Developmental Neurobiology
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2026
·Vol. 86
·期 4
·e70067
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IF 2
Jinping Jiang,Ling Fan,Yejun Zhao,Yanwen Wang,Minzhi He,Weinong Mo,Jianhong Li,Mengzao He
Neonatal hypoxic-ischemic brain damage (HIBD) is the leading cause of neonatal death and long-term neurological dysfunction. Dexmedetomidine (DEX) has been shown to have neuroprotective effects, but its mechanisms in HIBD remain incompletely understood. This study aimed to explore whether DEX inhibits neuroinflammation and pyroptosis via activating adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) axis, thereby reducing HIBD. A HIBD model was established. Histological staining observed the pathological changes and neuronal survival. Primary cortical neurons were cultured to establish an oxygen–glucose deprivation/reoxygenation (OGD/R) model. DEX was used for intervene, and siAMPK was transfected to knock down AMPK expression. Inflammatory and oxidative stress indicators within brain tissue and neuronal cells were measured using enzyme-linked immunosorbent assay (ELISA) and biochemical kits. The AMPK/SIRT1 pathway and pyroptosis protein expressions were evaluated using fluorescence staining and Western blot. DEX dose-dependently reduced cerebral infarction volume, improved cerebral cortex pathological damage, enhanced neuronal nuclei (NeuN) positive neurons, decreased interleukin (IL)-6 and malondialdehyde (MDA) contents, enhanced superoxide dismutase (SOD) activity, and inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)/cleaved Caspase-1 double positive cells and N-terminal domain of Gasdermin D (GSDMD-N) protein expressions. DEX significantly upregulated p-AMPK and SIRT1 expression, whereas the AMPK inhibitor Compound C reversed the neuroprotective effect of DEX. In vitro experiments confirmed that DEX increased neuronal cell viability, reduced lactate dehydrogenase (LDH) release and propidium iodide (PI)-positive cell rate, reduced oxidative stress, and inhibited inflammatory factor release and pyroptosis-related protein expression. AMPK knockdown significantly reversed this axis activation by DEX and attenuated the neuroprotective effect of DEX. In conclusion, DEX improved neurological function in HIBD rats via the activating AMPK/SIRT1 pathway, reducing neuroinflammation and inhibiting neuronal pyroptosis.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Huang Zhangrui,Yin Feiying,Tan Ying,Huang Yuqi,Li Tianjie,Ma Chuwen,Pang Zhiquan,Zhang Rongwei,Zhao Xin,Su Yongfeng,Zheng Li,Zhong Jingping,Liu Jianwei
Aberrant endoplasmic reticulum (ER)–mitochondria crosstalk at mitochondria-associated ER membranes (MAMs) drives oxidative stress, calcium dysregulation, pyroptosis, and ferroptosis in nucleus pulposus cells, accelerating intervertebral disc degeneration (IVDD). Nanozymes that mimic antioxidant enzymes and remodel the oxidative stress microenvironment are promising for IVDD treatment, but their efficacy is limited by low enzyme-like activity and poor targeting of MAMs. To address this, we developed a space-confined pyrolysis strategy to synthesize N/O co-doped hollow bamboo-like porous carbon nanotubes loaded with atomically Janus MnSe dual atoms, and functionalization with the MAM-targeting protein GRP75 and σ1R-regulator CGI1746 yielded GC-MnSe DA /BCNT, an integrated nanozyme platform for precise IVDD intervention. The hollow BCNT framework exposed atomically dispersed MnSe sites, while the MnSeN 5 O Janus active center optimizes Mn’s local electronic structure via Se-mediated p-d orbital hybridization, promoting electron transfer and lowering the reaction energy barrier, thereby boosting SOD-, CAT-, and GPx-like activities. This platform exhibited high biosafety and potent multi-enzyme antioxidant activity, enabling efficient ROS scavenging and inhibition of lipid peroxidation. Importantly, it restored the integrity of MAMs and mitochondrial function, maintained Ca 2 ⁺ homeostasis, and suppressed NLRP3-mediated pyroptosis and ferroptosis, thereby delaying IVDD progression. This work provides an efficient, safe, and precise new strategy for the treatment of degenerative and inflammatory diseases. Graphical abstract
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Journal of Pharmaceutical Analysis
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2026
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IF 11.2
Yi Liu,Haocheng Feng,Yi Chi,Siyan Zhu,Guting Gao,Enze Zhang,Liang Guo,Yang Pan,Po Hu
Black soybean oil (BSO) is a traditional Chinese medicine (TCM) for inflammatory skin disorders, yet its active basis remains unclear. Inspired by BSO preparation's similarity to carbon dot synthesis, we isolated fluorescent carbon-based nanoparticles (BSO-CNPs) from BSO. Analyses confirmed their characteristic nanostructure and fluorescence. Functionally, BSO-CNPs showed potent antioxidant activity, scavenging reactive oxygen species (ROS) and restoring cell viability under in vitro oxidative stress. In murine models of atopic dermatitis, topical BSO-CNPs alleviated clinical symptoms, reduced epidermal hyperplasia, suppressed mast cell infiltration, and downregulated inflammatory cytokines. Mechanistically, BSO-CNPs attenuate the NOD-like receptor family pyrin domain containing 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pyroptosis pathway by suppressing mitochondrial ROS and stabilizing lysosomal function. Furthermore, BSO-CNPs demonstrated high biosafety in vitro and in vivo . These findings elucidate the material basis of BSO’s therapeutic effects and highlight BSO-CNPs as a novel nanotherapeutic candidate for atopic dermatitis, bridging traditional herbal medicine with modern nanomedicine.
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BRAIN RESEARCH BULLETIN
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2026
·
IF 4.5
Chang ZHOU,Tian-shan LIANG,Yi-bo ZHAN,FU Shan-shan,XU Jian-peng,Yuan-qi ZHAO,Ze-quan ZHENG
Background The cerebral ischemia-reperfusion injury (CIRI) induced by endovascular treatment represents a research challenge. Microglial pyroptosis plays a critical role in the neuroinflammatory damage associated with CIRI. Gasdermin D (GSDMD) is a key executor of pyroptosis, mediating plasma membrane rupture. Interestingly, research on pyroptosis has long focused on cell membrane rupture. We further hypothesize that cytoskeletal collapse during pyroptosis may facilitate cell rupture. This new perspective will contribute to a comprehensive understanding of the mechanisms of morphological changes during pyroptosis. Recent research has proposed disulfidptosis, an emerging form of cell death characterized by cytoskeletal collapse. Therefore, we speculated that disulfidptosis might occur concurrently with pyroptosis-associated cell rupture, and investigated whether DSL could inhibit microglial pyroptosis and the associated disulfidptosis-related changes in a CIRI model. Materials Middle cerebral artery occlusion (MCAO) was established on rats, and the optimal dosage of DSL was determined. Neurological function, infarct volume, vascular diameter, cellular morphology, and key molecular mediators of microglial pyroptosis and disulfidptosis were tested. Furthermore, microglial mitochondrial fragmentation was investigated at the subcellular structural level. Results High-dose DSL (500 mg·Kg -1 d -1 ) significantly improved neurological function in rats. Moreover, high-dose DSL reduced infarct size and attenuated cellular shrinkage in the ischemic penumbra. GSDMD and SLC7A11 were co-localized in microglia. DSL suppressed the expression of pyroptosis-related proteins, including GSDMD-N-terminal, caspase-1 p10, and cleaved caspase-11. In addition, DSL mitigated SLC7A11 loss and inhibited the expression of NOX4 and ARP2. At the mitochondrial level, DSL alleviated microglial mitochondrial fragmentation and downregulated the expression of DRP1 and VDAC1. Conclusion Following CIRI, disulfiram suppressed pyroptosis by inhibiting the caspase-1/11-GSDMD pathway and attenuated disulfidptosis-like changes via modulation of the SLC7A11-NOX4-ARP2 axis, suggesting its potential neuroprotective effect.
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Frontiers in Immunology
·
2026
·
IF 7
Jianlong Li,Zhe Li,Pengran Wang,Zhian Jiang
PurposeMyocardial ischemia-reperfusion (I/R) is characterized by myocardial cell death and exacerbated inflammatory responses that seriously affect cardiac function and patient prognosis. Limonin is a natural compound extracted from citrus fruits and has various biological activities, including anti-inflammatory and antioxidant activities. However, the role and mechanism of action of limonin in myocardial I/R injury remain unclear. This study aimed to explore the effects and underlying mechanisms of action of limonin on myocardial cell pyroptosis and inflammatory responses in mouse myocardial I/R injury.MethodsBy analyzing the GSE225105 dataset in the Gene Expression Omnibus database, differentially expressed genes in I/R injury were screened and combined with the target genes of limonin in the Comparative Toxicogenomics Database. In the in vitro experiments, The oxygen-glucose deprivation/reoxygenation (OGD/R) model was used to simulate I/R injury in in vitro experiments.ResultsLimonin significantly inhibited OGD/R-induced pyroptosis and the release of inflammatory factors in AC16 myocardial cells, and these effects could be reversed by the caspase-3/gasdermin E (GSDME) pathway activator triclabendazole. Using in vivo experiments, we established a myocardial I/R model in C57BL/6 mice and found that limonin pretreatment improved cardiac function-related indicators, reduced myocardial tissue damage and inflammatory responses, inhibited apoptosis, and reduced myocardial fibrosis. This mechanism is closely related to the inhibition of caspase-3/GSDME pathway activation.ConclusionThis study revealed the protective effects of limonin in reducing myocardial I/R injury by inhibiting the caspase-3/GSDME pathway, thereby providing a theoretical basis for the development of limonin-based myocardial protection strategies.
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Materials Today Bio
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2026
·
IF 11
Rui Zhang,Xiaoyu Zhang,Jiangbo Guo,Yilin Yang,Junjie Niu,Hao Shen,Yi Zheng,Jiaqi Wang,Suhao Wang,Li Ni,Huilin Yang,Qin Shi
Intervertebral disc degeneration (IVDD) is the major pathological cause of low back pain and global disability. Its chronic and persistent inflammatory microenvironment, resembling a flowing flood to erode the ecosystems relentlessly, disrupts the intervertebral disc homeostasis. In the present study, we first verified that Notch signaling is negatively correlated with inflammation in IVDD samples. Meanwhile, we identified a natural flavonoid hesperetin (Hes) as a potential agonist of Notch1 by molecular docking predicting. Herein, we developed an EV-inspired bioactive reservoir system, in which the natural extracts hes was encapsulated into liposomes (Hes@lipo) and embedded within a gelatin methacryloyl (GM) hydrogel (GM/Hes@lipo)to achieve sustained release. By mimicking the extracellular matrix (ECM)-like microenvironment of the intervertebral disc (IVD), GM/Hes@lipo provided physiological environment for nucleus pulposus cells (NPCs) adhesion and growth maintenance. Furthermore, by activating Notch signaling, GM/Hes@lipo effectively restored the dynamic balance between pro- and anti-inflammatory cytokines and maintained ECM metabolic homeostasis, attenuating NOD-like receptor signaling, thereby inhibiting NPC pyroptosis. Based on these aspects, GM/Hes@lipo relieved the IVDD process, maintained annulus fibrosus integrity, and effectively alleviated discogenic pain after the platform was administrated into the intervertebral disc of the rats. Collectively, as an anti-inflammatory “flood-control” system, the Notch signaling-targeted biomimetic hydrogel presents a biomimetic–natural compound combinatorial strategy offering promising therapy for mitigating IVDD progression.
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Advanced Science
·
2025
·
IF 14.1
Sijie Wen,Dongsheng Tang,Lingpu Zhang,Hanchen Zhang,Zheng Cao,Kong Wai Tan,Xiaojun Wang,Haihua Xiao,Kun Shang
Zinc(II) complexes have emerged as promising antitumor agents due to their favorable biosafety and biocompatibility, and demonstrated effectiveness in photodynamic therapy (PDT). However, their therapeutic potential is limited by the poor tissue penetration of PDT agents. Herein, a novel zinc(II) complex designed for sonodynamic therapy (SDT), capable of producing substantial amounts of singlet oxygen upon ultrasonic activation, is introduced. This sonosensitizer effectively induces pyroptosis in breast cancer cells, significantly promoting the antitumor immune response. This work represents the first exploration of zinc(II) complexes in SDT, establishing a new avenue for enhanced therapeutic outcomes against breast cancer.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Xiaozhuo Ba,Xiaoqi Yang,Yu He,Tao Ye,Xiaoyong Zeng,ZiChen Zhong,XiaoLin Guo,Kun Tang
Kidney stones are among the most common renal diseases with high global incidence and recurrence rates, with calcium oxalate (CaOx) stones constituting 65.9% to 80% of all cases. Minimally invasive surgery remains the primary approach for kidney stones, while limited progress has been made in the drug therapy for CaOx kidney stones over the recent years. The limitations of traditional drug therapy, such as renal toxicity and poor targeting, along with an elusive pathogenesis of CaOx kidney stones, have prevented its widespread clinical application. Renal tubular epithelial cells injury has been reported to play a crucial role in the occurrence and development of CaOx kidney stones. Nanozymes with potent antioxidant and anti-inflammatory properties have the potential to treat CaOx crystal-induced kidney injury. Moreover, as a key stone inhibitor, potassium citrate is widely used to inhibit stone formation due to its ability to modify urinary chemistry. Herein, we designed citrate-coated Prussian blue nanozyme hitchhiking on the neutrophils (NM@CPBzyme) with injured kidney targeting capability and good biosafety. The results showed that NM@CPBzyme alleviated CaOx crystal-induced kidney injury and CaOx crystals deposition. On the one hand, NM@CPBzyme has been demonstrated to not only suppress oxidative stress but also chelate calcium ions, thereby facilitating crystal dissolution. On the other hand, NM@CPBzyme could mitigate neutrophil infiltration, NETosis and inhibit pyroptosis in vitro and in vivo. In addition, RNA sequencing and bioinformatic analysis further showed that NM@CPBzyme ameliorates CaOx crystal-induced kidney injury via oxidative stress and neutrophil mediated inflammatory response. In summary, our results revealed that NM@CPBzyme is a novel strategy for protecting against CaOx crystal-induced kidney injury.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
·
IF 5
Shuang Zhou,Yuhua Li,Yi Hong,Zhitao Zhong,Min Zhao
Puerarin (Pue), an isoflavone compound extracted from Pueraria, has been shown to inhibit inflammation and reduce cerebral edema. The neuroprotective effect of puerarin has attracted much attention in recent years. Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that causes damage to the nervous system. This study aimed to investigate the effect of puerarin on SAE and elucidate the potential underlying mechanisms. A rat model of SAE was established by cecal ligation and puncture, and puerarin was injected intraperitoneally immediately after the operation. Puerarin was found to improve the survival rate and neurobehavioral score of SAE rats, alleviate symptoms, inhibit the level of brain injury markers NSE and S100β, and improve the pathological changes in rat brain tissue. Puerarin was also found to inhibit the level of factors related to the classical pathway of pyroptosis, such as NLRP3, Caspase-1, GSDMD, ASC, IL-1β, and IL-18. Puerarin also reduced the brain water content and penetration of Evan’s Blue dye in SAE rats, and reduced the expression of MMP-9. In the in vitro experiments, we further confirmed the inhibitory effect of puerarin on neuronal pyroptosis by establishing a pyroptosis model in HT22 cells. Our findings suggest that puerarin may improve SAE by inhibiting the classical pathway of NLRP3/Caspase-1/GSDMD-mediated pyroptosis and reducing blood-brain barrier damage, thus playing a role in brain protection. Our study may provide a novel therapeutic strategy for SAE.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
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IF 3.8
Jiaxi Chen,Mengyue Pan,Jingjie Wang,Mengling Zhang,Mingmei Feng,Xiaoming Chai,Qi Zhang,Yang Sun
Hydroxysafflor yellow A (HSYA), a chalcone glycoside, is a component of Carthamus tinctorius L. and exerts anti-inflammatory and antioxidative effects. However, the therapeutic effect and the underlying mechanism of HSYA on ulcerative colitis is unclear. This study aimed to investigate the unexplored protective effects and underlying mechanisms of HSYA on UC. In vitro analyses showed that HSYA reduced the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 and inhibited nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD)-mediated pyroptosis in lipopolysaccharide/ adenosine-5′-triphosphate (LPS/ATP)-stimulated macrophages. Gas chromatography–mass spectrometry (GC–MS) profiling of intracellular metabolites showed that HSYA reduced the increased levels of glucose, glucose 6-phosphate, and lactic acid, and inhibited the increased hexokinase 1 (HK1) expression caused by LPS/ATP stimulation. HK1 shRNA transfection further confirmed that HSYA inhibited the NLRP3/GSDMD-mediated pyroptosis via HK1 downregulation. In vivo analyses showed that HSYA drastically attenuated UC symptoms by relieving body weight loss, a decline in colon length, and inflammatory infiltration in colonic tissues induced by dextran sulfate sodium (DSS). HSYA also reduced the secretion of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IL-18. Moreover, HSYA inhibited HK1/NLRP3/GSDMD-mediated pyroptosis in DSS-induced colitis mice. Finally, 16S rRNA sequencing analyses of gut microbiota revealed that HSYA reversed gut microbiota dysbiosis by reducing the abundance of Proteobacteria and increasing that of Bacteroidetes. This study demonstrated that HSYA not only exerted anti-inflammatory effects by inhibiting HK1/NLRP3/GSDMD and suppressing pyroptosis but also regulated gut microbiota in mice with DSS-induced colitis. Our findings provide new experimental evidence that HSYA might be a potential candidate for treating inflammatory bowel diseases.
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Advanced Science
·
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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INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
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IF 5.714
Shaomin Liu,Qiufang Chen,Liang Yan,Yuehong Ren,Jun Fan,Xingwang Zhang,Shiping Zhu
Inflammation mediates a variety of physiological and pathological events, prompting an importance of inflammation management for prevention and treatment of inflammatory diseases. This study formulated tripterine (Tri) into selenized phytosomes in an attempt to attenuate its cytotoxicity and potentiate its inflammation-regulating effect with selenium. Tri-loaded phytosomes (Tri-PTs) with selenium modification were prepared by a melting-hydration followed by in situ reduction technique. Then, selenized Tri-PTs ( [email protected] ) were characterized by particle size, entrapment efficiency, and transmission electron microscope. The in vitro drug release and cellular uptake were performed to examine the formulation performance of [email protected] The cytotoxicity and anti-inflammatory efficacy through inhibiting NLRP3 inflammasome activation and pyroptosis were appreciated in murine J774A.1 macrophage cell line, respectively. The resultant [email protected] presented a particle size of 125 nm around. [email protected] exhibited attenuated cytotoxicity and improved cellular uptake in macrophages compared with free Tri or Tri-PTs. Also, [email protected] inhibited the releases of caspase-1p20 and mature IL-1β, resulting in restriction of NLRP3 inflammasome activation that inhibits the formation of GSDMD-NT whereby to initiate pyroptosis. Altogether, our findings suggest that [email protected] can inhibit inflammatory response by regulating the NLRP3/caspase-1 pathway, which in turn reduces pyroptosis via suppressing the cleavage of GSDMD.
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