ANALYTICAL CHEMISTRY
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2025
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IF 6.7
Bin Li,Weikang Peng,Zhihang Jin,Shusheng Zhang,Lei Yang,Mingming Yu,Zhanxian Li
Pyroptosis, a specialized cell death mechanism crucial in cancer therapy, is distinct from apoptosis and primary necrosis. It is linked to inflammation and reactive oxygen species, particularly peroxynitrite (ONOO–), which is implicated in disease. Monitoring pyroptosis is challenging due to its connection with cellular polarity and the tumor environment. In this research, we developed a near-infrared probe, PBQI, which is highly sensitive and responsive to polarity and ONOO– fluctuations. PBQI targets mitochondria and lipid droplets, enabling real-time tracking of pyroptosis-associated subcellular alterations. It was found to differentiate between normal and cancer cells during pyroptosis triggered by cisplatin and metformin. To mitigate pyroptosis-induced inflammation, disulfiram was used as an inhibitor, significantly alleviating excessive inflammation. This study highlights PBQI’s utility in studying the interplay between polarity, ONOO–, and pyroptosis, and contributes to the development of more targeted cancer therapies that optimize pyroptosis’s antitumor benefits while minimizing inflammatory side effects.
研究领域:
生物化学
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肿瘤学
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药理学
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Lei Yang,Chao Song,Xiaofei Wu,Chaoqi Chen,Fei Liu,Feng Chen,Xiongqin Liang
Background In orthopedics, osteoarthritis (OA) is a prevalent joint damage condition. Pyroptosis is a modifiable cell death that relies on Gasdermin family proteins to create plasma membrane holes. One potential therapy approach for OA is to modulate pyroptosis proteins and inhibit the expression of inflammatory cytokines. Many researches have found that resveratrol can improve OA, but the molecular mechanism is still unclear. Method Using bioinformatics to find the pyroptosis proteins that are expressed in OA. The TCM database was used to extract the resveratrol proteins, and the intersection was used to determine the resveratrol therapeutic proteins for OA. Molecular docking was used to validate the results. Lastly, the invasion of immune cells was investigated. CCK-8 was used to determine the intervention concentration of resveratrol, protein detection, Q-PCR detection, and immunofluorescence assay was used to examine key proteins and genes. Results In OA, 14 pyroptosis proteins with differential expression were found. IL1β, IL6, and NLRP3 were further identified as significant hub genes. Furthermore, GSDMD, and CASP3 were found to be involved in the regulation of pyroptosis. CCK8 indicates that 10 μ mol/L resveratrol is the optimal intervention concentration for 24 h. Further cell experiments revealed that after intervention with resveratrol, the expression of pyroptosis and inflammation related proteins and genes was recovered. Among them, immunofluorescence assay once again confirmed that the key protein NLRP3 of pyroptosis was regulated in fluorescence intensity. Conclusion We showed that resveratrol attenuates OA via modulating apoptosis, pyroptosis, and immunological processes, these findings may offer a fresh approach to treating OA.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6
Huiyan Hu,Fan Zhang,Zhujun Sheng,Shuang Tian,Gechang Li,Shuanghui Tang,Yajie Niu,Jiawan Yang,Yunjun Liu
This paper introduces a new ligand, 4,6-dichloro-5-(1 H -imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy) 2 (DPPA)](PF 6 ) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq) 2 (DPPA)](PF 6 ) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq) 2 (DPPA)](PF 6 ) (2c) (piq denoting deprotonated 1-phenylisoquinoline). The cytotoxic effects of both DPPA and 2a, 2b, and 2c were evaluated against human lung carcinoma A549, melanoma B16 , colorectal cancer HCT116, human hepatocellular carcinoma HepG2 cancer cell lines, as well as the non-cancerous LO2 cell line using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. While DPPA exhibited moderate anticancer activity toward A549, B16, HCT116 and HepG2 cells, complexes 2a, 2b, and 2c displayed remarkable efficacy against A549, B16, and HCT116 cells. The cell colonies and wound healing were investigated. Moreover, various aspects of the anticancer mechanisms were explored. The cell cycle analyses revealed that the complexes block cell proliferation of A549 cells during the S phase. Complex 2c induce an early apoptosis, while 2a and 2b cause a late apoptosis. The interaction of 2a, 2b and 2c with endoplasmic reticulum and mitochondria was identified, leading to elevated ROS and Ca 2+ amounts. This resulted in a reduced mitochondrial membrane potential , mitochondrial permeability transition pore opening, and an increase of cytochrome c . Also, ferroptosis was investigated through measurements of intracellular glutathione (GSH), malondialdehyde (MDA), and recombinant glutathione peroxidase (GPX4) protein expression . The pyroptosis was explored via cell morphology, release of lactate dehydrogenase (LDH) and expression of pyroptosis-related proteins. RNA sequencing was applied to examine the signaling pathways . Western blot analyses illuminated that the complexes regulate the expression of Bcl-2 family proteins. Additionally, an in vivo antitumor study demonstrated that complex 2c exhibited a remarkable inhibitory rate of 58.58% in restraining tumor growth. In summary, the findings collectively suggest that the iridium(III) complexes induce cell death via ferroptosis , apoptosis by a ROS-mediated mitochondrial dysfunction pathway and GSDMD-mediated pyroptosis .
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
高影响因子
Nature Communications
·
2026
·Vol. 17
·期 1
·2565
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IF 18.1
He Mingbin,Wang Weiwei,Zhou Haiwu,Liu Cong,Zhao Chunbei,Li Jian,Han Yuewen,Qin Yali,Chen Mingzhou
Pyroptosis plays a crucial role in immune defense against infections and endogenous threats by eliminating harmful cells and modulating the immune response through inflammation. However, the natural activation of pyroptosis involves intricate signaling pathways, posing significant challenges for its artificial manipulation in research and therapies. Here, we present DAMAGE ( D e a th Ma nipulation Ge ne), an innovative system that integrates gasdermins within the type III-E CRISPR framework, enabling the specific recognition of target RNA (tgRNA) and triggering pyroptosis. This mechanism allows DAMAGE to selectively identify and eliminate virus-infected, cancerous, and senescent cells, all of which exhibit altered RNA transcriptomes. Additionally, DAMAGE exhibits considerable promise as a platform for mRNA-LNP therapy. Our study highlights the potential of this CRISPR-based system in the controllable induction of pyroptosis, offering an innovative therapeutic strategy for treating RNA-heterogeneous diseases.
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Acta Biomaterialia
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2026
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IF 10.4
Wenfeng Zeng,Juntao Xie,Yeqi Shen,Yiqiu Fu,Xinyi Wang,Wen Li,Qingyun Liu,Hanyue Li,Jiahui Cao,Yongkang Yu,Jisheng Xiao,Meitong Ou,Lin Mei
Immune suppression of tumor microenvironment (TME) limits the effectiveness of the immune therapy. Although inducing tumor cell pyroptosis and activating innate immunity are effective strategies to reverse this microenvironment, current methods are often hindered by non-targeted toxicity and the inability to precisely control drug release. To address these challenges, we synthesized an ROS-responsive R848 prodrug with a maleimide structure. Then, Hemin was coupled to bovine serum albumin (BSA) and the disulfide bonds within the BSA molecule were reduced, exposing free thiol groups. The R848 prodrug was then conjugated to the thiol groups, and the photosensitizer Ce6 was loaded, allowing self-assembly into the HBSA@CR nanoagonist. This strategy not only achieved a higher drug loading capacity than traditional albumin nanoparticles, but also retained the biocompatibility of natural albumin and the advantages of receptor-mediated cellular uptake. HBSA@CR can be activated by 660 nm laser irradiation to efficiently generate ROS through photodynamic and enzymatic catalysis. In vitro experiments show that this nanoparticle can efficiently kill tumor cells, induce pyroptosis through the Caspase-3/GSDME pathway and trigger the release of R848. In tumor-bearing mouse models, HBSA@CR effectively inhibited primary tumor growth and lung metastasis, and reprogrammed the immunosuppressive TME. In a tumor rechallenge model, this strategy prevented tumor recurrence and conferred long-lasting immunological memory. Moreover, when used in combination with the immune checkpoint inhibitor αPD-L1, this nanoparticle exhibits synergistic therapeutic effects. The designed nanoagonist offers a biomimetic platform for combined photo-immunotherapy, which achieves controlled R848 release while inducing tumor cell pyroptosis, reprogramming the immunosuppressive TME, and eliciting durable antitumor immunological memory. Statement of Significance The immunosuppressive tumor microenvironment is one of the main obstacles to effective immunotherapy, severely restricting the clinical efficacy. Inducing pyroptosis and stimulating innate immune activation are effective strategies for reprogramming the tumor microenvironment, but existing methods often face problems such as the lack of selectivity in inducing pyroptosis and the high toxicity of systemic administration of immune agonists. In this study, a nanoagonist HBSA@CR was constructed, which retains the biocompatibility and receptor-mediated tumor uptake of native albumin. This nanoplatform utilizes ROS to induce tumor cell pyroptosis and drive the controlled release of R848, achieving precise local pyroptosis induction and innate immune activation, effectively reprogramming the immunosuppressive microenvironment and stimulating persistent anti-tumor immune memory. Download: Download high-res image (309KB) Download: Download full-size image
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高影响因子
METABOLIC BRAIN DISEASE
·
2025
·Vol. 40
·期 8
·324
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IF 3.5
Tian Lei,Su Pan,Feng Gang,Peng Shuaijun,Liu Liming,Yan Xiangli,Liu Xianghua,Li Yucheng,Bai Ming,Wang Baoying,Xu Erping
Modified Xiaoyao San (MXYS) is a well-established clinical prescription for the treatment of depression in China. While MXYS shows considerable promise for the development of new antidepressants, its pharmacological mechanisms remain poorly understood. This study aims to investigate the antidepressant potential and underlying mechanisms of MXYS in lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Behavioral assessments (sucrose preference test, tail suspension test, open field test) demonstrated that MXYS significantly ameliorated LPS-induced anhedonia and behavioral despair. Histopathological and molecular analyses revealed that MXYS mitigated LPS-induced neuronal damage in the prefrontal cortex (PFC), restored dendritic spine density, and rebalanced neuroinflammatory cytokines by reducing the pro-inflammatory IL-1β and elevating the anti-inflammatory IL-10. Moreover, MXYS promoted microglial polarization toward the anti-inflammatory M2 phenotype (CD206⁺) while suppressing the pro-inflammatory M1 phenotype (CD68⁺). Mechanistically, MXYS inhibited NLRP3 inflammasome activation and pyroptosis through the upregulation of the E3 ubiquitin ligase TRIM31, which facilitated NLRP3 degradation. Transmission electron microscopy confirmed that MXYS inhibited LPS-induced microglial pyroptosis, as evidenced by reduced Gasdermin D (GSDMD) expression and preserved cellular ultrastructure. In vitro validation using LPS-stimulated BV2 microglia further corroborated the MXYS-mediated suppression of NLRP3 inflammasome activity, pyroptosis, and inflammatory cytokine dysregulation, alongside enhanced TRIM31 expression. Collectively, these findings demonstrate that MXYS exerts antidepressant effects by modulating neuroinflammation through TRIM31-dependent NLRP3 ubiquitination, microglial phenotype switching, and the inhibition of pyroptosis, providing novel insights into its therapeutic potential for the treatment of depression. Graphical
研究领域:
药理学
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神经科学
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免疫学
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中医中药
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分子生物学
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CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Shuxiang Xu,Shuyi Zhou,Luoyijun Xie,Wenlong Dou,Rongjun Zhang,Bingxia Zhao,Yang Xu,Xuemei Fu,Miaomiao Yuan
Due to the heterogeneous and complex tumor microenvironment (TME), it remains challenging to effectively treat solid tumors with monotherapy. The development of a versatile nanomaterial strategy for synergistic chemodynamic/photodynamic/photothermal therapies has the potential to overcome this challenge. Herein, we designed and synthesized NiS 2 /FeS 2 hybrid nanoparticles (NiS 2 /FeS 2 NPs), which are further modified with polyvinyl pyrrolidone (PVP) to improve their biocompatibility. PVP-NiS 2 /FeS 2 NPs exhibit synergistic activities of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) with multimodal imaging capabilities. With the presence of Fe 2+ /Fe 3+ and Ni 2+ /Ni 3+ redox couples, the PVP-NiS 2 /FeS 2 NPs exhibit GSH peroxidase-like reactivity and trigger Fenton reaction, leading to robust ·OH generation and pyroptosis/ferroptosis after near infared irradiation (NIR). In response to the PVP-NiS 2 /FeS 2 NPs and PVP-NiS 2 /FeS 2 NPs + NIR treatment, the breast tumors formed in the syngeneic BABL/c mice were eliminated and their metastases suppressed by inhibiting the EMT pathway. Consistent with the apparent involvement of these programmed cell death pathways in activating tumor immunity, we demonstrate that PVP-NiS 2 /FeS 2 NPs + NIR can eliminate metastatic tumors in an immune system dependent manner. Therefore, PVP-NiS 2 /FeS 2 NPs represent a promising strategy to treat metastatic breast cancer.
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Scientific Reports
·
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.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Chai Yuhui,Cai Yawen,Fu Yu,Wang Yingdi,Zhang Yiming,Zhang Xue,Zhu Lingpeng,Miao Mingxing,Yan Tianhua
Depression is a common and serious mental disorder. Data on its pathogenesis remain unclear and the options of drug treatments are limited. Here, we explored the role of pyroptosis, a novel pro-inflammatory programmed cell death process, in depression as well as the anti-depression effects and mechanisms of salidroside (Sal), a bioactive extract from Rhodiola rosea L. We established a corticosterone (CORT)-induced or lipopolysaccharide (LPS)-induced mice in vivo, and CORT, or nigericin (NLRP3 agonist)-induced PC12 cells in vitro. Our findings demonstrated that Sal profoundly mediated CORT or LPS-induced depressive behavior and improved synaptic plasticity by upregulating the expression of brain-derived neurotrophic factor (BDNF) gene. The data showed upregulation of proteins associated with NLRP3-mediated pyroptosis, including NLRP3, cleaved Caspase-1, IL-1β, IL-18, and cleaved GSDMD. The molecular docking simulation predicted that Sal would interact with P2X7 of the P2X7/NF-κB/NLRP3 signaling pathway. In addition, our findings showed that the NLRP3-mediated pyroptosis was regulated by P2X7/NF-κB/NLRP3 signaling pathway. Interestingly, Sal was shown to ameliorate depression via suppression of the P2X7/NF-κB/NLRP3 mediated pyroptosis, and rescued nigericin-induced pyroptosis in the PC12 cells. Besides, knock down of the NLRP3 gene by siRNA markedly increased the inhibitory effects of Sal on pyroptosis and proinflammatory responses. Taken together, our findings demonstrated that pyroptosis plays a crucial role in depression, and Sal ameliorates depression by suppressing the P2X7/NF-κB/NLRP3-mediated pyroptosis. Thus, our study provides new insights into the potential treatment options for depression.
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ACS Nano
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2022
·
IF 18.027
Yuan Chen,Ruiheng Luo,Jing Li,Shengfeng Wang,Jinsong Ding,Kai Zhao,Ben Lu,Wenhu Zhou
Sepsis, a life-threating illness caused by deregulated host immune responses to infections, is characterized by overproduction of multiple reactive oxygen and nitrogen species (RONS) and excessive pyroptosis, leading to high mortality. However, there is still no approved specific molecular therapy to treat sepsis. Here we reported drug-free tea polyphenols nanoparticles (TPNs) with intrinsic broad-spectrum RONS scavenging and pyroptosis-blocking activities to treat endotoxin (LPS)-induced sepsis in mice. The RONS scavenging activities originated from the polyphenols-derived structure, while the pyroptosis blockage was achieved by inhibiting gasdermin D (GSDMD) mediating the pore formation and membrane rupture, showing multifunctionalities for sepsis therapy. Notably, TPNs suppress GSDMD by inhibiting the oligomerization of GSDMD rather than the cleavage of GSDMD, thus displaying high pyroptosis-inhibition efficiency. As a result, TPNs showed an excellent therapeutic efficacy in sepsis mice model, as evidenced by survival rate improvement, hypothermia amelioration, and the organ damage protection. Collectively, TPNs present biocompatible candidates for the treatment of sepsis.
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PHYTOMEDICINE
·
2021
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IF 5.34
Yan Guo,Jie-hong Yang,Yu He,Hui-fen Zhou,Yu Wang,Zhi-shan Ding,Bo Jin,Hai-tong Wan
Background Pyroptosis is a pro-inflammatory cell death characterized by the formation of inflammasomes . Abnormal inflammation in brain microvascular endothelial cells (BMECs) has been correlated with ischemic stroke . Protocatechuic aldehyde (PCA) is a hydrophilic phenolic acid derived from the traditional Chinese herb Salvia miltiorrhiza with significant anti-inflammatory effects. However, the mechanism of PCA on BMEC pyroptosis under ischemic injury has been largely unexplored. Purpose We aimed to study the effects and mechanism of PCA on BMEC pyroptosis under ischemic injury. Methods Sprague-Dawley (SD) rats were injected through the tail vein with different concentrations of PCA after transient middle cerebral artery occlusion (MCAO) was performed. The protective effects of PCA in SD rats were examined via neurological scores, infarct volume evaluation, and anti-pyroptosis effects using immunofluorescence staining and western blot . Rat BMECs (rBMECs) were treated with different concentrations of PCA after oxygen and glucose deprivation (OGD). The ability of PCA to protect rBMECs was examined via cell viability , anti-oxidative activity, and anti-pyroptosis effects as determined by qRT-PCR and western blot. Additionally, the role of lncRNA Xist in anti-pyroptosis responses of PCA-treated rBMECs was validated with lncRNA Xist siRNA . Results We found that treatment with MCAO and OGD increased the expression of NOD-like receptor protein 3 , gasdermin D, Caspase-1, interleukin-1β, and NIMA-related kinase 7, which was reversed by treatment with PCA or MCC950 (a pyroptosis inhibitor). In addition, PCA reduced the cerebral infarct volume in MCAO rats and promoted cell survival and proliferation in OGD/reperfusion-treated rBMECs. PCA enhanced the antioxidant activity and mitochondrial membrane potential in rBMECs. PCA also enhanced lncRNA Xist expression, and when the expression of lncRNA Xist was silenced, PCA could not alleviate pyroptosis well in rBMECs. Conclusion Protocatechuic aldehyde prevents ischemic injury by attenuating rBMEC pyroptosis via lncRNA Xist.
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FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Kaiyuan Chen,Yahui Tang,Linhua Lan,Mengxuan Li,Zhongqiu Lu
Acute kidney injury (AKI) induced by diquat (DQ) progresses rapidly, leading to high mortality, and there is no specific antidote for this chemical. Our limited knowledge of the pathogenic toxicological mechanisms of DQ has hindered the development of treatments against DQ poisoning. Pyroptosis is a form of programmed cell death and was recently identified as a novel molecular mechanism of drug-induced AKI. To explore the role of pyroptosis in HK-2 cells exposed to DQ, the plasma membrane damage of the cells was detected by LDH release assay. Western blot was performed to detect the cleavage of GSDME. Proteomics analysis was performed to explore the mechanism of DQ induced nephrotoxicity . FerroOrange probe was used to measure the intracellular Fe 2+ levels. Herein, we show that DQ induces pyroptosis in HK-2 cells. Mechanistically, DQ induces the accumulation of mitochondrial ROS and initiates the cleavage of gasdermin E (GSDME) in an intrinsic mitochondrial pathway. Knockout of GSDME attenuated DQ-induced cell death. Further analysis revealed that loss of FTH1 induces Fe 2+ accumulation, contributing to DQ-induced pyroptosis. Knockdown LC3B could help restore the expression of FTH1 and improve cell viability . Moreover, we found DFO , an iron chelator , could reduce cellular Fe 2+ levels and inhibit pyroptosis. Collectively, these findings suggest an unrecognized mechanism for GSDME-dependent pyroptosis in DQ-induced AKI.
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