HUMAN & EXPERIMENTAL TOXICOLOGY
·
2022
·
IF 3.247
Shengwei Li,Guangqing Feng,Min Zhang,Xing Zhang,Jihong Lu,Chenyahui Feng,Fangshi Zhu
Objective: Due to its well-known anti-inflammatory property, oxymatrine (OMT) has received more attention on the aspect of treating ulcerative colitis. Although efforts have been undertaken to understand the therapeutic mechanism of OMT on ulcerative colitis (UC), the remedial principle is still ambiguous. Numerous studies have shown that TLR9/Myd88/NF-κB signal pathway played a key role in the pathogenesis of UC. Moreover, TLR9/Myd88/NF-κB signal pathway is a part of the most important pathways for regulating the immune response.Methods: We explored the influence of OMT with different dosages on UC by establishing a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Moreover, the participation of TLR9/Myd88/NF-κB signal pathway and whether OMT protects against UC though targeting this pathway are further studied.Results: Our data revealed that OMT could significantly relieve the symptom of TNBS-induced colitis in rats by reactivating the tight junction protein and, more important, by inhibiting the activation of TLR9/Myd88/NF-κB pathway and protein expression levels of its downstream inflammatory factors.Conclusion: OMT could relieve colitis in rat models by impacting tight junction proteins’ TLR9/Myd88/NF-κB signal pathways and activity.
研究领域:
药理学
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免疫学
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胃肠病学
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DOI
PubMed
高影响因子
Science of Advanced Materials
·
2024
·Vol. 16
·期 3
·415-425
·
IF 0.9
Zhao Xue,Xu Yuanshen,Fang Jinyan
This research aimed to better exert the efficacy of dexamethasone (DEX) and fabricate an intercellular adhesion molecule A (ILDMA) monoclonal antibody (mAb)-modified nanostructured lipid carrier (NSLC). The anionic DEX NSLC was fabricated by the aqueous solvent diffusion methodology
using DEX as the model drug and in combination with various types of lipids. Using N,N’-succinimidyl carbonate as the link, anti-ILDMA mAb-modified anion DEX NSLC (ILDM/DEX/NSLC) and anti-IgG mAb-modified cation DEX NSLC (IgG/DEX/NSLC) were prepared. The total lipid content was controlled
unchanged, 3% mass ratio of glyceryl monostearate (MS) in the original prescription was replaced with 3% mass ratio of octadecylamine (ODA), and ILDM/DEX/ODA-NSLC and IgG/DEX/ODA-NSLC were fabricated in the same way. The four NSLCs prepared in the experiment were round in shape and uniform
in size. The nanoparticles with a size of approximately 230 nm were similar, and the zeta potentials were (−29.8±21.5) mV, (−27.9±1.6) mV, (36.8±0.8) mV, and (33.7±2.9) mV, respectively. In vitro drug release demonstrated a cumulative release
rate of more than 55% of DEX NSLC. The inhibitory rate of DEX NSLC on the activated human vascular endothelial cell line (EAhy926 cell) was dose dependent, and ILDM/DEX/NSLC could transport DEX to activated endothelial cells more efficiently, thus enhancing the intervention ability on diseased
endothelium. For the establishment of a sepsis-induced acute lung injury (ALI) mouse model, ILDM/DEX/NSLC was highly distributed in the lung of the model, and its infiltration effect on inflammatory cells was superior to that of other drugs (P < 0.05). Meanwhile, ILDM/DEX/NSLC could
more markedly repair the pathological features in the mouse model than other drugs did (P < 0.05). The nanodrug inhibited the protein level of TLR9 in mouse lung tissue to the maximum extent (P < 0.05), thereby enhancing the survival rate of the mice.
研究领域:
药剂学
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免疫学
·
病理学
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DOI
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2022
·Vol. 45
·期 12
·1733-1742
·
IF 2.264
Yongbin Jing,Mingkun Jia,Jinpeng Zhuang,Dong Han,Changlong Zhou,Jinglong Yan
Osteosarcoma (OS) is the most common primary malignant bone tumor and is mainly diagnosed in children. Toll-like receptor 9 (TLR9) is expressed in various tumor cells and was correlated with cancer progression. However, the underlying mechanism of TLR9 on the OS progression remains unclear. Our previous study demonstrated that the expression of TLR9 was positively correlated with the development stage of OS. Herein, we further evaluated the actual roles and the molecular mechanism of TLR9 on regulating OS cell proliferation and metastasis. Our data showed that TLR9 was upregulated in OS cells compared to normal osteoblastic cells, and knockdown of TLR9 inhibited OS cell proliferation and induced cell cycle arrest by the decreased expression of cyclin D1, CDK2, and p-Rb, while TLR9 overexpression exerted the inverse effects. Furthermore, TLR9 overexpression could enhance the migration and invasion activities of the OS cells by the upregulation of matrix metalloproteinases 2 (MMP2) and MMP9, and the opposite result was observed in TLR9-silenced cells. Moreover, the nuclear factor kappa B (NF-κB) signaling pathway was activated by TLR9, and TLR9-induced malignant phenotype of OS cells was abrogated by the NF-κB antagonist BAY11-7082. Our study indicated that TLR9 might play a critical role in facilitating OS progression by activating the NF-κB signaling pathway, which may provide a valuable therapeutic target for OS.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
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2025
·
IF 5.4
Chunfa Chen,Cheng Tian,Zhuoer Jin,Yuandong Wen,Xiaoyu Xia,Qiao Ren,Cheng Zhi Huang,Hua Zuo
TLR9 agonists hold significant potential in vaccine development and cancer immunotherapy. While synthetic CpG oligodeoxynucleotides (ODNs) have been employed in immunotherapies, their clinical application remains constrained by dose-limiting toxicity and metabolic instability. DNA nanotechnology provides a promising strategy for the precise modulation of ligand-TLR9 interactions. In this study, DNA nanostructure-based TLR9 agonists were rationally designed by optimizing the spatial orientation of 5′-TCG ligands based on the two DNA-binding sites revealed in the TLR9 receptor crystal structure. Fine-tuning DNA nanostructure configurations enabled controllable modulation of TLR9 activation with structural flexibility identified as a critical determinant. Notably, the oligomerization of DNA nanostructures markedly enhanced TLR9 stimulation efficacy, establishing a paradigm for the rational design of TLR9 agonists. These findings advance innovative approaches for developing next-generation immunotherapeutic agents.
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PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Lulu Liu,Chenxin Lu,Zhenchao Tao,Zhengbao Zha,Hua Wang,Zhaohua Miao
Polydopamine nanomaterials have emerged as one of the most popular organic materials for management of oxidative stress-mediated inflammatory diseases. However, their current anti-inflammatory ability is still unsatisfied because of limited phenolic hydroxyl groups and oxidation reaction-medicated reactive oxygen and nitrogen species (RONS) scavenging. Herein, via fusing dimension engineering and surface charge engineering, we reported two-dimension (2D) cationic polydopamine nanosheets (PDA NSs) capable of scavenging multiple danger signals to enhance anti-inflammatory capability. Compared with conventional spherical polydopamine nanoparticles, 2D PDA NSs exhibited 3∼4-fold enhancement in RONS scavenging capability, which should be attributed to high specific surface area and abundant phenol groups of 2D ultrathin structure. To further enhance the anti-inflammatory ability, polylysine molecules were absorbed on the surface of PDA NSs to endow the scavenging capability of cell-free DNA (cfDNA), another typical inflammatory factor to exacerbate the pathogenesis of inflammation. Molecular mechanisms revealed that cationic PDA NSs could concurrently activate Keap1-Nrf2 and block TLR9 signaling pathway, achieving synergistical inflammation inhibition. As a proof of concept, cationic PDA NSs with RONS and cfDNA dual-scavenging capability effectively alleviated the inflammatory bowel disease in both delayed and prophylactic models, much better than the clinical drug 5-aminosalicylic acid. This article is protected by copyright. All rights reserved
研究领域:
材料科学
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纳米技术
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药学
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炎症研究
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Yue Shang,Yan-Gui Peng,Yan Wang,Xiao-Kui Huo,Hou-Li Zhang,Tang-Na Hao,Xiao-Chi Ma
Background Liver fibrosis is a critical pathological stage in the progression of chronic liver diseases, yet safe and effective antifibrotic agents remain lacking. Anwulignan (Anwu), a lignan component derived from the traditional hepatoprotective herb Schisandra chinensis (Turcz.) Baill., possesses hepatoprotective properties; however, its antifibrotic potential and underlying mechanism remain undefined. Purpose To evaluate the antifibrotic efficacy of Anwu and elucidate the role of the interleukin-36 receptor (IL-36R)/Toll-like receptor 9 (TLR9) signaling pathway in its mechanism of action. Methods Thioacetamide-induced liver fibrosis in mice and TGF-β-activated LX-2 cells were employed to evaluate Anwu’s antifibrotic activity. Transcriptomic profiling and pathway enrichment were performed, and functional validation was achieved through IL-36R and TLR9 knockdown in vivo and in vitro. Results Anwu markedly alleviated hepatic injury and collagen deposition, reduced serum aminotransferase levels, and restored extracellular matrix homeostasis by suppressing α-smooth muscle actin and type I collagen while upregulating matrix metalloproteinase-9. Transcriptomic analysis revealed that IL-36R and TLR9 were markedly upregulated during liver fibrosis but were significantly downregulated following Anwu treatment, suggesting that the IL-36R/TLR9 signaling axis may serve as a key target for its antifibrotic action. Genetic knockdown further confirmed this pathway dependence, as silencing either IL-36R or TLR9 mimicked Anwu’s therapeutic effects and occluded any additional benefit from Anwu treatment. Consistent findings were validated in human liver transcriptomic data, highlighting the clinical relevance of this pathway. Conclusion Anwu exerts antifibrotic effects via a previously unrecognized IL-36R/TLR9-mediated mechanism that links inflammatory resolution to matrix remodeling, underscoring its distinctive pharmacology and translational promise.
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PubMed
高影响因子
Nanomedicine
·
2026
·
IF 3.9
Weixia Li,Yang Sun,Yi Guan,Xiao Zhi
Background Aluminum adjuvants remain the most widely used adjuvants in licensed vaccines. Their broader application, however, is restricted by local and systemic adverse effects and limited antigen compatibility, slowing vaccine development.Methods A nanoscale aluminum – fumarate metal – organic framework (AlFu‑MOF) was synthesized in water using Pluronic F127 and acetic acid. Based on this framework, a composite nanoadjuvant—(D)-mannose‑cTAT‑CpG@M@AlFu‑MOF (DCC@M@AlFu‑MOF) – was designed and characterized. The loading capacity for immunostimulatory cargos, including MSA‑2, CpG, cTAT, (D)-mannose, and OVA, was evaluated. Cellular uptake and immune activation of antigen‑presenting cells were tested in vitro. AlFu‑MOF displayed high loading efficiency and improved antigen availability. DCC@M@AlFu‑MOF promoted dendritic cell maturation and activation and also triggered the STING signaling pathway.Conclusion DCC@M@AlFu‑MOF is an aluminum‑based nanoadjuvant with potential dendritic cell‑targeting ability. It can coordinate innate immune signaling and shows promise for enhancing vaccine‑induced immune responses.
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 4.7
Kexing Zhuo,Man Mou,Jianlun Li,Sijian Huang,Zihang Zeng,Xu Li,Lijuan Wang,Yingjie Wei,Shijia Qiu,Xianghong Wei,Lei Li,Yuan Cao,Maohua Zhong
The development of effective cancer vaccines remains challenged by tumor heterogeneity and insufficient T-cell activation. Whole-cell vaccines, which deliver a broad spectrum of tumor-associated antigens, represent a promising approach, especially when their immunogenicity is enhanced via strategies such as immunogenic cell death (ICD). Here, we developed a novel whole-cell vaccine, termed MDLSD, by combining mitoxantrone (MTX)-induced ICD with the TLR9 agonist SD-101. In murine Lewis lung carcinoma (LLC) models, MDLSD demonstrated superior prophylactic and therapeutic efficacy. Mechanistically, MTX-induced dying tumor cells (MDL) promoted dendritic cell (DC) phagocytosis, while the addition of SD-101 was essential for driving complete DC maturation through potent upregulation of CD80. Consequently, only the combined MDLSD vaccine robustly primed antigen-specific T cells in vivo , eliciting elevated IFN-γ secretion. Prophylactic vaccination with MDLSD conferred 100 % protection against initial tumor challenge and durable immunity upon rechallenge. In a therapeutic setting, MDLSD treatment achieved a 55 % complete regression rate, significantly suppressing established tumor growth and prolonging survival. This potent antitumor immunity was driven by MDLSD-enhanced Th1/Tc1 polarization, evidenced by increased T-bet, IFN-γ, and TNF-α, along with boosted cytolytic function via Granzyme B in both systemic and tumor-infiltrating T cells. Furthermore, mice cured by MDLSD developed long-term immunological memory, characterized by a recall response dominated by IFN-γ + CD8 + and TNF-α + T cells, enabling rejection of secondary tumor challenges. Collectively, our findings illustrate that the MDLSD vaccine synergizes the antigenic breadth of ICD with potent TLR9 stimulation to elicit robust DC activation, polyfunctional T-cell responses, and durable immunological memory, offering a compelling strategy for cancer immunotherapy.
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DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Junfeng Song,Yang Song,Xirui Huang,Xingjin Li,Lifei Gao,Yixiang Wang,Tianbao Zhu,Xiaomin Li,Shuai Wang,Tiancong Zhao,Dongyuan Zhao
Chronic diabetic foot infections are severely hindered by tough biofilms and a self-fueling hyperinflammatory microenvironment, primarily orchestrated by the synergistic interplay between extracellular DNA (eDNA) and lipopolysaccharides (LPS) which facilitates the assembly of impenetrable biofilm architectures while inducing cross-inflammatory activation through the TLR4/9 axis. Conventional therapies often fail to resolve these “dual traps” of structural resistance and immunological interference. Herein, we developed a multifunctional mesoporous nano-regulator composed of Colistin (CT) and m-aminophenol formaldehyde (mAPF) framework, hence termed CT/mAPF to implement a “triad-strategy”: biofilm disruption, bacterial eradication, and debris neutralization. The CT/mAPF nano-regulator achieves potent bactericidal activity (99.99%) and initiates ROS-mediated oxidative fragmentation of eDNA to destroy the biofilm scaffold. Crucially, the platform effectively neutralizes LPS and degrades eDNA, leading to the simultaneous silencing of TLR4 and TLR9 signaling pathways. This dual-targeting approach weakens the eDNA/LPS-mediated synergistic inflammatory response, and suppresses pro-inflammatory cytokines ( IL-6 , IL-1β , TNF-α ). In diabetic mouse models, CT/mAPF significantly accelerated bacterial clearance and wound closure through enhanced angiogenesis and collagen maturation. This integrated strategy resolves the cycle of chronic infection and inflammation, offering a robust strategy for Gram-negative bacteria-infected diabetic wound management.
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2026
·Vol. 51
·期 1
·73
·
IF 4.5
Zhou Juan,Li Haipeng,Wen Ying,He Lingli,He Yangli,Meng Heng
Neuromyelitis optica spectrum disorder (NMOSD) is a rare but serious inflammatory demyelinating disease. A key characteristic of NMOSD is the presence of a pathogenic autoantibody in serum called aquaporin-4 immunoglobulin G (AQP4-IgG). This study investigates the mechanism of astrocyte-derived small extracellular vesicles (EVs) carrying mitochondrial DNA (mtDNA) to promote AQP4-IgG-induced microglial activation in neuromyelitis optica (NMO) via the toll-like receptor 9 (TLR9)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway. Serum IgG was isolated from NMOSD patients (AQP4-IgG) and healthy controls (Con-IgG). Astrocytes were treated with AQP4-IgG or Con-IgG. EVs were isolated via ultracentrifugation, characterized, and examined for internalization. Microglia were exposed to EVs, and mtDNA levels were assessed. An NMO mouse model was established, with neurological damage, mouse behaviors, tissue damage, and microglial characterization evaluated using modified neurological severity score, open-field test, rotarod test, luxol fast blue staining, and flow cytometry. Inflammatory cytokines, TLR9, MyD88, p65, IκBα, p-p65, and p-IκBα in BV2 cells and spinal cord tissues were analyzed via ELISA, RT-qPCR, and western blot. AQP4-IgG-induced astrocyte-derived EVs increased Iba1-high-expressing and CD86/tumor necrosis factor-α-high-expressing cells, reduced CD206/transforming growth factor-β-high-expressing cells, and boosted inflammatory responses. AQP4-IgG-induced EVs carried mtDNA to activate microglia via the TLR9/MyD88/NF-κB pathway. TLR9/MyD88/NF-κB pathway inhibition reversed AQP4-IgG-induced EVs’ promotion on microglial activation. In vivo, AQP4-IgG-induced EVs-mtDNA exacerbated microglial activation and NMO through the TLR9/MyD88/NF-κB pathway. AQP4-IgG-induced EVs carried mtDNA to upregulate TLR9, further activating the MyD88/NF-κB pathway, thereby promoting microglial activation and transition toward pro-inflammatory gene-high-expressing cells to drive NMO progression.
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PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Chendong Yang,Yuanzhan Wang,Yuxue Han,Huiling Dong,Wei Tong,Xuanjun Wu
CpG oligodeoxynucleotides (ODNs) are synthetic Toll-like receptor 9 (TLR9) agonists that promote Th1-biased immune responses. However, their clinical utility is limited by rapid nuclease degradation and poor cellular uptake in antigen-presenting cells (APCs). To overcome this, we developed a pH-responsive nanoadjuvant, Ace-Dex-PC7A@CpG, composed of a cyclic seven-membered tertiary amine-based polymer (PC7A) grafted onto ethoxy-acetalated dextran (Ace-Dex) encapsulating CpG ODN 1668. In vitro, this nanoadjuvant significantly increased the levels of TNF-α, IL-6, IFN-β, and CXCL10 in RAW macrophages, indicating the simultaneous activation of both the TLR9 and stimulator of interferon genes (STING) pathways. In vivo, Ace-Dex-PC7A@CpG significantly enhanced the immunogenicity of the receptor-binding domain (RBD) of SARS-CoV-2, eliciting robust humoral responses with mean anti-RBD IgG titers exceeding 300,000, a 15-fold increase over free RBD (20,000). Sera from immunized mice showed >50% inhibition of RBD-hACE2 binding, far surpassing the 6% inhibition observed with free RBD. Furthermore, in a tumor-associated carbohydrate antigen (TACA) vaccine model, GM2-conjugated bacteriophage MX1 (GM2-MX1) virus-like particles (VLPs) adjuvanted with Ace-Dex-PC7A@CpG produced 10-fold higher anti-GM2 IgG titers than GM2-MX1 alone. More importantly, vaccination with 9NHAc-GD2-mQβ VLPs (a leading TACA vaccine candidate) plus Ace-Dex-PC7A@CpG significantly suppressed liver metastasis in an EL4 lymphoma model. These findings establish Ace-Dex-PC7A@CpG as a versatile nanoadjuvant for subunit vaccines against infectious diseases and cancer.
研究领域:
免疫学
·
纳米技术
·
疫苗学
·
生物化学
·
分子生物学
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肿瘤学
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传染病学
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产品关联
DOI
PubMed
高影响因子
Nano Research
·
2021
·Vol. 15
·期 2
·1183-1192
·
IF 8.897
Xu Yudi,Ma Sheng,Zhao Jiayu,Si Xinghui,Huang Zichao,Zhang Yu,Song Wantong,Tang Zhaohui,Chen Xuesi
Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death (ICD), which provides a promising alternative way for cancer immunotherapy. However, the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone. Herein, we proposed a trinity immune enhancing nanoparticles (TIENs) for boosting antitumor immune responses of chemo agents. The TIENs was constructed with Food and Drug Administration (FDA) approved polylactic acid (PLA), canonical proton-sponging cationic polymer polyethyleneimine (PEI), and Toll-like receptor 9 (TLR9) agonist cytosine phosphate guanine oligodeoxynucleotide (CpG-ODN). In in vitro studies, the TIENs was proved to (1) promote antigen capturing, (2) antigen-presenting cells (APCs) activation, and (3) antigen cross-presentation. In in vivo studies, intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models, respectively. Furthermore, after decoration with a detachable shielding, the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection. The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.
研究领域:
癌症免疫疗法
·
纳米医学
·
化疗
·
免疫学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）