INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
·
IF 4.7
Wenyang Zhou,Zhenhao Liu,Xichuan Qiu,Minghao Tian,Baoqiang He,Chao Tang,Qiang Tang,Rupei Ye,Dejun Zhong,Yehui Liao
Following spinal cord injury (SCI), pyroptosis plays a significant role in regulating neuroinflammation during the secondary phase of injury. Although 1,8-cineole possesses anti-inflammatory effects, its role in SCI and underlying molecular mechanisms remains unclear. This study revealed that 1,8-cineole promoted motor function recovery in spinal cord-injured rats, reduced NLRP3 inflammasome-mediated microglial pyroptosis and activation, enhanced neuronal regeneration, and suppressed neuronal apoptosis and glial scar formation. Network pharmacology analysis showed that 1,8-cineole targets the PI3K/AKT and P38 MAPK pathways to inhibit microglial activation and pyroptosis. Finally, using a conditional co-culture system, we demonstrated that 1,8-cineole-treated microglia facilitated neuronal regeneration while inhibiting apoptosis. These findings indicate that 1,8-cineole promotes functional recovery post-SCI by protecting neurons by suppressing microglial pyroptosis and activation through the PI3K/AKT and P38 MAPK axes.
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Journal of Extracellular Vesicles
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2024
·Vol. 13
·期 12
·e70028
·
IF 15.5
Qimeng Liu,Tianliang Ma,Zheyu Zhang,Jiangyu Nan,Guanzhi Liu,Yute Yang,Yihe Hu,Jie Xie
The development of strategies for the prevention and treatment of aseptic loosening of prostheses stands as a critical area of global research interest. The pyroptosis of local macrophages triggered by wear particles plays a pivotal role in the onset of periprosthetic osteolysis and subsequent loosening. Extracellular vesicles, carrying the surface components and regulatory molecules of their parent cells, embody the cellular characteristics and biological functions of these progenitors. In a pioneering approach to precisely inhibit the pyroptosis of local macrophages induced by wear particles, we have engineered fused extracellular vesicles (fEV) from M 2 macrophages and human umbilical cord mesenchymal stem cells. These fEV boast the distinctive capability for targeted transport and immune evasion, collectively enhancing the anti‐pyroptosis effect of the therapeutic extracellular vesicles. Our research demonstrates the targeted, significant preventive and therapeutic potential of fEVs against periprosthetic osteolysis prompted by wear particles, highlighting its crucial clinical significance and application prospects. These findings suggest that extracellular vesicle fusion technology heralds a novel paradigm in the design and development of targeted extracellular vesicle‐based drug delivery systems.
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Chemical Biology & Drug Design
·
2019
·Vol. 94
·期 1
·1368-1377
·
IF 2.256
Liping Chen,Qian Li,Zhiwei Zheng,Jingwen Xie,Xiaoming Lin,Chengxi Jiang,Haineng Xu,Xiaoping Wu,Jianzhang Wu,Huajie Zhang
As NF-κB signaling pathway is constitutively activated in lung cancer, targeting NF-κB has a potential for the treatment. EF24 has been proved to be a NF-κB inhibitor with good antitumor activity, while whose toxicity possibly became one of the obstacles to enter into clinical application. In order to find high efficiency and low toxicity NF-κB inhibitors, EF24 was modified and 13d was screened out. It was proved that 13d possessed an effective combination of inhibiting NF-κB pathway and showing lower cytotoxicity on normal cells as well as less toxicity in acute toxicity experiment compared with the lead compound of EF24. In addition, 13d was found to inhibit cell vitality, arrest cell cycle in G2/M phase, promote cell apoptosis, and suppress the xenograft tumor growth. Furthermore, 13d was elucidated to induce pyroptosis developing from apoptosis, which was associated with the inhibition of NF-κB. Taken together, it was suggested that 13d was a potent antitumor agent.
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Materials Today Bio
·
2026
·
IF 11
Jing P,Wang L,Qiu X,Chen L,Xie D,Yu Y,Li B,Yan S,Wang G,Zhong Z,Fu W.
Effective cancer immunotherapy relies on robust infiltration and sustained functionality of tumor-resident cytotoxic CD8 + T cells. Here we report a magnetic resonance imaging (MRI)-visible nanotheranostic that integrates redox modulation, inflammatory cell death, and innate immune sensitization to establish a self-amplifying pyroptosis-STING-IFN-β circuit for CD8 + T cell immunoactivation. The nanotheranostic is constructed through manganese ion (Mn 2+ )-catalyzed oxidative polymerization of polyphenols, enabling engineered reactive oxygen species (ROS) generation and localized metal ion availability. Functionally, intracellular ROS triggers caspase-3-dependent gasdermin E (GSDME) cleavage and pyroptosis, while concomitant mitochondrial perturbation increases cytosolic mitochondrial DNA (mtDNA) and sensitizes the cGAS-STING pathway to Mn 2+ -enhanced activation, resulting in IFN-β production. IFN-β further reinforces dendritic cells maturation and CD8 + T cells priming, whereas inflammatory pyroptosis amplifies mtDNA availability, together forming a self-amplifying positive-feedback circuit that magnifies antitumor immunity. In vivo , this coordinated mechanism promotes effective CD8 + T cells infiltration and memory formation. Owing to its high longitudinal relaxivity, the nanotheranostic enables clear T 1 -weighted MRI contrast with pronounced tumor accumulation and prolonged retention, supporting imaging-guided immunotherapy. This work presents a functional materials strategy that couples mechanistic immune amplification with diagnostic imaging, offering a conceptual framework for translatable immunotheranostics.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Yanwei Lv,Mengni Jiang,Qiwen Jiang,Xinyuan Zhang,Yijie Xie,Yunyi Yang,Shige Wang,Lianghao Hu,Jiulong Zhao
Pyroptosis is involved in various inflammatory and fibrotic processes, but its specific role in the progression of chronic pancreatitis (CP) remains insufficiently explored. This study first investigated the dynamic expression changes of pyroptosis-related proteins during CP development and verified the regulatory effects of disulfiram (DSF) on key effector cells in CP, namely pancreatic stellate cells (PSCs) and macrophages. Building on these findings, a gut microenvironment-responsive nanoplatform, CuSe/DSF/EL nanoflowers, was designed and synthesized by integrating CuSe (as a carrier and selenium donor), DSF (as the core therapeutic agent), and Eudragit ® L100-55 (EL, a pH-sensitive polymer for intestinal targeting). Results demonstrated that the CuSe/DSF/EL nanoflowers exhibited excellent biocompatibility, robust antioxidant capacity, and efficient electrostatic targeting to inflamed pancreatic tissues via charge interactions. In vivo experiments using a mouse CP model confirmed that the nanoflowers significantly alleviated pancreatic inflammation, fibrosis, and pyroptosis, while effectively repairing pancreatic structure and restoring its function. Further RNA sequencing (RNA-seq) analysis revealed that the nanoflowers reversed CP-associated transcriptomic dysregulation, with a notable focus on correcting impaired pancreatic secretion pathways. This study clarifies the critical role of pyroptosis in CP pathogenesis and provides a novel, multi-mechanistic nanotherapeutic strategy for CP treatment by enhancing the bioavailability and targeting efficiency of DSF.
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RENAL FAILURE
·
2025
·
IF 3
Shuai Liu,Yuchen Gao,Jun Luo,Yanhua Chen,Heng Cao,Zhuifeng Guo,Hongmin Zhou,Zhongwen Hong,Bowen Chen,Xiao Xu,Jingcheng Zhang,Nengliang Duan,Xiangcheng Zhan,Xudong Yao,Tiancheng Xie,Yunze Dong,Yunfei Xu
Background Urolithiasis is one of the most common urological diseases, and its incidence has increased globally in recent years. Multiple potential mechanisms are involved in urolithiasis, including renal oxidative stress, inflammatory response, fibrosis, pyroptosis, and gut microbiota disturbance. Sodium bicarbonate (NaHCO3) is commonly used clinically to alkalize urine and slow the progression of chronic kidney disease, including urolithiasis. However, the specific mechanism of NaHCO3 in the treatment of urolithiasis is unclear.Methods In this study, we constructed a mice urolithiasis model via intraperitoneal injection of glyoxylate (50 mg/kg) for one week in C57BL/6 mice. Meanwhile, 5% NaHCO3 was added to drinking water in the treatment group. Biochemical detection, immunohistochemical staining, RT-qPCR, and Western blotting were used to assess kidney function and levels of inflammation and pyroptosis. The alteration of gut microbiota in mice treated with NaHCO3 was measured using 16S rDNA sequencing.Results The results demonstrated that NaHCO3 effectively reduced the deposition of CaOx crystal, as well as restored kidney function in urolithiasis-induced kidney injury mice. Moreover, NaHCO3 alleviated oxidative stress and inflammatory response and ameliorated pyroptosis by modulating the NLRP3 inflammasome pathway in kidney. Additionally, it enhanced the intestinal barrier function by up-regulating the expression of tight junction proteins (ZO-1, occludin, and claudin 5), remodeling the gut microbiota, and reducing intestinal inflammation.Conclusion In summary, NaHCO3 exerted a protective effect via the gut-kidney axis in the urolithiasis mice model, suggesting its potential use as a dietary supplementation to be added to daily drinking water for the management of urolithiasis.
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EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2024
·
IF 2.8
Shaoyi Cao,Huaqiu Li,Xiaoyan Ye,Xinxing Xing,Yonghuan Xie,Xiangfeng Zeng,Hongjiao Liu,Xing Zhong,Xinyi Yang,Wenxiu Xing,Cairong Zhu,Xiaoping Wu
Background The T790M mutation in the epidermal growth factor receptor ( EGFR ) gene is the primary cause of resistance to EGFR-tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients. Previous research demonstrated that certain traditional Chinese medicine (TCM) monomers exhibit anti-tumor effects against various malignancies. This study aims to investigate the potentials of shikonin screened from a TCM monomer library containing 1060 monomers in killing EGFR -T790M drug-resistant NSCLC cells and elucidate the underlying mechanisms. Methods MTT method was used to screen for the TCM monomers with significant killing effects on H1975 cells carrying the EGFR -T790M mutation. The influences of the identified monomer shikonin on cell growth were determined by the colony formation assay. Annexin-V/PI staining and JC-1 staining were applied to detect the effects of shikonin on cell apoptosis. The influences of shikonin on cell membrane integrity were detected by lactate dehydrogenase (LDH) release assay. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA as probe. The mechanisms of shikonin affecting the stability of cyclooxygenase-2 (COX-2) were evaluated by using specific inhibitors for protein degradation pathways. Western blotting was performed to assess the effects of the alteration of COX-2 expression or enzymatic activity on the related signal pathways as well as the apoptotic and pyroptotic markers. Results Shikonin was identified as a potent cytotoxic compound against EGFR -T790M-mutant NSCLC cells. Shikonin induced cell apoptosis and pyroptosis by triggering the activation of the caspase cascade and cleavage of poly (ADP-ribose) polymerase and gasdermin E by elevating intracellular ROS levels. Further investigations revealed that shikonin induced the degradation of COX-2 via the proteasome pathway, thereby decreasing COX-2 protein level and enzymatic activity and subsequently inhibiting the downstream PDK1/Akt and Erk1/2 signaling pathways through the induction of ROS production. Notably, COX-2 overexpression attenuated shikonin-induced apoptosis and pyroptosis, whereas COX-2 inhibition with celecoxib enhanced the cytotoxic effects of shikonin. Conclusions Combination treatment with shikonin and COX-2 inhibitor may be a suitable therapeutic strategy for EGFR -T790M-mutant NSCLC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-024-02187-7.
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FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Lei Diao,Wenjie Liu,Yawei Xu,Bin Zhang,Lingnan Meng,Rui Yin,Huijie Chen
Deoxynivalenol (DON) is one of the most common sources of fungal toxins in fish feed, posing a significant risk to the immune and reproductive systems of fish. Microalgal astaxanthin (MIA), a potent antioxidant derived from microalgae , confers multifarious advantages upon piscine organisms, notably encompassing its anti-inflammatory and antioxidant prowess. Herein, we investigated the potential of MIA in ameliorating the immunotoxicity of DON on carp (Cyprinus carpio L.) based on spleen lymphocytes treated with DON (1.5 ng/ml) and/or MIA (96 μM). Firstly, CCK8 results showed that DON resulted in excessive death of spleen lymphocytes. Secondly, spleen lymphocytes treated with DON had a higher proportion of pyroptosis , and the mRNA and protein levels of pyroptosis (NLRP3, IL-1β and ASC) in spleen lymphocytes were increased. Thirdly, the relative red fluorescence intensity of JC-1 and DCFH-DA showed decreased mitochondrial membrane potential and increased ROS in spleen lymphocytes treated with DON. Mitochondrial ATP, DNA and NADPH/NADP + analysis revealed decreased mitochondrial ATP, DNA and NADPH/NADP + levels in DON-treated lymphocytes, corroborating the association between DON exposure and elevated intracellular ATP, DNA and NADPH/NADP + in lymphocytes. DON exposure resulted in the downregulation of mitophagy-related genes and proteins (PINK1, Parkin and LC3) in lymphocytes. Notably, these effects were counteracted by treatment with MIA. Furthermore, DON led to the elevated secretion of inflammatory factors (TNF-α, IL-4 and IFN-γ), thereby inducing immune dysfunction in spleen lymphocytes. Encouragingly, MIA treatment effectively mitigated the immunotoxic effects induced by DON, demonstrating its potential in ameliorating pyroptosis, mitochondrial dysfunction and mitophagy impairment via regulating the mtROS-NF-κB axis in lymphocytes. This study sheds light on safeguarding farmed fish against agrobiological threats posed by DON, highlighting the valuable applications of MIA in aquaculture.
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ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Yating Sheng,Chengpeng Zhang,Dandan Cai,Guangtao Xu,Shipiao Chen,Weijian Li,Jingjian Dong,Bin Shen,Jie Tang,Long Xu
We have previously found that a mixture exposure of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand–receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Luyao Liu,Ruikun Wang,Weijuan Gao,Xianming Hou,Xiaofei Jin,Yanmeng Zhao,Xiaohong Zhou,Yi Zhang
Ethnopharmacological relevance Cerebral ischemia-reperfusion (I/R) injury is a common complication of ischemic stroke, with autophagy and pyroptosis playing key roles. Huangqi and Danggui (HQDG) are a commonly used drug pair of Chinese traditional medicine for clinical treatment of ischemic stroke. Aim of the study The study aims to investigate the interaction between autophagy and pyroptosis regulated by HQDG through the AMPK/mTOR signaling pathway during cerebral I/R injury. Materials and methods Model of middle-cerebral artery occlusion/reperfusion (MCAO/R) in SD rats was established using the Longa suture method. The components of traditional Chinese medicine were detected by liquid chromatography coupled to quadrupole orbitrap high resolution mass spectrometry (LC/MS). Neurological deficits were evaluated by neurological function score. Changes of cerebral blood flow were detected by a laser speckle blood flow imaging instrument. The volume of cerebral infarction was observed by 2,3,5-Chlorotriphenyltetrazolium (TTC) staining. The permeability of the blood-brain barrier was measured by Evans blue test. Neurovascular unit and autophagosomes in brain tissue were assessed by transmission electron microscopy. Neuronal pyroptosis was detected by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL)/Caspase-1 staining. The expression of autophagy related proteins, pyroptosis related proteins, and AMPK/mTOR pathway related proteins were detected by Western blot. Results After cerebral I/R injury, autophagy and pyroptosis, were characterized by increased number of autophagosomes and pyroptosis cells, upregulated expression of Beclin 1, LC3-II/LC3-I, NLRP3, cleaved Caspase-1, IL-1beta, IL-18 proteins, and downregulated expression of P62 proteins. HQDG significantly improved neurological function, reduced the volume of cerebral infarction, increased cerebral blood flow, improved blood-brain barrier permeability and the function of neurovascular units. Autophagy was further activated and pyroptosis was significantly inhibited by HQDG, which promoted increased number of autophagosomes, enhanced expression of Beclin 1, LC3-II/LC3-I proteins, reduced expression of P62, NLRP3, cleaved Caspase-1, IL-1beta, and IL-18 proteins, and downregulated the number of pyroptosis cells. On the other hand, after administering 3-Methyladenine (3-MA) to inhibit autophagy, the above effects of HQDG were significantly inhibited. Besides, HQDG promoted AMPK phosphorylation, and weakened mTOR phosphorylation. However, after the administration of AMPK inhibitor Compound C, HQDG caused increase in Beclin 1 and LC3-II/LC3-I, reduced P62 and NLRP3, and cleaved Caspase-1 protein expression, whereas cerebral blood flow decreased. Conclusion HQDG alleviated pyroptosis by promoting autophagy via AMPK/mTOR signaling pathway after middle-cerebral artery occlusion/reperfusion in rats, showing its potential for treatment of cerebral I/R injury in humans.
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SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Shanshan Li,Xuedie Gu,Muyue Zhang,Qihang Jiang,Tong Xu
Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n -acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yuao Feng,Zeliang Wu,Hui Liu,Rong Xu
Triple-negative breast cancer (TNBC) presents a formidable challenge due to its poorest prognosis and limited array of treatment options available. Photodynamic therapy (PDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to insufficient tumor accumulation and therapeutic resistance. Herein, an “all-in-one” tumor-therapeutic nanomedicine named HA@IR780@KU55933@BSA (HIKB) which integrated photosensitizer IR780 with ATM kinase inhibitor KU55933 was designed to facilitate drug delivery and target specific pathways involved in tumor PDT treatment resistance. Co-delivery of IR780 and KU55933 exacerbated intracellular ROS production, mitochondrial dysfunction and DNA damage to form a potent anti-TNBC therapeutic cyclical feedback loop and then induced pyroptosis and apoptosis of TNBC cells by activating the Caspase3/GSDME signaling pathway and regulating apoptosis-related protein expression, respectively. In vivo evaluations in the TNBC orthotopic xenograft mouse model demonstrated that the designed HIKB NPs could accumulate in tumor tissues and exert synergistic therapeutic effects. Altogether, this study described a self-assembling strategy for constructing an all-in-one nanomedicine that effectively integrates multiple therapeutic modalities to provide a comprehensive and systemic approach to tumor suppression.
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