NATURE
·
2025
·
IF 48.5
Zhu Yunfeng,Xiao Fang,Wang Yiling,Wang Yufang,Li Jialin,Zhong Dongmei,Huang Zhilei,Yu Miao,Wang Zhirong,Barbara Joshua,Plunkett Christopher,Zeng Mengxue,Song Yiyan,Tan Tian,Zhang Ruibin,Xu Kezhen,Wang Zhongxing,Cai Changjie,Guan Xiangdong,Hammack Scott,Zhang Liang,Shi Zheng,Xiang Fu-li,Shao Feng,Xu Jie
Plasma membrane integrity is vital for nearly all aspects of cell functioning 1 . Mechanical forces can cause plasma membrane damage 2 , but it is not known whether there are large molecules that regulate plasma membrane integrity under mechanical strain. Here we constructed a 384-well cellular stretch system that delivers precise, reproducible strain to cultured cells. Using the system, we screened 10,843 siRNAs targeting 2,726 multi-pass transmembrane proteins for strain-induced membrane permeability changes. The screen identified NINJ1, a protein recently proposed to regulate pyroptosis and other lytic cell death 3,4 , as the top hit. We demonstrate that NINJ1 is a critical regulator for mechanical strain-induced plasma membrane rupture (PMR), without the need of stimulating any cell death programs. NINJ1 level on the plasma membrane is inversely correlated to the amount of force required to rupture the membrane. In the pyroptosis context, NINJ1 on its own is not sufficient to fully rupture the membrane, and additional mechanical force is required for full PMR. Our work establishes that NINJ1 functions as a bona fide determinant of membrane biomechanical properties. Our study also suggests that PMR across tissues of distinct mechanical microenvironments is subjected to fine tuning by differences in NINJ1 expression and external forces.
研究领域:
细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Gan Xin,Xie Jingwen,Dong Zhaojun,Wu Yuna,Zeng Xiaoqing,Yang Zhenzhen,Liu Bo,Zhu Min,Wang Bozhen,Li Wulan,Wang Ledan,Zhang Huajie,Wu Jianzhang,Hu Yue
Background: Pyroptosis, a cell death process triggered by chemotherapy drugs, has
emerged as a highly promising mechanism for combating tumors in recent years. As the lead of
new drugs, natural products play an important role in the discovery of anticancer drugs. Compared
to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior
safety profile. Among a series of MFHNP molecular skeletons, this study found that only
benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity
of 1 remains to be improved.
Aims: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by
modifying the chalcone structure.
Methods: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis,
several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer
activity was tested by MTT assay, and morphological indications of pyroptosis were observed
in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore,
to improve the activity of the chalcone skeleton, the anticancer group 3,4,5-
trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed,
synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally,
a quantitative structure-activity relationship (QSAR) model was established using the
eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore.
Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular
mechanisms of pyroptosis induced by the active compound.
Results: α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a
pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients
(R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these
compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was
found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing
the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft
tumors.
Conclusion: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis
axis and is a kind of promising pyroptosis inducer.
研究领域:
肿瘤学
·
药理学
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药物化学
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分子生物学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2026
·Vol. 34
·期 3
·1-12
·
IF 5
Chaochu Cui,Jinyu Zhao,Xiaoqian Li,Shengming Huang,Gang Liu,Xinhui Xu,Can Guo,Tiesuo Zhao,Jiang Du,Shipeng Li,Xianwei Wang,Jianbo Yang
Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.
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DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Chenglu Gu,Dongmei Wang,Shuang Zhu,Xue Wang,Xinyi Tian,You Liao,Zhanjun Gu
Hypoxia-related tumor radioresistance markedly impairs the efficacy of radiotherapy. Herein, a targeted radiosensitization strategy is introduced, leveraging the upregulation of gasdermin C (GSDMC) in hypoxic tumor cells, aiming to induce pyroptosis through the application of a cobalt-containing polyoxometalate-based radiosensitizer. This novel radiosensitizer is designed for the precisely controlled release of cobalt ions upon X-ray irradiation, thereby activating caspase-8 and prompting the cleavage of GSDMC. This sequence of events selectively triggers pyroptosis in hypoxic tumor cells, directly addressing radioresistance. The ensuing results highlight the enhanced radiotherapy efficacy and tumor necrosis both in vitro and in vivo models. Overall, the findings confirm the effectiveness of this strategy targeting high GSDMC expression in hypoxic tumors to induce pyroptosis for precise radiotherapy. Such findings encourage further exploration of hypoxia-driven pyroptosis to improve cancer treatment outcomes.
研究领域:
肿瘤学
·
放射生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Xinggang Fang,Zhuo Chen,Wenhui Zhou,Tongfei Li,Man Wang,Yujiu Gao,Shinan Ma,Ying Feng,Shiming Du,Peimin Lan,Hanyu Chen,Jiarui Wei,Sisi Zhang,Zixiang Li,Xinglin Liu,Hongbo Zhang,Xingrong Guo,Jie Luo
Glioblastoma (GBM) is a highly aggressive cancer that currently lacks effective treatments. Pyroptosis has emerged as a promising therapeutic approach for cancer, but there is still a need for new pyroptosis boosters to target cancer cells. In this study, it is reported that Aloe-emodin (AE), a natural compound derived from plants, can inhibit GBM cells by inducing pyroptosis, making it a potential booster for pyroptosis-mediated GBM therapy. However, administering AE is challenging due to the blood-brain barrier (BBB) and its non-selectivity. To overcome this obstacle, AE@ZIF-8 NPs are developed, a biomineralized nanocarrier that releases AE in response to the tumor's acidic microenvironment (TAM). Further modification of the nanocarrier with transferrin (Tf) and polyethylene glycol-poly (lactic-co-glycolic acid) (PEG-PLGA) improves its penetration through the BBB and tumor targeting, respectively. The results show that AE-NPs (Tf-PEG-PLGA modified AE@ZIF-8 NPs) significantly increase the intracranial distribution and tumor tissue accumulation, enhancing GBM pyroptosis. Additionally, AE-NPs activate antitumor immunity and reduce AE-related toxicity. Overall, this study provides a new approach for GBM therapy and offers a nanocarrier that is capable of penetrating the BBB, targeting tumors, and attenuating toxicity.
研究领域:
肿瘤学
·
神经科学
·
药理学
·
纳米医学
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DOI
PubMed
高影响因子
Science China-Life Sciences
·
2026
·
IF 9.6
Lei Mingzhu,Zhu Wenying,Wang Chao,Zhang Fan,Li Miaolin,Zhang Yi,Qu Jia,Luo Zhiguo,Li Jintao,Li Zeng-Xia,Yin Miao,Lei Qun-Ying
Pyroptosis is an inflammatory form of programmed cell death that plays a critical role in tumor immunity. However, the metabolic signals involved in this process remain undefined. In the present study, we uncover that methionine metabolism plays an important role in the pyroptosis of bone marrow-derived macrophages (BMDMs). The depletion of methionine adenosyltransferase 2A ( Mat2a ) in macrophages leads to cell death by activating GSDME, resulting in suppression of tumor growth in vivo. Furthermore, pharmacological inhibition of MAT2A induces macrophage pyroptosis by activating Gasdermin E (GSDME) but not Gasdermin D (GSDMD). Moreover, we identify a natural compound 1,2,3,4,6-O-pentagalloylglucose (PGG), not only inhibiting the enzymatic activity of MAT2A but also promoting its proteasome degradation through E3 ligase SMURF1-mediated polyubiquitylation. Consequently, PGG can induce pyroptosis by cleaving GSDME in various tumor cells and suppress tumor cell growth through enhancing anti-tumor immune response. Collectively, our findings reveal that MAT2A is an essential metabolic regulator of pyroptosis, and PGG could potentially boost anti-tumor immunity by targeting MAT2A.
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DOI
高影响因子
INFLAMMATION RESEARCH
·
2024
·
IF 4.8
Yue Xiyue,Lai Lunmeng,Wang Ruina,Tan Lulu,Wang Yanping,Xie Qing,Li Yunsen
Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14β-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1β. DGA significantly reduced the protein expression of IL-1β and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP.
研究领域:
药理学
·
炎症
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免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
·
2025
·Vol. 93
·期 5
·e70084
·
IF 2.4
Heng Wang,Zhaofei Liu,Xiangjun Xu,Haitao Zhang,Lei He,Ming Li
Background Chronic prostatitis (CP), a frequent male urological disease, is featured with chronic pelvic pain and various discomfort. Calycosin has anti-inflammatory effect and its exact mechanism in CP remains unknown. Objective Our research was designed to explain the underlying mechanism of calycosin in CP and illustrate our findings in the rats and LPS-ATP-induced RWPE-1 cells. Methods The pathology of prostate tissues was analyzed by HE staining and histological inflammation score. The concentration of inflammatory factors were detected via ELISA assay. Besides, the representative biomarkers of oxidative stress were measured through detection kits. The ROS production, NLRP3 and GSDMD expression were evaluated by immunofluorescence or immumohistochemical staining. Furthermore, the expression of NF-kBp65 pathway-associated proteins and pyroptosis-associated proteins were detected by western blotting. RWPE-1 cells growth and pyroptosis were assessed by CCK-8 and flow cytometry, respectively. mRNA levels of pyroptosis markers were detected by qRT-PCR analysis. Results The CP model in vivo and in vitro was successfully established by carrageenan and LPS-ATP, respectively. Calycosin substantially ameliorated the pathological damage of prostate tissue. Moreover, calycosin treatment promoted RWPE-1 cells viability and reduced pyroptosis. Calycosin remarkably reduced the inflammatory factors secretion and oxidative stress markers. Calycosin stimulation effectively suppressed the pyroptosis, which was linked with inactivation of the NF-kBp65 signaling pathway. These beneficial effects of calycosin were similar to the NLRP3 inhibitor (MCC950). Conclusion To sum up, our observations indicated that calycosin protects against CP via suppressing inflammation, oxidative stress, and pyroptosis through NF-kBp65 pathway, thereby serving as a promising therapy for CP treatment.
研究领域:
医学
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药理学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2026
·
IF 6.3
Fu-Wei Jiang,Jing-Han Lin,Jia-Xin Wang,Ming- Shan Chen,Shuo Liu,Hong-Mei Zhu,Yu-Sheng Shi,Ming Lou,Zi-Yan Hu,Yi Zhao,Jin-Long Li
As a widely used brominated flame retardant, tetrabromobisphenol A (TBBPA) is heavily utilized and has led to major concerns about its environmental and health implications. Although TBBPA has been detected in various environmental and biological matrices globally, its impact on the spleen and the underlying mechanisms remain poorly understood. HMGB1 is a protein released during pyroptosis which can trigger inflammation by activating the TLR4/MyD88/NF-κB pathway, leading to the production of inflammatory cytokines and chemokines. Nonetheless, its impact of HMGB1 on spleen damage caused by TBBPA is still uncertain. This study aims to explore the effect of TBBPA on spleen injury in mice and elucidates the role of HMGB1 in this process. In this study, male ICR mice were treated with TBBPA (50 mg/(kg·day)) for 28 days. Results showed that TBBPA induced splenic injury, characterized by white pulp reduction, red pulp congestion, lymphatic hyperplasia, and inflammatory infiltration. Moreover, vacuolation was observed in the mitochondria of the TBBPA exposed group, with the majority of mitochondrial cristae either disrupted or had vanished. Mechanistically, TBBPA upregulates HMGB1, which activates the TLR4/MyD88/NF-κB pathway and subsequently promotes NLRP3-mediated pyroptosis, ultimately exacerbating the inflammatory response. Our findings indicate that HMGB1 could be an effective target for addressing inflammatory and immune disorders.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Shiquan Sun,Yong He,Jiaqi Xu,Shaolong Leng,Yu Liu,Huanhuan Wan,Leping Yan,Yunsheng Xu
Despite the fact that immunotherapy has significantly improved the prognosis of melanoma patients, the non-response rate of monoimmunotherapy is considerably high due to insufficient tumor immunogenicity . Therefore, it is necessary to develop alternative methods of combination therapy with enhanced antitumor efficiency and less systemic toxicity. In this study, we reported a cancer cell membrane-coated zeolitic imidazole framework-8 (ZIF-8) encapsulating pyroptosis-inducer oxaliplatin (OXA) and immunomodulator imiquimod (R837) for chemoimmunotherapy. With the assistance of DNA methyltransferase inhibitor decitabine (DCT), upregulated Gasdermin E (GSDME) was cleaved by OXA-activated caspase-3, further inducing tumor cell pyroptosis , then localized antitumor immunity was enhanced by immune adjuvant R837, followed by triggering systemic antitumor immune responses. These results provided a proof-of-concept for the use of cell membrane-coated biomimetic nanoparticles as a promising drug carrier of combination therapy and a potential insight for pyroptosis-based melanoma chemo-immunotherapy.
研究领域:
肿瘤学
·
免疫疗法
·
纳米技术
·
癌症生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Xin Wang,Hao Yin,Ling Fan,Yiqun Zhou,Xiaolong Tang,Xiaojun Fei,Hailin Tang,Juan Peng,Junjun Zhang,Yi Xue,Jianping Luo,Qinglei Jin,Qingjiang Jin
Shionone is a triterpenoid component derived from the herbal medicine Aster tataricus , and it has been reported to possess marked anti-inflammatory properties. The activation of NLRP3 inflammasome plays an important role in cystitis, and the effect of Shionone on NLRP3 inflammasome-dependent pyroptosis remains unclear. In this study, we established an interstitial cystitis (IC) rat model and SV-HUC-1 cell model with CYP or LPS + ATP treatment to mimic inflammation response and induce NLRP3 inflammasome activation. Shionone treatment significantly attenuated the bladder wet weight, score of edema and hemorrhage, enhanced the viability of SV-HUC-1 cell, decreased the rate of pyroptosis. Moreover, Shionone reduced the expression of NF-κB, NLRP3, ASC, Pro-caspase-1, Caspase-1, GSDMD, GSDMD-N at the mRNA and protein levels both in rat and SV-HUC-1 cell model, demonstrating NLRP3 inflammasome pathway was blocked and pyroptosis degree was reduced. These results indicated that Shionone could alleviate interstitial cystitis in Rat model and enhancing the viability of SV-HUC-1 cells via NF-κB/NLRP3/GSDMD-N pathway, which illustrated that Shionone could be used as a drug candidate for the treatment of interstitial cystitis.
研究领域:
药理学
·
免疫学
·
泌尿学
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DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2025
·
IF 4.7
Shaoqi Sheng,Jiaxin Zhang,Licheng Yang,Zhuofan Diao,Yichen Zhang,Yue Wang,Haibao Peng,Wuli Yang
Pyroptosis has recently emerged as a promising therapeutic strategy owing to its unique advantages in inducing lytic cell death and eliciting immunogenic responses. Moderate induction of pyroptosis not only directly eliminates cancer cells but also activates antitumor immunity through the release of tumor-associated antigens and proinflammatory cytokines. However, most available pyroptosis inducers suffer from poor solubility, instability, and nonspecific biodistribution, which significantly hinder their translational potential. To address these challenges, we developed a pyroptosis-inducing delivery platform based on carboxybetaine zwitterionic nanogels for the efficient encapsulation of celastrol. These zwitterionic nanogels exhibit excellent resistance to protein adsorption and prolonged circulation in vivo. Upon drug release, celastrol promotes mitochondrial reactive oxygen species (ROS) accumulation, activates the caspase-3/GSDME axis, and triggers pyroptosis accompanied by immunogenic signals, including adenosine triphosphate (ATP) secretion, lactate dehydrogenase (LDH) release, and calreticulin (CRT) exposure. When combined with the anti-PD-1 checkpoint blockade, this platform further enhances dendritic cell maturation and antigen presentation, thereby amplifying pyroptosis-driven immune responses. In summary, our study demonstrates an effective strategy for inducing pyroptosis by integrating zwitterionic nanogel-mediated celastrol delivery with immune checkpoint inhibition, providing new insights and potential breakthroughs for cancer immunotherapy.
研究领域:
纳米医学
·
肿瘤免疫学
·
药物递送系统
·
分子肿瘤学
·
免疫治疗
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）