EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
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IF 4.2
Yiming Sun,Hui Cai,Daofeng Yang,Nengyi Yu,Lejie Sun,Jingxuan Xu,Hongwei Yuan,Rong Yang,Lele Song,Hao Liu,Chengyao Ma,Zhe Liu
β-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of β-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and β-arrestin2 −/− mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the β-arrestin2 −/− CMS group, these results of the β-arrestin2 −/− CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out β-arrestin2. Mass spectrometry implying that FLX promoted the binding of β-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT 2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to β-arrestin2. We further found that the lack of β-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, β-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT 2B R-β-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.
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CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 5
·e70437
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IF 5
Hai‐Qian Zhang,Yan Wang,Xiao Geng,Mingxin Dong,Ziwei Liu,Chengbiao Sun,Kaikai Yu,Wenwen Xin,Ye Xu,Na Xu,Wensen Liu
ANG‐modified liposomes encapsulating α‐melittin and resveratrol increase their blood–brain barrier penetration and GB cell selectivity. The combined treatment of α‐melittin with resveratrol markedly facilitates apoptosis and pyroptosis, and promotes the apoptosis–pyroptosis switch in the GB cells via downregulating the Wnt/β‐catenin signaling.
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Frontiers in Pharmacology
·
2024
·
IF 4.4
Chencen Lai,Shuo Zhang,Zhiyu Chen,Xiaoyu Fu,Min Zhang,Pengjiao Wang,Xiuli Gao
Pyroptosis induced by oxidative stress is a significant contributor to mental health disorders, including depression (+)-Catechin (CA), a polyphenolic compound prevalent in various food sources, has been substantiated by prior research to exhibit potent antioxidant properties and potential antidepressant effects. Nonetheless, the precise antidepressive mechanisms and effects of CA remain incompletely elucidated. In this study, we employed corticosterone (CORT) and PC12 cells to develop a cellular model of depression, aiming to investigate the protective effects of CA against CORT-induced cellular damage. Our objective was to elucidate the underlying mechanisms of protective action. We utilized transcriptomic analysis to identify differentially expressed genes and employed bioinformatics approaches to predict the potential mechanisms of CA’s protective effects in PC12 cells. These transcriptomic predictions were subsequently validated through western blot analysis. The findings indicated that CA possesses the capacity to mitigate oxidative stress and suppress pyroptosis in PC12 cells via the activation of the PI3K/AKT signaling pathway. This activation subsequently modulates the Nrf2/HO1/NF-κB pathways, thereby providing protection to PC12 cells against damage induced by CORT. Furthermore, we investigated the interaction between CA and the Keap1 protein employing molecular docking and protein thermal shift assays. We propose that CA can activate Nrf2 through two mechanisms to decrease reactive oxygen species (ROS) levels and inhibit pyroptosis: one mechanism involves the activation of the PI3K/AKT signaling pathway, and the other involves direct binding to Keap1, leading to an increase in p-Nrf2.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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生物信息学
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ADVANCED FUNCTIONAL MATERIALS
·
2026
·
IF 19
Wenjia Liu,Nina Zhang,Xu Guo,Xiaofan Zhang,Ying Wang,Jinchao Zhang,Kun Ge,Guoqiang Zhou
Immunotherapy is rapidly emerging as a potent, targeted therapy for breast cancer. However, the low immunogenicity and immunosuppressive tumor microenvironment (TME) in breast cancer limit its efficacy. In this study, a novel nanoreactor, CeO 2 :Mn (CM) embedded with the zeolitic imidazolate framework-90 (ZIF-90) and loaded with 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), is developed and designated CeO 2 :Mn/ZIF-90/ABTS (CMZA). Zn 2+ release from ZIF-90 degradation in the TME triggers pyroptosis and elevates intracellular •O 2 − levels by inhibiting the electron-transport chain. Furthermore, the CM nanozyme exhibits multienzyme activities, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), which convert •O 2 − to H 2 O 2 , generate •OH, produce O 2 , and oxidize ABTS to oxidized ABTS (oxABTS). The oxABTS exhibits strong near-infrared absorption and converts 808 nm light into heat, enhancing CM catalysis and depleting intracellular glutathione (GSH), thereby further amplifying the accumulation of reactive oxygen species (ROS). Collectively, CMZA induces NLRP3/c-Caspase-1/GSDMD-N pyroptosis through Zn 2+ release and photothermal-enhanced multienzyme activity, reshaping the TME and boosting immunogenicity to limit tumor progression and metastasis.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Rucui Yu,Yan Zhang,Ruiying Wu,Jingwei Xu
Objective Mitochondrial dysfunction and dysregulated cell death are key drivers of diabetic kidney disease (DKD) progression. This study aimed to construct CD44-targeted chitosan (Cs) nanoparticles encapsulating ginsenoside Rg1 (CD44-Cs@Rg1) for targeted delivery, and to evaluate their ability to regulate autophagy, pyroptosis, and mitochondrial function in DKD. Methods CD44-Cs@Rg1 nanoparticles were synthesized using a covalent modification strategy. Their targeting uptake, effects on GSDMD-mediated pyroptosis, autophagic flux, and energy metabolism were systematically evaluated in renal tubular epithelial cells under high-glucose (HG) conditions and in DKD mouse models. Mitochondrial function was assessed by Western blotting, immunostaining, MitoSOX, JC-1, and ATP assays. Transcriptomic profiling and pharmacological interventions were applied to elucidate the involvement of the AMPK/mTOR signaling axis. Results CD44-Cs@Rg1 nanoparticles were efficiently internalized by renal tubular epithelial cells, significantly reducing pyroptosis while restoring autophagic flux through AMPK activation and mTOR inhibition. These effects improved mitochondrial membrane potential, reduced reactive oxygen species accumulation, and enhanced ATP production. In vivo , CD44-Cs@Rg1 treatment markedly ameliorated renal dysfunction and histopathological injury in DKD mice. Transcriptomic and protein-level analyses consistently revealed enrichment of pathways related to AMPK signaling, autophagy, and energy metabolism. Conclusion CD44-targeted Cs nanoparticles enable precise delivery of ginsenoside Rg1 to renal tubular cells in DKD, restoring mitochondrial homeostasis and regulating autophagy–pyroptosis balance via the AMPK/mTOR axis. This nanotherapeutic platform demonstrates strong translational potential for DKD treatment.
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Chinese Medicine
·
2026
·Vol. 21
·期 1
·40
·
IF 5.7
Yao Qianfang,Hu Guishan,Yin Can,Wu Anguo,Hu Guangqiang,Qin Dalian,Zhou Xiaogang,Law Betty Yuen-Kwan,Du Xi,Chen Li,Li Jianqiao,Lin Hong,Long Xin,Wu Jianming,Yu Lu
Background Cerebral ischemia/reperfusion injury (CI/RI) remains a critical barrier to effective ischemic stroke (IS) treatment. While mitophagy activation has been shown to attenuate apoptosis and pyroptosis, thereby ameliorating CI/RI, the therapeutic potential of natural compounds targeting this pathway remains underexplored. Penthorum chinense Pursh (PCP), a traditional hepatoprotective herb, contains Thonningianin A (TA), a bioactive compound with reported autophagic properties. However, the role and mechanisms of TA in CI/RI mitigation remain unclear. Methods In vivo, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established to evaluate TA’s neuroprotective effects via TTC staining, Longa neurological scoring, and immunofluorescence staining. In vitro, oxygen–glucose deprivation/reoxygenation (OGD/R)-treated HT22 and BV2 cells were used to assess TA’s impact on cell viability (MTT, Hoechst/PI staining), mitochondrial oxidative stress (DHE, TMRM, JC-1, Mito-Tracker staining and Western blot), apoptosis (flow cytometry, immunofluorescence staining, Hochest and PI staining and Western blot), and pyroptosis (EthD-2/YO-PRO-1 staining and Western blot). Autophagy and mitophagy modulation was investigated using rapamycin (Rap), 3-MA (autophagy inhibitor), CCCP (mitophagy inducer), and AC220 (mitophagy inhibitor) in EGFP-LC3-U87 and mCherry-GFP-FIS1-293T cells. Co-localization immunofluorescence and Western blotting were employed to validate PINK1/Parkin pathway involvement. Results TA administration significantly improved neurological function, reduced cerebral infarct volume, and attenuated neuronal damage in MCAO/R rats. In vitro, TA suppressed OGD/R-induced mitochondrial oxidative stress and apoptosis in HT22 cells while mitigating pyroptosis in BV2 microglia. Mechanistically, TA activated PINK1/Parkin-dependent mitophagy, as evidenced by enhanced LC3-II/I ratio, and increased mitochondrial-autophagosome co-localization. Crucially, TA’s anti-apoptotic and anti-pyroptotic effects were abolished upon mitophagy inhibition. These findings were corroborated in the MCAO/R model, where TA upregulated PINK1/Parkin signaling and mitigated cell damage. Conclusion This study identifies TA as a novel natural agent alleviating CI/RI by activating PINK1/Parkin-mediated mitophagy, thereby concurrently suppressing apoptosis and pyroptosis. These findings provide the first elucidating the molecular mechanis underlying TA's potential as a therapeutic candidate for IS. Graphical
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Genes & Diseases
·
2023
·
IF 6.8
Yifan Hong,Xiazhu Zhou,Qi Li,Jing Chen,Yuexin Wei,Chunlan Long,Lianju Shen,Xiangqin Zheng,Dinggang Li,Xia Wang,Chenjun Yu,Shengde Wu,Guanghui Wei
As a widely used plasticizer, di-(2-ethylhexyl) phthalate (DEHP) is known to induce significant testicular injury. However, the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear. In vivo , postnatal day (PND) 21 male rats were gavaged with 0, 250, and 500 mg/kg DEHP for ten days. Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure. Meanwhile, oxidative stress-induced injury and pyroptosis were activated. Both endoplasmic reticulum (ER) stress and mitophagy were involved in this process. Monoethylhexyl phthalate (MEHP) was used as the biometabolite of DEHP in vitro . The GC-1 and GC-2 cell lines were exposed to 0, 100 μM, 200 μM, and 400 μM MEHP for 24 h. Reactive oxygen species (ROS) generation, oxidative stress damage, ER stress, mitophagy, and pyroptosis were significantly increased after MEHP exposure. The ultrastructure of the ER and mitochondria was destroyed. X-box binding protein 1 (XBP1) was observed to be activated and translocated into the nucleus. ROS generation was inhibited by acetylcysteine. The levels of antioxidative stress, ER stress, mitophagy, and pyroptosis were decreased as well. After the administration of the ER stress inhibitor 4-phenyl-butyric acid, both mitophagy and pyroptosis were inhibited. Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis. The equilibrium between pyroptosis and mitophagy was disturbed by XBP1 accumulation. In summary, our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1. Moreover, XBP1 might be the key target in DEHP-related testis dysfunction.
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FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Hao Cai,Ke Li,Yilin Yin,Xiaotong Ni,Shiwen Xu
Bis(2-ethylhexyl) phthalate (DEHP) is not only a widely used plasticizer but also a common endocrine disruptor that frequently lingers in water, posing a threat to the health of aquatic organisms . Quercetin (Que) is a common flavonol found in the plant kingdom known for its antioxidant, anti-inflammatory, and immunomodulatory effects. However, it is still unclear whether DEHP can cause pyroptosis and affect the expression of cytokines of grass carp L8824 cells and whether Que has antagonistic effect in this process. In our study, grass carp L8824 cells were treated into four groups after 24 h, namely NC group, DEHP group (1000 μM DEHP), Que group (5 μM Que), and DEHP + Que group (1000 μM DEHP + 5 μM Que). Our results indicate a significant increase in the level of ROS in L8824 cells after exposure to DEHP. DEHP upregulated oxidative stress markers (H 2 O 2 and MDA) and downregulated antioxidant markers (CAT, GSH, SOD , and T-AOC). DEHP also upregulated MAPK and NF-κB signal pathway-related proteins and mRNA expressions (p-p38, p-JNK, p-EPK, and p65). As for cell pyroptosis and its related pathways, DEHP upregulated pyroptosis-related protein and mRNA expressions (GSDMD, IL-1β, NLRP3, Caspase-1, LDH , pro-IL-18, IL-18, and ASC). Finally, DEHP can up-regulated cytokines (IL-6 and TNF-α) expression, down-regulated cytokines (IL-2 and IFN-γ) expression, and antimicrobial peptides (β-defensin, LEAP2, and HEPC). The co-treatment of L8824 cells with DEHP and Que inhibited the activation of the ROS/MAPK/NF-κB axis, alleviated pyroptosis, and restored expression of immune-related indicators. Finally, NAC was applied to reverse intervention of oxidative stress. In summary, Que inhibited DEHP-induced pyroptosis and the influence on cytokine and antimicrobial peptide expression in L8824 cells by regulating the ROS/MAPK/NF-κB pathway. Our results demonstrate the threat to fish health from DEHP exposure and confirmed the harm of DEHP to the aquatic ecological environment and the detoxification effect of Que to DEHP, which provides a theoretical basis for environmental toxicology.
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MICROBIOLOGICAL RESEARCH
·
2024
·
IF 6.1
Ting Fang,Juan Xiong,Xin Huang,Xinyu Fang,Xuqing Shen,Yuanying Jiang,Hui Lu
Strategies aimed at targeting fungal extracellular heat shock protein 90 (eHsp90) using vaccines and antibodies have demonstrated encouraging potential in the prevention and management of invasive fungal diseases (IFDs). However, the precise underlying mechanism by which eHsp90 contributes to the heightened virulence of Candida albicans ( C. albicans ) remains an enigma, awaiting further elucidation. In our current research, we have found that the 47-kDa fragment of C. albicans Hsp90 (CaHsp90), which serves as the primary antigenic determinant, is not degraded within C. albicans cells. Moreover, we have discovered that extracellular CaHsp90 (eCaHsp90) is derived from the components of lysed C. albicans cells. We also generated recombinant CaHsp90 in Escherichia coli , and found that eCaHsp90 spreads beyond the initial C. albicans colonization site, thereby enhancing the overall virulence of the organism. Our results further clarify that eCaHsp90 activates the nuclear factor kappa-B (NF-κB) signaling pathway and upregulates the expression of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3). This upregulation results in the activation of Gasdermin D (GSDMD) and subsequent macrophage pyroptosis, ultimately increasing the virulence of C. albicans . This study provides valuable insights into the mechanism by which eCaHsp90 contributes to the virulence of C. albicans , offering a pharmacological basis for antifungal strategies targeting fungal eHsp90.
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ENVIRONMENTAL TOXICOLOGY
·
2024
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IF 4.4
Xiaotong Ni,Haozheng Hong,Haotian Xu,Meng Qi,Shiwen Xu
Trimethyltin chloride (TMT) is a highly toxic organotin pollutant frequently found in aquatic environments, posing a significant threat to the ecological system. The kidney plays a vital role in the body's detoxification processes, and TMT present in the environment tends to accumulate in the kidneys. However, it remained unclear whether exposure to different doses of TMT could induce pyroptosis and immune dysfunction in grass carp kidney cells (CIK cells). For this purpose, after assessing the half-maximal inhibitory concentration (IC50) of TMT on CIK cells, we established a model for exposure of CIK cells at varying concentrations of TMT. CIK cells were treated with various doses of TMT (2.5, 5, 10 μM) for 24 h. Oxidative stress levels were measured using kits and fluorescence methods, whereas the expression of related genes was verified through western blot and quantitative real-time PCR (qRT-PCR). The results indicated that TMT exposure led to oxidative stress, with increased levels of ROS, H 2 O 2 , MDA, and GSH, and inhibited activities of T-AOC, SOD, and CAT. It activated the NF-κB pathway, leading to the upregulation of NF-κB p65, NF-κB p50, GSDMD, NLRP3, ASC, and Caspase-1. Furthermore, TMT exposure also resulted in increased expression of cytokines (IL-18, IL-6, IL-2, IL-1β, and TNF-α) and decreased expression of antimicrobial peptides (LEAP2, HEPC, and β-defensin). In summary, exposure to TMT induces dose-dependent oxidative stress that activates the NF-κB pathway, leading to pyroptosis and immune dysfunction in grass carp CIK cells.
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JOURNAL OF ANIMAL PHYSIOLOGY AND ANIMAL NUTRITION
·
2024
·
IF 2.2
Wenyue Qiu,Wenxin Jiang,Yiman Su,Hui Huang,Jiali Ye,Rongmei Wang,Zhaoxin Tang,Rongsheng Su
Lipopolysaccharides (LPS) is the major compoent of Gram-negative bacteria and an important factor in inducing inflammation, which usually leads to multiple organ failure in broilers, seriously affecting the growth performance of broilers and hindering the development of poultry farming. Under the policy of prohibiting antibiotics in feed, it has become more urgent to find natural drugs to prevent liver damage caused by LPS in broilers. Asiatic acid (AA) is a pentacyclic triterpene that has been proven to have anti-inflammatory and antioxidant effects. However, the protective effects of AA in LPS-induced liver damage in broilers still need to be clarified. This study aims to explore the complete mechanism of AA against LPS-induced acute liver injury (ALI) in broilers. A total of 60 broilers (1 day old) were randomly divided into the control group, LPS group, LPS+AA (15, 30 and 60 mg/kg) group and control+AA (60 mg/kg) group. At 16, 18 and 20 days of age, the broilers were attacked with LPS (0.5 mg/kg) to construct liver injury model. H&E staining assessed liver pathological changes. The mRNA and protein expression levels related to the HMGB1/TLR4/NF-κB pathway, pyroptosis, and ERS-mediated apoptosis in the liver tissue were detected. Our results founded that intraperitoneal injection of LPS in broilers increased the activities of AST and ALT, as well as raising the related gene and protein expression of the HMGB1/TLR4/NF-κB pathway, pyroptosis, and ERS-mediated apoptosis. Interestingly, AA improved LPS-induced liver damage and decreased the activities of AST and ALT in broilers. Additionally, AA mitigated LPS-induced ALI by reducing the mRNA levels and protein expressions of the HMGB1/TLR4/NF-κB pathway, pyroptosis and ERS-mediated apoptosis. In conclusion, the present study investigated that AA mitigated LPS-induced ALI in broilers by reducing pyroptosis and ERS-mediated apoptosis via inhibition of the HMGB1/TLR4/NF-κB pathway. Therefore, AA may serve as a potential feed additive for the prevention of LPS-induced ALI in broilers.
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MOLECULAR NUTRITION & FOOD RESEARCH
·
2024
·Vol. 68
·期 19
·2400098
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IF 4.5
Xinqi Huang,Lu Xiu,Yumei An,Yuan Gong,Sunao Li,Xueshi Chen,Chao Liu,Jianghuiwen Lu,Haiyan Shan,Jie Chang,Mingyang Zhang
The objective of this study is to elucidate how Royal jelly (RJ) and 10-hydroxy-2-decanoic acid (10-HDA) prevents diabetic skin dysfunction by modulating the pyroptosis pathway. Type 2 diabetes models are induced by fat diet consumption and low dose of streptozotocin (STZ) in C57BL/6J mice and treated with RJ (100 mg kg –1 day –1 ) and 10-HDA, the major lipid component of royal jelly (100 mg kg −1 day −1 ) for 28 weeks. The results show that serum concentrations of glucose and triglyceride are significantly lower in the RJ group or 10-HDA than diabetes mellitus (DM) group. Compared to the control group, pyroptosis proteins, GSDMD, ASC, Caspase-1, and IL-1β are increased in the skin of the diabetic model, accompanied by the activation of the Wnt/β-catenin signal pathway. Further evaluations by RJ exhibit superior improvement of skin damage, repress activation of the Wnt/β-catenin pathway, and attenuate keratinocyte pyroptosis, but 10-HDA cannot completely suppress the activation of Wnt/β-catenin pathway and pyroptosis, which shows a relatively weak protective effect on skin damage which shows that RJ is a better effect on skin injury after DM.
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