Advanced Science
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2023
·Vol. 10
·期 14
·2207448
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IF 15.1
Jiahui Yan,Jingwen Zhang,Yanan Wang,Hong Liu,Xueping Sun,Aixin Li,Pengfei Cui,Liangmin Yu,Xuefeng Yan,Zhiyu He
Pyroptosis, systemic inflammation, and mitochondrial apoptosis are the three primary contributors to sepsis's multiple organ failure, the ultimate cause of high clinical mortality. Currently, the drugs under development only target a single pathogenesis, which is obviously insufficient. In this study, an acid-responsive hollow mesoporous polydopamine (HMPDA) nanocarrier that is highly capable of carrying both the hydrophilic drug NAD + and the hydrophobic drug BAPTA-AM, with its outer layer being sealed by the inflammatory targeting peptide PEG-LSA, is developed. Once targeted to the region of inflammation, HMPDA begins depolymerization, releasing the drugs NAD + and BAPTA-AM. Depletion of polydopamine on excessive reactive oxygen species production, promotion of ATP production and anti-inflammation by NAD + replenishment, and chelation of BAPTA (generated by BA-AM hydrolysis) on overloaded Ca 2+ can comprehensively block the three stages of sepsis, i.e., precisely inhibit the activation of pyroptosis pathway (NF- κ B-NLRP3-ASC-Casp-1), inflammation pathway (IL-1 β , IL-6, and TNF- α ), and mitochondrial apoptosis pathway (Bcl-2/Bax-Cyt-C-Casp-9-Casp-3), thereby restoring intracellular homeostasis, saving the cells in a state of “critical survival,” further reducing LPS-induced systemic inflammation, finally restoring the organ functions. In conclusion, the synthesis of this agent provides a simple and effective synergistic drug delivery nanosystem, which demonstrates significant therapeutic potential in a model of LPS-induced sepsis.
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Analytical Methods
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2024
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IF 2.7
Xiaoxia Lu,Wenlong Lu,Dong Hua
In the study, a novel surface-enhanced Raman scattering (SERS)-lateral flow assay (LFA) tray for the real-time detection of pyroptosis-associated miR-155-5p in breast cancer cells was established and validated. The SERS probe modified with monoclonal antibodies and functionalized HP1@5-FAM was first synthesized. When miR-155-5p was present, HP1@5-FAM on the SERS probe specifically recognized target miRNAs and hybridized with them, resulting in HP2 on the T line only capturing some SERS probes that were not bound to miR-155-5p. The T line appeared as a light orange band or there was no color change, and the corresponding Raman detection result showed a weak or insignificant Raman signal. The SERS probe showed high selectivity, satisfactory stability, and excellent reproducibility, and the limit of detection (LOD) for miR-155-5p was 7.26 aM. Finally, the proposed SERS-LFA tray was applied to detect miR-155-5p in MBA-MD-468 cells that underwent varying degrees of pyroptosis, and the detection results of SERS were consistent with those of the conventional real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. The study demonstrated that the SERS-LFA tray was a convenient and ultrasensitive method for miR-155-5p real-time detection, which could provide more detailed information for pyroptosis and be of potential value in guiding the treatment of breast cancer.
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CANCER LETTERS
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2024
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IF 9.1
Erbao Zhang,Qi Sun,Chang Zhang,Huimin Ma,Jing Zhang,Yue Ding,Guoqing Wang,Chen Jin,Chenying Jin,Yating Fu,Caiwang Yan,Meng Zhu,Cheng Wang,Juncheng Dai,Guangfu Jin,Zhibin Hu,Hongbing Shen,Hongxia Ma
Approximately 51 non-small-cell lung cancer (NSCLC) risk loci have been identified by genome-wide association studies (GWASs). We conducted a high throughput RNA-interference (RNAi) screening to identify the candidate causal genes in NSCLC risk loci. KIAA0391 at 14q13.1 had the highest score and could promote proliferation and metastasis of NSCLC in vitro and in vivo . We next prioritized rs3783313 as a causal variant at 14q13.1, by integrating a large-scale population study consisting of 27,120 lung cancer cases and 27,355 controls, functional annotation, and expression quantitative trait locus (eQTL) analysis. Then we found that rs3783313 could facilitate a promoter-enhancer interaction to upregulate KIAA0391 expression by affecting the affinity of transcription factor NFYA. Mechanistically, KIAA0391 knockdown dramatically influenced pyroptosis-related pathways and increased the expression of CASP1. And KIAA0391 transcriptionally repressed CASP1 by binding to SMAD2 and induced an anti-pyroptosis phenotype, promoting tumorigenesis of NSCLC, which provides new insights and potential target for NSCLC.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
·
IF 8.5
Xuefei Fu,Bing Yu,Lin Lu,Yafei Han,Yancheng Liu,Jingyu Zhang,Tao Chen,Defu Yu
Cartilage injury is one of the most prevalent, distressing, and disabling chronic conditions affecting degenerative joints worldwide; however, its underlying mechanisms remain elusive. Various biomaterials have been widely employed in the treatment of articular cartilage (AC) injuries. Despite these efforts, the key role of reactive oxygen species (ROS) as primary instigators of pyroptosis, combined with the lack of effective interventions, often results in suboptimal cartilage repair outcomes. Thus, there is an urgent need for the development of novel antioxidants and inflammasome-mediated pyroptosis modulators to create a favorable microenvironment for cartilage repair. In this study, we synthesized Prussian blue nanoparticles (PBNPs) capable of efficiently scavenging ROS. In vitro, these PBNPs protected against oxidative stress-induced cytotoxicity, preserved mitochondrial integrity, reduced the activation of nucleotide-binding domain and leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasomes and caspase-1, and subsequently downregulated gasdermin D (GSDMD) cleavage and inflammatory factor production, leading to the inhibition of chondrocyte pyroptosis. To extend these findings in vivo, we developed an injectable and photocurable methacrylate-silk fibroin (SilMA) hydrogel with homogeneously incorporated PBNPs, designed for releasing PBNPs. The resulting PBNPs@SilMA hydrogel decreased ROS production, reduced chondrocyte pyroptosis, and supported chondrocyte proliferation and matrix secretion, subsequently improved AC repair. Overall, our results indicate that the PBNPs@SilMA platform holds significant promise as a therapeutic strategy for AC injury.
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BRITISH JOURNAL OF PHARMACOLOGY
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2025
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IF 7.7
Yiling Mei,Xudong Chen,Si Shi,Wante Lin,Zhenfeng Cheng,Xiaoxi Fan,Wenqi Wu,Jibo Han,Weijian Huang,Bozhi Ye,Shanshan Dai
Background and Purpose Myocardial dysfunction is a significant complication associated with sepsis. However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)-mediated pyroptosis has shown promise in mitigating sepsis-induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI-Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI-Y2 offers a cardioprotective effect in the context of sepsis-induced myocardial dysfunction. Experimental Approach A mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI-Y2 or macrophage membrane-encapsulated GI-Y2 nanoparticles (GI-Y2@MM-NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI-Y2 in treating septic cardiomyopathy. Key Results We observed that GI-Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI-Y2 reduced macrophage pyroptosis and attenuated macrophage-mediated cardiomyocyte injury induced by LPS/nigericin. Concurrently, we confirmed the protective effect of GI-Y2 against LPS-induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI-Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI-Y2@MM-NPs to enhance the targeting capability of GI-Y2 towards macrophages in heart tissues and demonstrated its protective effect in vivo . Conclusion and Implications These findings indicate that GI-Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD-mediated pyroptosis and mitochondrial damage. Both GI-Y2 and GI-Y2@MM-NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction. Graphical
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ACS Nano
·
2024
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IF 15.8
Wenying Li,Dong Chen,Yanmei Zhu,Qiange Ye,Yang Hua,Ping Jiang,Ying Xiang,Yuejie Xu,Yinya Pan,Hua Yang,Yichun Ma,Hang Xu,Cheng Zhao,Chang Zheng,Changrong Chen,Yun Zhu,Guifang Xu
Current therapies primarily targeting inflammation often fail to address the root relationship between intestinal mucosal integrity and the resulting dysregulated cell death and ensuing inflammation in ulcerative colitis (UC). First, UC tissues from human and mice models in this article both emphasize the crucial role of Gasdermin E (GSDME)-mediated pyroptosis in intestinal epithelial cells (IECs) as it contributes to colitis by releasing proinflammatory cytokines, thereby compromising the intestinal barrier. Then, 4-octyl-itaconate (4-OI), exhibiting potential for anti-inflammatory activity in inhibiting pyroptosis, was encapsulated by butyrate-modified liposome (4-OI/BLipo) to target delivery for IECs. In brief, 4-OI/BLipo exhibited preferential accumulation in inflamed colonic epithelium, attributed to over 95% of butyrate being produced and absorbed in the colon. As expected, epithelium barriers were restored significantly by alleviating GSDME-mediated pyroptosis in colitis. Accordingly, the permeability of IECs was restored, and the resulting inflammation, mucosal epithelium, and balance of gut flora were reprogrammed, which offers a hopeful approach to the effective management of UC.
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Research
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2024
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IF 8.5
Guanrui Huang,Haotian Shen,Kaiwang Xu,Yifan Shen,Jiale Jin,Guangyu Chu,Hongyuan Xing,Zhiyun Feng,Yue Wang
While mesenchymal stem cell (MSC) shows great potentials in treating intervertebral disc degeneration, most MSC die soon after intradiscal transplantation, resulting in inferior therapeutic efficacy. Currently, bulk hydrogels are the common solution to improve MSC survival in tissues, although hydrogel encapsulation impairs MSC migration and disrupts extracellular microenvironment. Cell hydrogel encapsulation has been proposed to overcome the limitation of traditional bulk hydrogels, yet this technique has not been used in treating disc degeneration. Using a layer-by-layer self-assembly technique, we fabricated alginate and gelatin microgel to encapsulate individual MSC for treating disc degeneration. The small size of microgel allowed intradiscal injection of coated MSC. We demonstrated that pyroptosis was involved in MSC death under oxidative stress stimulation, and microgel coating suppressed pyroptosis activation by maintaining mitochondria homeostasis. Microgel coating protected MSC in the harsh disc microenvironment, while retaining vital cellular functions such as migration, proliferation, and differentiation. In a rat model of disc degeneration, coated MSC exhibits prolonged retention in the disc and better efficacy of attenuating disc degeneration, as compared with bare MSC treatment alone. Further, microgel-coated MSC exhibited improved therapeutic effects in treating disc degeneration via suppressing the activation of pyroptosis in the disc. For the first time, microgel-encapsulated MSC was used to treat disc degeneration and obtain encouraging outcomes. The developed biocompatible single-cell hydrogel is an effective strategy to protect MSC and maintain cellular functions and may be an efficacious approach to improving the efficacy of MSC therapy in treating disc degeneration. The objective of this study is to improve the efficacy of cell therapy for treating disc degeneration using single-cell hydrogel encapsulation and further to understand related cytoprotective mechanisms.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
·
IF 9.7
Jiaying Chang,Man Wang,Junrong Wang,Guoqing Zhu,Yulin Xie,Yanrong Qian,Qianqian Sun,Chunxia Li
Autologous tumor cells demonstrate considerable promise as individualized therapeutic vaccines owing to their endogenous neoantigen repertoire. Nevertheless, their suboptimal immunogenicity substantially impedes clinical translation. Herein, we engineered an innovative whole tumor cell vaccine platform utilizing photothermal Cu 2- x Se nanoparticles, which encapsulate comprehensive tumor-associated antigens and intrinsic immunostimulatory molecules to elicit a polyvalent antitumor immune response. In this work, Cu 2-x Se was applied to prepare the whole tumor cell vaccine for the first time. As a pyroptosis inducer, Cu 2-x Se triggered the expression of damage-associated molecular patterns (DAMPs) as endogenous adjuvants in 4T1 cells (mouse breast cancer cells) under near-infrared (NIR) irradiation. Repeated freeze-thaw cycles inactivated and lysed Cu 2-x Se-loaded 4T1 cells, releasing DAMPs for laser-activated Cu 2-x Se-based whole tumor cell vaccine (LC-TCV) preparation. Mild photothermal therapy (PTT) at the vaccination site by NIR irradiation effectively suppressed tumor growth. This efficacy was primarily attributed to the synergistic effects of multiple natural antigens and adjuvants in LC-TCV, which promoted dendritic cells (DCs) maturation and subsequent immune activation. Consequently, it potentiates the recruitment of cytotoxic T lymphocytes, elicits immunogenic cell death (ICD), and consequently initiates a potent antigen-specific immune cascade. Collectively, this study presents an innovative approach to unleash the potential of personalized whole tumor cell vaccines in cancer therapy.
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Molecular & Cellular Toxicology
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2025
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IF 1.4
He Chaojie,Fan Hongyan,Zhu Chunyan,Huang Yueqing
Background Ischemia–reperfusion (I/R) injury is a severe disorder during revascularization therapy against acute myocardial infarction. Objective Our study aims to investigate the role and regulation mechanism of Annexin A1 (ANXA1) against I/R injury. Results Western blotting analysis showed that ANXA1 expression in rat cardiomyocytes (H9C2 cells) was notably decreased by oxygen–glucose deprivation/reperfusion (OGD/R) treatment. Meanwhile, the NLRP3 inflammasome activation accompanied by pyroptosis and inflammation was observed in H9c2 cells under OGD/R induction. Besides, overexpression or knockdown of ANXA1 dramatically inhibited or aggravated NLRP3-mediated pyroptosis and inflammation. Further investigations found that the m 6 A level of ANXA1 was upregulated by OGD/R, thus leading to decreased mRNA stability in H9C2 cells. FTO, a N6-methyladenosine (m 6 A) “eraser”, was downregulated in H9C2 cells by OGD/R and shown to increase the ANXA1 protein expression by demethylating mRNA in H9c2 cells under OGD/R induction. Moreover, knockdown FTO reversed the protection of ANXA1 against NLRP3-mediated pyroptosis and inflammation in OGD/R-induced H9C2 cells. Conclusion ANXA1 protects cardiomyocytes against I/R injury by alleviating NLRP3-mediated pyroptosis and inflammation via FTO-mediate demethylation. These findings innovatively suggest the therapeutic potential of ANXA1 for myocardial I/R injury.
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Materials Today Bio
·
2025
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IF 10.2
Xiaoyuan Yi,Huaying Xie,Kunzhao Huang,Jianzhang Luo,Wen Li,Qingyu Zeng,Feifei He,Wuxiang Shi,Duo Wang,Liyan Wang
Activating a robust immune response is an effective strategy for achieving tumor eradication. In this study, copper-based metal-organic framework nanoparticles (referred to as FA-PZ@MOF NPs), which have the ability to simultaneously induce cuproptosis and pyroptosis in tumor cells, were designed to utilize the synergistic effects of cuproptosis and pyroptosis to trigger immunogenic cell death (ICD). This can inhibit tumor growth, migration, and metastasis while enabling efficient antitumor immunotherapy. The nano inducer targets hepatocellular carcinoma tumor cells via folic acid, dissociates and releases copper ions in the tumor microenvironment (TME), which has a high glutathione concentration, leading to copper ion overload, thereby mediating cuproptosis. Additionally, the released ZnO 2 generates substantial amounts of H 2 O 2 and Zn 2+ in the acidic environment, enhancing the Cu 2+ -based Fenton-like reaction for chemokinetic therapy. This exacerbates the reactive oxygen species (ROS) storms and mitochondrial damage, and combined with the action of Polyphyllin VI (PPVI), induces pyroptosis and cuproptosis. This multilayered interaction strategy also triggers robust ICD while inhibiting hepatocellular carcinoma tumor metastasis and invasion.
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PHYTOTHERAPY RESEARCH
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2024
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IF 6.1
Gang Kuang,Yisi Zhao,Liuyang Wang,Tingyu Wen,Panting Liu,Bei Ma,Qiaozhi Peng,Fang Xu,Lin Ye,Jing Fan
Acute hepatic injury (AHI) is associated with poor prognosis in sepsis patient; however, to date, no specific therapeutic approach has been established for this disease. Therefore, we aimed to explore the effects and action mechanisms of Astragaloside IV (AS) on AHI. C57BL/6 mice, RAW264.7 cells, and bone marrow-derived macrophages were used in this study. Sepsis-associated AHI model mice were established using lipopolysaccharide + D-galactosamine. Pathological examination of liver tissues and serum alanine aminotransferase/aspartate aminotransferase was performed to evaluate the liver function. Moreover, inflammatory cytokine levels, proportion of M1/M2 macrophages and their marker levels, and cell pyroptosis-related indicator levels were determined in the liver of the AHI model mice with or without AS treatment. AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) expression was determined after AS treatment. Additionally, inflammatory cytokine levels, liver injury, and macrophage polarization were evaluated after inhibiting the AMPK/SIRT1 pathway. AS alleviated lipopolysaccharide + D-galactosamine-induced AHI and inhibited inflammatory reactions in the blood and liver of mice. AS also promoted the M1-to-M2 phenotypic transformation of macrophages in the liver of AHI model mice and in vitro, thereby decreasing the pro-inflammatory cytokine levels and increasing the anti-inflammatory cytokine levels. AS increased AMPK and SIRT1 levels in the liver and macrophages. Furthermore, AS improved liver injury by elevating the expression of the AMPK/SIRT1 signaling pathway and inhibiting pyroptosis in macrophages. Overall, AS alleviated AHI by promoting M1-to-M2 macrophage transformation and inhibiting macrophage pyroptosis via activation of the AMPK/SIRT1 signaling pathway.
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FISH & SHELLFISH IMMUNOLOGY
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2022
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IF 4.622
Zhiying Miao,Zhiruo Miao,Xiaohua Teng,Shiwen Xu
Lead (Pb) has been concerned as one of the most severe hazardous contaminants, because it can cause pyroptosis in multiple tissues of mammals and birds. Melatonin (Mel) has attracted much interest for its role in governing intestinal injury via microRNAs (miRNAs). To explore the effect of Mel on Pb exposure-induced intestinal epithelial cell pyroptosis in common carps by regulating miR-17-5p/TXNIP axis, the Pb exposure and Pb-Mel treated models were constructed in vivo . The results elucidated that the suppressed expression of miR-17-5p and intensified level of TXNIP were primarily detected in Pb-exposed gut tissues, and both abolished with Mel addition, along with downregulated Pb-mediated elevated expression of NLRP3, CASP1, IL1β and GSDMD. Additionally, the targeting relationship between miR-17-5p and TXNIP were demonstrated by dual-luciferase reporter assay, and on this basis, miR-17-5p NC, mimic and inhibitor cell models were established. Thereby, Thereby, the expression of TXNIP in the miR-17-5p mimic groups was significant lower in the Pb-exposure but still elevated than the Control group, and the expression of NLRP3 and NLRP3-dependent pyrotposis-related genes performed consistent alterations. Noticeably, the expression of TXNIP suppressed with Mel addition even in the miR-17-5p inhibitor cell model, resulting in the inactivation of NLRP3 inflammasome-dependent pyroptosis. Overall, we draw the conclusion as Mel attenuates Pb-induced intestinal epithelial cell pyroptosis via miR-17-5p/TXNIP axis. The present study provides a novel perspective for toxicological mechanism of Pb, and new insights for the detoxification mechanism of Mel.
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