (GSDME) was activated with cleavage of GSDME-NT, which was retarded by z-VAD. Additionally, p38 MAPK signaling pathway was activated. Our data demonstrate GSDME-activated pyroptosis in Cd toxicity, implying a potential impact on TNBC.
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LABORATORY INVESTIGATION
·
2021
·Vol. 102
·期 1
·90-101
·
IF 5.662
Zhang Kailun,Chai Bo,Ji Hao,Chen liuqing,Ma Yanbing,Zhu Lifei,Xu Jingyu,Wu Yanqing,Lan Yinan,Li Hao,Feng Zhiguo,Xiao Jian,Zhang Hongyu,Xu Ke
Bioactive glass (BG) has recently shown great promise in soft tissue repair, especially in wound healing; however, the underlying mechanism remains unclear. Pyroptosis is a novel type of programmed cell death that is involved in various traumatic injury diseases. Here, we hypothesized that BG may promote wound healing through suppression of pyroptosis. To test this scenario, we investigated the possible effect of BG on pyroptosis in wound healing both in vivo and in vitro. This study showed that BG can accelerate wound closure, granulation formation, collagen deposition, and angiogenesis. Moreover, western blot analysis and immunofluorescence staining revealed that BG inhibited the expression of pyroptosis-related proteins in vivo and in vitro. In addition, while BG regulated the expression of connexin43 (Cx43), it inhibited reactive oxygen species (ROS) production. Cx43 activation and inhibition experiments further indicate that BG inhibited pyroptosis in endothelial cells by decreasing Cx43 expression and ROS levels. Taken together, these studies suggest that BG promotes wound healing by inhibiting pyroptosis via Cx43/ROS signaling pathway.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Lan Yang,Wenshuai Li,Kamiran Aihemaiti,Guangwei Jiang,Wenjia Gao,Hongyuan Li,Rongqin Huang
The limited immunogenic cell death (ICD) in tumors, particularly the difficulty in inducing pyroptosis, along with the persistence of breast cancer stem cells (BCSCs), lead to treatment resistance, relapse and metastasis in triple-negative breast cancer (TNBC). To counter these issues, a dual-drug nanoparticle was created by optimizing the encapsulation of clinical decitabine (DCT) and doxorubicin (DOX) into poly(lactic-co-glycolic acid) with a hyaluronic acid modification (DD@PH NPs). This platform targeted both TNBC cells and BCSCs via hyaluronic acid mediation. In 4 T1 cells, DCT was firstly and rapidly released from DD@PH NPs with programmed release feature to induce the up-regulation of gasdermin E through DNA demethylation, and then DOX was significantly released in acidic tumor environments to activate caspase-3 via mitochondrial damage. This process synergistically instigates pyroptosis in otherwise pyroptosis-resistant breast cancer cells, thereby enhancing ICD. Furthermore, the dual-drug release could depolymerize and eliminate BCSCs. Critically, this tumor pyroptosis and BCSCs death triggered a potent anti-tumor immune response, in terms of activating dendritic cells and T cells, and polarizing M2-type macrophages into M1-type. This immune response further inhibited both 4 T1 cells and BCSCs. As a result, the synergistic chemoimmunotherapy of DD@PH NPs led to improved therapeutic outcomes. These include significant inhibition of tumor development and metastasis in TNBC, demonstrating the potential from this nanomedicine for efficient TNBC treatment.
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JOURNAL OF ENVIRONMENTAL MANAGEMENT
·
2025
·
IF 8.4
Ke Li,Kun Wang,Tong Xu,Chencong Lyu,Xuejiao Yang,Hongjin Lin,Shiwen Xu
With the widespread application of the brominated flame retardant tetrabromobisphenol A (TBBPA), it poses a threat to human health, especially intestinal health. Quercetin (Que) is a flavonol compound with anti-inflammatory and antioxidant properties. However, whether Que can prevent TBBPA-induced intestinal toxicity remains unknown. Therefore, in this study, a TBBPA (75 μM) exposure model and a Que (0.1 μM) treatment model were established using mouse colon epithelial cells (MCEC). The p38 pathway, pyroptosis, and intestinal barrier function-related indicators were analyzed using an oxidative stress reagent kit, immunofluorescence staining, western blotting, and qRT-PCR. The results showed that TBBPA exposure dose-dependently reduced cell viability, impaired the antioxidant function of cells, promoted ROS accumulation, activated the p38 signalling pathway, induced pyroptosis, and decreased the expression levels of ZO-1, Occludin, and Claudin-1. Notably, Que treatment significantly restored the antioxidant enzyme activity in MCEC cells, reduced the ROS level, inhibited the p38 axis, alleviated MCEC cell pyroptosis, and recovered the intestinal barrier function. Further studies found that using LX-3 (a p38 activator) treatment disrupted the therapeutic effect of Que. In summary, Que can exert a protective effect by inhibiting the ROS-mediated p38 pathway, thereby alleviating the damage of TBBPA to MCEC cells.
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Biofabrication
·
2025
·
IF 8
Ruoyu Li,Wenfeng Li,Yungshan Teng,Runze Li,Siyi Kong,Xin Chen,Haotian Luo,Danying Chen,Yuqing Guo,Yangqiao Qing,Hio Cheng leong,Bingyan Guo,Meihan Chen,Zixin Pan,Shushuo Zheng,Yihong Deng,Yang Cao,Chen Zhou,Xuenong Zou,Weicai Wang
Craniofacial bone defect healing in periodontitis patients with diabetes background has long been difficult due to increased blood glucose levels which cause overproduction of reactive oxygen species (ROS) and a low pH environment. These conditions negatively affect the function of macrophages, worsen inflammation and oxidative stress, and ultimately, hinder osteoblasts' bone repair potential. In this study, we for the first time found that ANXA1 expression in macrophages was reduced in a diabetic periodontitis environment, with the activation of the NLRP3/Caspase-1/GSDMD signaling pathway, and, eventually, increased macrophage pyroptosis. Next, we have developed a new GPPG intelligent hydrogel system which was ROS and pH responsive, and loaded with Ac2-26, an ANXA1 bioactive peptide, and osteogenic peptide OGP as well. We found that Ac2-26/OGP/GPPG can effectively reduce ROS, mitigates macrophage pyroptosis via the ANXA1/NLRP3/Caspase-1/GSDMD pathway and enhanced osteogenic differentiation. The effect of Ac2-26/OGP/GPPG in regulation of pyroptosis and bone defect repair was also further validated by animal experiments on periodontitis-induced tooth loss model in diabetic rats. To conclude, our study unveils the effect of ANXA1 on macrophage pyroptosis in periodontitis patients with diabetes, based on which we introduced a promising innovative hydrogel system for improvement of bone defects repair in diabetic periodontitis patients via targeting macrophage pyroptosis and enhancing osteogenic potential.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Junjie Liu,Jingjing Liu,Yuxin Qiao,Hanxin Zhong,Jiaoxia Wei,Dongyang Han,Jin Peng,Yongzhou Feng,Danni Wang,Yujie Cheng,Haitao Lu,Li Yao
Ethnopharmacological relevance We previous study verified that decadienyl-L-carnitine (C10:2) biosynthesis has therapeutic-target capacity for RCE inhibiting pulmonary vascular remodeling to modulate experimental pulmonary hypertension(PH). However, the profound molecular mechanism remains incompletely elucidated. Aim of study This study aim to investigate whether C10:2 biosynthesis regulates pulmonary vascular remodeling by activating cell pyroptosis. Materials and methods Rats and pulmonary artery smooth musle cells (PASMCs) model with PH were successfully induced with monocrataline (MCT) and platelet-derived growth factor-BB (PDGF-BB) in present study. Following RCE treatment, cell targeted metabolomics assay combining biological information analysis and molecular biological methods were used to investigate the modulatory function of C10:2 on pulmonary vascular remodeling by activating cell pyroptosis and accordingly pharmacological mechanism of RCE against cell pyroptosis. Results We found that C10:2 activated NLRP3/Caspase-1/GSDMD signaling pathway to promote PASMCs pyroptosis, and decreased the level of azelaic acid in PASMCs. RCE can significantly upregulate miR-149-5p to targeting bind Cpt1a mRNA, thus, to decrease CPT1A expression, by which low level of C10:2 was maintained to further promote the biosynthesis of anti-inflammatory azelaic acid in vivo, along with this functional molecule is also one main compound of RCE. Our data further demonstrated that the biosynthesis of azelaic acid directly regulates NLRP3/Caspase1/GSDMD axis to inhibit pyroptosis by targeting NLRP3, we therefore argue that azelaic acid is a key functional compound of RCE for treating PH by inhibiting cell pyroptosis. Conclusion Collectively, our work characterized that azelaic acid is a key functional compound in RCE to express pharmacological efficacy against PH, which was observed to inhibit cell pyroptosis to ameliorate pulmonary vascular remodeling in rats through the regulation of decadienyl-L-carnitine/NLRP3/GSDMD axis. Such work will provide essentially molecular basis for developing anti-PH strategy and associated drug discovery.
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ADVANCED MATERIALS
·
2025
·
IF 26.8
Ying-Tao Zhong,Zi-Wen Qiu,Ke-Yan Zhang,Zhen-Ming Lu,Zhuo-Feng Li,Yi Cen,Shi-Ying Li,Hong Cheng
Immune checkpoint blockade (ICB) therapy has achieved remarkable benefits in the treatment of malignant tumors, but the clinical response rates are unsatisfied due to the low tumor immunogenicity and the abundant immunosuppressive cells. Herein, a plasma membrane targeted photodynamic nanoagonist (designated as PMTPN) is developed to potentiate ICB therapy by initiating tumor cell pyroptosis and depleting infiltrating B cells. PMTPN is composed of a rationally designed chimeric peptide sequence loaded with Bruton's tyrosine kinase inhibitor (Ibrutinib). Notably, PMTPN is capable of sequentially targeting tumor and tumor cell membrane to trigger immunogenic pyroptosis and cause overwhelming release of cytokines, promoting dendritic cells maturation, and cytotoxic T lymphocytes (CTLs) activation. Meanwhile, PMTPN can also deplete infiltrating B cells and reduce the secretion of interleukin-10 to decrease immunosuppressive regulatory T cells and enhance CTLs infiltration. Beneficially, the synergistic immune modulating characteristics of PMTPN potentiate ICB therapy to simultaneously eliminate primary and distant tumors. This study offers a promising strategy to elevate the immunotherapeutic response rate in consideration of the complex immunosuppressive factors.
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