Environment & Health
·
2026
·
IF 6.3
Shiyin Zhong,Qiongli Zhou,Jirui Yang,Zhimin Zhang,Xueting Chai,Jinghao Luo,Xin Zhang,Jingjing Liu,Yangzong Yixi,Lei Shi,Xuhong Chang,Hui Wang
Manganese (Mn) is an essential trace element, but increasing industrial and agricultural use has led to elevated levels of environmental Mn levels. Chronic overexposure to Mn can cause a Parkinson’s-like neurodegenerative disorder; however, the underlying mechanisms remain incompletely understood. This study combined in vitro and in vivo models to investigate the role of the cGAS–STING/NLRP3 axis in regulating the p38 MAPK/NF–κB pathway in the process of Mn-induced Tau aggregation leading to neurotoxicity. Our results demonstrated that MnCl2 exposure significantly activated both the cGAS–STING/NLRP3 signaling axis and the p38 MAPK/NF–κB pathway, accompanied by increased Tau expression. Genetic ablation of cGAS, STING, or NLRP3 attenuated Mn-induced Tau upregulation, indicating that the cGAS–STING/NLRP3 signaling axis mediates Tau expression. RNA-seq analysis further revealed that the decreased Tau expression in knockout cells is associated with the MAPK/NF–κB signaling pathway. Pharmacological inhibition of p38 MAPK or NF–κB markedly downregulated cGAS–STING signaling, inflammatory cytokine release, and phosphorylated Tau (p-Tau) levels. Moreover, we observed colocalization and interaction among p-p38, p-p65, and p-Tau. Overall, these findings reveal that Mn activates the cGAS–STING/NLRP3 signaling axis regulated by the p38 MAPK/NF–κB pathway, driving pathological Tau aggregation.
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高影响因子
Advanced Science
·
2025
·
IF 14.1
Jiaxin Huang,Jieru Yang,Yuanying Yang,Xiaofeng Lu,Juan Xu,Shan Lu,Hong Pan,Wenhu Zhou,Wenqun Li,Songwen Chen
Doxorubicin (Dox) is a potent chemotherapeutic agent commonly used in cancer treatment. However, cardiotoxicity severely limited its clinical application. To address this challenge, a novel self-assembled nanomedicine platform, PMDDH, is developed for the co-delivery of Dox and metformin, an antidiabetic drug with cardioprotective and anti-tumor properties. PMDDH integrates metformin into a polyethyleneimine-based bioactive excipient (PMet), with Dox intercalated into double-stranded DNA and a hyaluronic acid (HA) coating to enhance tumor targeting. The PMDDH significantly improves the pharmacokinetics and tumor-targeting capabilities of Dox, while metformin enhances the drug's anti-tumor activity by downregulating programmed cell death ligand 1 (PD-L1) and activating the AMP-activated protein kinase (AMPK) signaling pathway. Additionally, the DNA component stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which synergizes with Dox-induced immunogenic cell death (ICD) to promote a robust anti-tumor immune response. PMDDH markedly reduces Dox-induced cardiotoxicity by preserving mitochondrial function, reducing reactive oxygen species (ROS) production, and inducing protective autophagy in cardiomyocytes. These findings position PMDDH as a promising dual-function nanomedicine that enhances the anti-tumor efficacy of Dox while minimizing its systemic toxicity, offering a safer and more effective alternative for cancer therapy.
研究领域:
肿瘤学
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药理学
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纳米技术
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分子生物学
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免疫疗法
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DOI
PubMed
高影响因子
IMMUNITY
·
2025
·
IF 26.3
Jing Han,Shuhao Zhang,Yanfei Hou,Yi Wang,Zhengyin Zhang,Jiaming Yang,Yifang Xu,Zexu Peng,Hang Yin,Kehong Chen,Xiangyu Liu,Conggang Zhang
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.
研究领域:
免疫学
·
结构生物学
·
细胞信号传导
·
天然免疫
·
药理学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Fei Wang,Shuhan Chen,Yinhe Xia,Caihong Liu,Zhou Xu,Ruilong Song,Wenfeng Liu,Tingting Liu,Gang Chen,Qingquan Liu
Influenza epidemics remain a global public health challenge. Vaccination with nucleic acid-based vaccines, which trigger strong cellular and humoral immune responses, represents a promising approach for preventing virus infection. However, its effectiveness relies on efficient delivery and an immunoadjuvant. Here, we constructed a gene- and nanoengineered vaccine delivery platform via modifying MnO2 nanoparticles (NPs) onto the surface of the M13 phage, which carried the hemagglutinin stem gene of influenza A virus preceded by a eukaryotic initial transcriptional region. Specifically, the M13 phage protected the inserted nucleic acid vaccine against degradation due to the existence of capsid proteins. MnO2 NPs released Mn2+ ions under the acidic condition of endolysosomes, thereby promoting the cytoplasmic delivery of phage vaccines, which significantly improved the antigen expression. Moreover, Mn2+ acted as a potent adjuvant for dendritic cell maturation by activating the cGAS/STING pathway. Immunization with the engineered phage vaccine induced CD4+ T cell, CD8+ T cell, and humoral immune responses in mice. In infected mouse models, the vaccines ameliorated weight loss, survival rate, lung virus titers, and pulmonary pathologies and conferred full protection against influenza viruses. Collectively, we developed a dual-engineered phage vaccine platform, offering an alternative regimen for optimizing nucleic acid vaccines, which may have broad applications in the rational design of vaccine formulations.
研究领域:
病毒学
·
免疫学
·
药学
·
纳米技术
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DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Quguang Li,Yifan Yan,Chunjie Wang,Ziliang Dong,Yu Hao,Minming Chen,Zhuang Liu,Liangzhu Feng
Autologous cancer vaccines represent a promising therapeutic approach against tumor relapse. Herein, a concise biomineralization strategy was developed to prepare an immunostimulatory autologous cancer vaccine through protein antigen-mediated growth of flower-like manganese phosphate (MnP) nanoparticles. In addition to inheriting the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-activating capacity of Mn 2+ , the resulting ovalbumin (OVA)-loaded MnP (OVA@MnP) nanoparticles with superior stability and pH-responsiveness enabled efficient priming of antigen-specific CD8 + T cell expansion through promoting the endo/lysosome escape and subsequent antigen cross-presentation of OVA. Resultantly, OVA@MnP vaccines upon subcutaneous vaccination elicited both prophylactic and therapeutic effects against OVA-expressing B16-F10 melanoma. Furthermore, the biomineralized autologous cancer vaccines prepared from the whole tumor cell lysates of the dissected tumors suppressed the growth of residual tumors, particularly in combination with anti-PD-1 immunotherapy. This study highlights a simple biomineralization approach for the controllable synthesis of cGAS-STING-activating autologous cancer vaccines to suppress postsurgical tumor relapse.
研究领域:
癌症免疫疗法
·
纳米技术
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免疫学
·
分子生物学
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PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2024
·
IF 3.6
Wang Li,Cao Limin,Li Zhihong,Shao Zhugui,Chen Xia,Huang Zhicheng,He Xiaoxiao,Zheng Junke,Liu Li,Jia Xin-Ming,Xiao Hui
The cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells’ cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-β response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-β response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-β response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC’s obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.
研究领域:
免疫学
·
癌症生物学
·
细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yinghan Wang,Pengyu Xue,Liang Gao,Xuefei Wang,Shilin Zhou,Xiaochen Wu,Chuanlong Guo
Cisplatin induced acute kidney injury (AKI) is clinically prevalent, with a complex pathogenesis and a lack of effective therapeutic drugs. Polydatin (Po) has excellent biological activity, but its low solubility and bioavailability limit its application. In this study, fucoidan (Fu) and carboxymethyl chitosan (Cs) self-assembled into nanoparticles through electrostatic interactions/hydrogen bonding and loaded Po (Fu/Cs Po NPs). In vitro studies found that Fu/Cs Po NPs protected human renal tubular epithelial (HK-2) cells from cisplatin induced damage and accumulation of reactive oxygen species (ROS). Mechanistic studies showed that Fu/Cs Po NPs inhibited cisplatin induced DNA damage and activation of cyclic guanosine monophosphate synthase (cGAS) and intron gene stimulator (STING) pathways. In vivo studies showed that Fu/Cs Po NPs treatment alleviated cisplatin induced AKI symptoms, including elevated blood urea nitrogen (BUN) and serum creatinine (SCr), as well as pathological damage to kidney tissues. In vivo mechanism studies also showed that Fu/Cs Po NPs treatment inhibited cisplatin induced DNA damage and activation of the cGAS-STING pathway. The pharmacokinetic and tissue distribution results demonstrated that the Fu/Cs delivery system enhanced the bioavailability and kidney accumulation of Po in vivo . In summary, our study provided potential drugs for the treatment of cisplatin induced AKI.
研究领域:
药理学
·
肾病学
·
药物递送系统
·
分子生物学
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高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Yihang Gong,Yusheng Cheng,Fanxin Zeng,Xiaoquan Liu,Yang Yang,Feng Zhang,Chaoyao Wen,Fan Yang,Hua Li,Yizhan He,Beibei Ni,Yan Xu,Lan Xiao,Qi Zhang,Lei Zhou,Jun Zheng,Wenjie Chen
Liver resection represents a main curative treatment for patients with early-stage hepatocellular carcinoma (HCC), but there is a rather high incidence of postoperative HCC relapse, which severely shortens long-term survival time. Currently, no standard adjuvant strategies are available for preventing HCC relapse in clinical practice. Impaired natural killer (NK) cell anti-tumor immunity has been disclosed as a crucial root of HCC relapse, indicating that reinstating NK cell anti-tumor immunity may show promise to curb HCC relapse. Coincidently, mounting evidence shows that radiotherapy (RT) can trigger NK cell anti-tumor immunity, though its mechanisms have never been completely elucidated. Herein, we uncover that RT can induce immunogenic cell death and activate cGAS-STING pathway in HCC cells to elicit NK cell anti-tumor immunity. However, RT is also revealed to enhance autophagy and CD73 expression in HCC cells, as well as neutrophil extracellular traps (NETs) formation, which largely limits RT-induced activation of NK cell anti-tumor immunity. Therefore, a cocktail of autophagy inhibitor 3-methyladenine, CD73 inhibitor ARL 67156 trisodium and NETs lyase DNase I may sensitize RT to reinvigorate NK cell anti-tumor immunity and thus prevent HCC relapse postresection. To minimize therapy-related side effects, a nanocomposite powder encapsulating such a triple-drug cocktail is developed. This powder can rapidly form adhesive hydrogel in situ after applied to surgical margin, consequently fulfilling liver-localized sustained drug delivery. Importantly, it can sensitize RT to reinstate NK cell anti-tumor immunity to combat postoperative HCC relapse in Heap1-6-HCC murine model. Besides, this powder can also generate rapid hemostasis in rat and porcine models. Altogether, this work provides an innovative strategy to thwart postoperative HCC relapse and bleeding.
研究领域:
肿瘤学
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免疫学
·
药剂学
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DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Yijie Feng,Caili Zhang,Yinuo Wei,Enhua Liu,Hongyu Sun,Peter Flatt,Victor Gault,Nigel Irwin,Christian Hölscher,Li Hao,Zijuan Zhang
Effective disease-modifying therapies for Alzheimer’s disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo , NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden ( P < 0.05), alleviated neuronal injury ( P < 0.01), improved synaptic integrity ( P < 0.01), and attenuated mitochondrial abnormalities ( P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) ( P < 0.05), cGAS ( P < 0.05), STING ( P < 0.05), and phosphorylated IRF3 ( P < 0.01), together with decreased IL-1β ( P < 0.05) and increased IL-10 ( P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling ( P < 0.05) and inflammatory responses ( P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-23
·
IF 12.6
Gong Zhaoyang,Chen Zhenhao,Li Dachuan,Lu Xiao,Wu Jianwei,Sun Hanqiu,Wang Ximeng,Liu Siyang,Xia Xinlei,Lu Feizhou,Jiang Jianyuan,Sun Chi,Wang Hongli,Zeng Feng,Ma Xiaosheng
Background Spinal cord injury (SCI) treatment remains a formidable challenge, as current therapeutic approaches provide only marginal relief and fail to reverse the underlying tissue damage. This study aims to develop a novel composite material combining enzymatic nanoparticles and nerve growth factor (NGF) to modulate the immune microenvironment and enhance SCI repair.Methods CeMn nanoparticles (NP) and CeMn NP-polyethylene glycol (PEG) nanozymes were synthesized via sol–gel reaction and DSPE-mPEG modification. Transmission Electron Microscopy, Selected-Area Electron Diffraction, X-ray Diffraction and X-ray Photoelectron Spectroscopy confirmed their crystalline structure, mixed-valence states, and redox properties. Size uniformity, biocompatibility, and catalytic activity were assessed via hydrodynamic diameter, zeta potential, and elemental analysis. The Lightgel/NGF/CeMn NP-PEG composite was synthesized and characterized via electron microscopy, compression testing, rheological analysis, NGF release kinetics, and 30-day degradation studies. Both in vitro and in vivo experiments were conducted to evaluate the therapeutic effects of the composite on SCI.Results The Lightgel/NGF/CeMn NP-PEG composite was successfully synthesized, exhibiting favorable physical properties. At a CeMn NP-PEG concentration of 4 µg/mL, the composite maintained cell viability and demonstrated enhanced biological activity. It also showed superior mechanical properties and an effective NGF release profile. Notably, the composite significantly upregulated the expression of nerve growth-associated proteins, reduced inflammatory cytokines, scavenged reactive oxygen species (ROS), and promoted M2 macrophage polarization by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. In a rat SCI model, it facilitated functional recovery and attenuated inflammation.Conclusion The Lightgel/NGF/CeMn NP-PEG composite shows significant therapeutic promise for SCI, effectively eliminating ROS, promoting M2 macrophage polarization, reducing pro-inflammatory cytokines, and supporting neuronal regeneration. These effects substantially enhance motor function in SCI rats, positioning it as a promising candidate for future clinical applications.Graphical
研究领域:
生物医学工程
·
纳米技术
·
神经科学
·
免疫学
·
组织工程
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Xiaohu Xi,Jiankuan Li,Yingjing Wang,Yan Ni,Jiangtao Zhou,Lingya Cao,Wei Wei,Jianping Gao
Background Dextran sulfate sodium-induced ulcerative colitis is featured by excessive intestinal inflammation and disrupted mucosal immune homeostasis. Codonopsis pilosula is the sovereign herb in Shenling Baizhu Formula for ulcerative colitis therapy, and Codonopsis pilosula polysaccharides are its key active components, while their immunomodulatory effects and molecular mechanisms in Shenling Baizhu Formula against ulcerative colitis remain elusive. This study explored the critical role of Codonopsis pilosula polysaccharides and the spermidine-AMPK-mediated mitophagy-cGAS-STING inflammatory axis in regulating intestinal inflammation and ameliorating ulcerative colitis. Methods A dextran sulfate sodium-induced ulcerative colitis mouse model was established to evaluate the indispensable role of Codonopsis pilosula polysaccharides in Shenling Baizhu Formula. Ultra-high performance liquid chromatography metabolomics and 16S ribosomal RNA sequencing were performed to identify key metabolites and gut microbiota. In vitro dextran sulfate sodium-induced ulcerative colitis cellular models (human colorectal adenocarcinoma Caco-2 and human normal colonic epithelial NCM460 cells) were constructed to validate the regulatory mechanism of spermidine on AMPK-mediated mitophagy, inflammatory balance and intestinal epithelial injury. Results Codonopsis pilosula polysaccharides were essential for the anti-ulcerative colitis efficacy of Shenling Baizhu Formula: removal of Codonopsis pilosula significantly aggravated colonic pathological lesions, intestinal inflammatory responses and oxidative stress in ulcerative colitis mice, whereas Codonopsis pilosula polysaccharides supplementation reversed these abnormal phenotypes ( P < 0.05). Metabolomics and microbiomics confirmed that Codonopsis pilosula polysaccharides exerted therapeutic effects via spermidine (a key metabolite in glutamate metabolism pathway) and Muribaculaceae. Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis, thereby restoring intestinal inflammatory homeostasis and alleviating epithelial cell injury in ulcerative colitis. Conclusion Codonopsis pilosula polysaccharides extracted from the sovereign herb Codonopsis pilosula in Shenling Baizhu Formula ameliorate dextran sulfate sodium-induced ulcerative colitis, and the core mechanism depends on spermidine-triggered AMPK-mediated mitophagy to suppress the cGAS-STING inflammatory signaling axis, which plays a pivotal role in regulating intestinal immunity and repairing mucosal epithelial damage.
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PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Yiyang Huang,Jiannan Mao,Ziang Li,Wenbo Wang,Zhengxia Ni,Feng Cai,Jincheng Tang,Wei Wang,Lichen Zhang,Liang Zhou,Xinzhao Jiang,Jie Wu,Qiangqiang Guo,Min Rui,Ziyan Huang,Haochen Jiang,Lingjun Wang,Kun Xi,Yong Gu,Liang Chen
The aging microenvironment promotes persistent inflammation and loss of intrinsic regenerative capacity. These are major obstacles to effective bone tissue repair in older adults. This study aims to explore how physical thermal stimulation can effectively delay the bone marrow mesenchymal stem cells (BMSCs) aging process. Based on this, an implantable physical signal-converter platform is designed as a therapeutic system that enables stable heat signals at the bone injury site under ultrasound stimulation (US). It is found that the therapeutic platform controllably reduces the mitochondrial outer membrane permeabilization of aging BMSCs, bidirectionally inhibiting mitochondrial reactive oxygen species and mitochondrial DNA (mtDNA) leakage. The leakage ratio of mtDNA decreases by 22.7%. This effectively mitigates the activation of the cGAS-STING pathway and its downstream NF-κB signaling induced by oxidative stress in aging BMSCs, thereby attenuating the pathological advancement of chronic inflammation. Thus, it effectively restores the metabolism and osteogenic differentiation of aging BMSCs in vitro, which is further confirmed in a rat model. In the GMPG/US group, the bone mineral density increases 2–3 times at 4 weeks in the rats femoral defect model. Therefore, this ultrasound-based signal-conversion platform provides a promising strategy for aging bone defect repair.
研究领域:
再生医学
·
老年学
·
生物医学工程
·
细胞生物学
·
组织工程
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高影响因子
危险品化学品经营许可证（带存储）