Small
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2024
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IF 13
Rong Chen,Tingting Hu,Yu Lu,Shuqing Yang,Min Zhang,Chaoliang Tan,Ruizheng Liang,Yuji Wang
Photodynamic therapy (PDT) is demonstrated to be effective in inducing antitumor immune responses for tumor metastasis treatment. However, tumor hypoxia, inferior tissue penetration of light, and low singlet oxygen ( 1 O 2 ) quantum yield significantly hamper the efficacy of PDT, thus weakening its immune function. Moreover, PDT-mediated neutrophil extracellular traps (NETs) formation can further reduce the therapeutic effectiveness. Herein, the use of defect-rich CoMo-layered double hydroxide (DR-CoMo-LDH) nanosheets as a carrier to load a typical peptidyl arginine deiminase 4 inhibitor, i.e., YW4-03, to construct a multifunctional nanoagent (403@DR-LDH) for PDT/immunotherapy, is reported. Specifically, 403@DR-LDH inherits excellent 1 O 2 generation activity under 1550 nm laser irradiation and improves the half-life of YW4-03. Meanwhile, 403@DR-LDH plus 1550 nm laser irradiation can stimulate immunogenic cell death to promote the maturation of dendric cells and activation/infiltration of T cells and significantly downregulate H3cit protein expression to inhibit NETs formation, synergistically promoting the antitumor metastasis effect. Taken together, 403@DR-LDH can kill cancer cells and inhibit tumor growth/metastasis under 1550 nm laser irradiation. Single-cell analysis indicates that 403@DR-LDH can regulate the ratio of immune cells and immune-related proteins to improve the tumor immune microenvironment, showing strong efficacy to inhibit the tumor growth, metastasis, and recurrence.
研究领域:
癌症研究
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纳米技术
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免疫治疗
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光动力疗法
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肿瘤生物学
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分子生物学
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生物医学工程
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Mei Bai,Ning An,Meng Cheng,Jia Qin,Jie Wang,Rumeng Jia,Wentao Liu,Jingcai Cheng,Qiang Xu,Xuefeng Wu
Neutrophil extracellular traps (NETs) play a key role in the development of psoriasis, a chronic inflammatory skin condition. We demonstrate the effects and possible mechanisms of phenethyl isothiocyanate (PEITC) in inhibiting NETs and alleviating psoriasis. In response to imiquimod (IMQ), multiple symptoms including scaly plaques and associated skin inflammations were induced in mice. IMQ additionally promotes the formation of NETs and the levels of inflammatory factors. Interestingly, a natural compound PEITC exerted an intensive activity in the treatment of psoriasis. It improved lesions and ameliorated ischemic coagulation symptoms in the dorsal skin of mice. PEITC also significantly reduced the expression of inflammatory factors in mice skin with an inhibition on NETs-related molecules, such as myeloperoxidase, neutrophil elastase and citrullinated histone H3. 16S rRNA sequencing analysis demonstrated that IMQ treatment induced significant gut microbiota dysbiosis in mice, suggesting potential detrimental effects on intestinal microbial homeostasis. However, PEITC administration did not show a statistically significant ameliorative effect on this IMQ-induced microbial imbalance. In vitro experiments demonstrated that PEITC significantly suppressed lipopolysaccharide (LPS)-induced NET formation, suggesting that its therapeutic effects in psoriasis may be due to the inhibition of bacterially driven neutrophil activation. Therefore, we identified PAD4, an important enzyme for post-translational modification of proteins in the production of NETs, as a new potential target of PEITC. Taken together, our findings suggest that PEITC could be a novel potential therapeutic drug to relieve psoriasis via the inhibition of NETs both in vitro and in vivo .
研究领域:
免疫学
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皮肤病学
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微生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
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IF 8
Songlin Song,Lin Gui,Qiqi Feng,Ayijiang Taledaohan,Yuanming Li,Wei Wang,Yanming Wang,Yuji Wang
Purpose Histone citrullination by peptidylarginine deiminases 4 (PAD4) regulates the gene expression of tumor suppressor. In our previously study, YW3-56 (356) was developed as a potent PAD4 inhibitor for cancer therapy with novel function in the autophagy pathway. To enhance the antitumor activity, the PAD4 inhibitor 356 was modified by the well-established cationic penetrating peptide RKKRRQRRR (peptide TAT) and gold nanoparticles to obtain 356-TAT-AuNPs which could enhance the permeability of chemical drug in solid tumor.Methods 356-TAT-AuNPs were prepared, and their morphology were characterized. The antitumor activity of 356-TAT-AuNPs was evaluated in vitro and in vivo.Results 356-TAT-AuNPs exhibited higher anticancer activity against HCT-116, MCF-7 and A549 cells than 356 and 356-AuNPs. Compared with 356 and 356-AuNPs, 356-TAT-AuNPs entered the cytoplasm and nuclear, exhibited stronger anticancer activity by increasing apoptosis, inducing autophagy and inhibiting of histone H3 citrullination, and in HCT-116 xenograft mouse model, 356-TAT-AuNPs could improve the antitumor activity.Conclusion The modified AuNPs with peptide TAT as drug delivery system are potent in delaying tumor growth and could be a powerful vehicle for profitable anticancer drug development. We believe that peptide TAT modification strategy may provide a simple and valuable method for improving antitumor activity of PAD4 inhibitors for clinical use.
研究领域:
癌症研究
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药学
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纳米技术
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分子生物学
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DOI
PubMed
高影响因子
Pharmaceutics
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2026
·Vol. 18
·期 1
·135
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IF 5.5
Kai Wang,Ayijiang Taledaohan,Liujia Chan,Yu Lu,Yijiang Jia,Yuji Wang
Background: Diabetic wound healing is hampered by persistent inflammation and excessive neutrophil extracellular traps (NET) formation. Peptidylarginine deiminase 4 (PAD4) is a key enzyme driving this pathology. This study developed a thermosensitive chitosan/β-glycerophosphate hydrogel for the local delivery of a novel PAD4 inhibitor, YJ-2, to promote diabetic wound repair.Methods: A YJ-2-loaded hydrogel (CGY) was synthesized and characterized.In vitrostudies used HaCaT cells and macrophages to assess proliferation, migration, NETs (via H3cit), and polarization. Efficacy was evaluated in diabetic C57 mouse wound models.Results: CGY exhibited temperature-sensitive gelation and sustained YJ-2 release.In vitro, YJ-2 inhibited NETs formation, reduced pro-inflammatory markers, promoted HaCaT migration, and induced M2 macrophage polarization.In vivo, CGY treatment significantly accelerated wound closure.Conclusions: Local hydrogel delivery of the PAD4 inhibitor YJ-2 effectively mitigates inflammation and NETs, promoting healing in diabetic wounds. This strategy represents a promising targeted therapy for diabetic wounds.
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DOI
PubMed
高影响因子
Nature Communications
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2025
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IF 15.7
Zhang Liqiang,Li Jia,Wei Xiao,Yang Wenguang,He Wangxiao,Liu Wenjia
Hyperglycemia impairs stem cell–mediated bone regeneration, yet the responsible immunometabolic block remains undefined. We identify a neutrophil–Pad4–metabolite axis that suppresses osteogenesis. In rat models of chronic and intermittent hyperglycemia, neutrophils activate ERK/JNK–AP‑1, upregulate Pad4, and generate 4‑guanidinobutyric acid (4‑GBA). 4‑GBA binds alkaline phosphatase (ALP) on jawbone mesenchymal stem cells (JBMSCs), inhibits ALP, and reduces mineralization. Padi4 deletion accelerates socket healing under hyperglycemia. To restore osteogenesis, we engineer GBASpongel, a peptide hydrogel that captures 4‑GBA at the defect. Local GBASpongel treatment rescues ALP activity, osteogenic gene expression, and bone formation in hyperglycemic rats, and improves jawbone regeneration in hyperglycemic rabbits and beagle dogs. Binding assays show micromolar affinity between 4‑GBA and ALP. Transcriptomic and metabolomic analyses corroborate pathway activation and rescue. Neutrophil-derived 4-GBA directly links hyperglycemia to impaired JBMSC function, and locally targeting this metabolite provides a translational approach to restore bone healing in dysglycemia.
研究领域:
免疫代谢
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再生医学
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干细胞生物学
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骨生物学
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代谢组学
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转化医学
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DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
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2026
·
IF 3.5
Zhen Huang,Zhe Wu,Guiyue Zhu,Fangyu Qiu,Lihui Li,Yujie Xie,Chunyu Wei,Yinhua Pan,Quanqing Zou,Yuntian Tang
Neutrophil extracellular traps (NETs) play crucial roles in cancer progression, but their regulatory mechanisms in breast cancer remain poorly understood. We developed a NETs-related prognostic risk model using TCGA breast cancer data and identified key biomarkers through bioinformatics analysis. AZU1 expression was validated in clinical samples using qRT-PCR and immunohistochemistry. In vitro experiments investigated AZU1's effects on neutrophil activation and NET formation using recombinant protein treatment, co-culture assays, and flow cytometry. Mechanistic studies employed phospholipase C (PLC) inhibition and PAD4 knockdown approaches. An orthotopic mouse model validated in vivo findings. Four NETs-related genes (F2RL2, AZU1, IL33, ELANE) constituted a robust prognostic model with good predictive performance. AZU1 showed significant upregulation in breast cancer tissues and correlated with advanced tumor stages. AZU1 overexpression in breast cancer cells enhanced neutrophil recruitment and NET formation through PLC signaling activation. Recombinant AZU1 dose-dependently activated neutrophils, promoted NET formation, and enhanced cancer cell invasion via epithelial-mesenchymal transition induction. PLC inhibition and PAD4 knockdown effectively blocked AZU1-induced neutrophil activation. In vivo experiments confirmed that AZU1 overexpression accelerated tumor growth and metastasis, while PAD4 inhibition reversed these effects. AZU1 promotes breast cancer progression through PAD4-dependent NET formation, representing a potential therapeutic target for breast cancer treatment.
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DOI
高影响因子
PHYTOTHERAPY RESEARCH
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2025
·
IF 6.3
Lin Cheng,Zhirui Du,Xueqiao Yan,Manju Che,Guoguo Zhi,Xiuying Ma,Funeng Geng,Baojie Li
Atopic dermatitis (AD) is a chronic inflammatory skin disorder with limited effective treatment. Sophora flavescens Aiton (Kushen) exhibits anti-inflammatory properties, but its key active components and mechanisms against AD remain unclear. This study aimed to identify its therapeutic compounds and the underlying molecular mechanisms. Network pharmacology and ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry were applied to screen for the potential bioactive compounds from Kushen, which were validated in AD mouse models. Formononetin (FMN) was topically administered to evaluate its curative efficacy through histopathological and immunofluorescent staining of skin lesions. Transcriptomic profiling explored the molecular mechanisms, with subsequent validation of neutrophil extracellular traps (NETs)-associated markers by immunofluorescent staining and western blotting. Co-treatment with PAD4 inhibitor GSK484 and molecular docking were used to study the underlying mechanisms. The study identified FMN as an important active component in Kushen, which showed therapeutic effects comparable to dexamethasone in AD models. FMN normalized cutaneous hyperplasia, reduced infiltration of CD3 + T cells, mast cells, and neutrophils, and suppressed inflammatory cytokine expression. Mechanistically, FMN inhibited NETs formation evidenced by decreased levels of citrullinated histone H3 (citH3), myeloperoxidase (MPO), and peptidylarginine deiminase 4 (PAD4). GSK484 co-treatment showed non-synergistic effects, suggesting that FMN suppresses NETs formation primarily through PAD4/MPO inhibition, which was confirmed by molecular docking. These findings highlight FMN as a primary anti-AD constituent of Kushen, therapeutically suppressing NETs-driven crosstalk of innate and adaptive immunity. FMN's multitarget mechanisms provide mechanistic insights and position it as a candidate for AD treatment.
研究领域:
药理学
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免疫学
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皮肤科学
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生物信息学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2021
·
IF 4.013
Lanqiu Zhang,Hejun Gao,Lei Yang,Tianyu Liu,Qi Zhang,Jing Xun,Caixia Li,Lihua Cui,Ximo Wang
FTY720 is an immunosuppressive agent which has been approved to treat multiple sclerosis (MS). The main object of the present study is to investigate whether FTY720 has the potential to induce the formation of neutrophil extracellular traps (NETs) in vitro. Using Sytox Green assay and fluorescence microscopy , our results showed that FTY720 trigged the NET formation. In contrast to classic NET formation induced by Phorbol 12-myristate 13-acetate (PMA), FTY720-induced NETs were detected earlier and independent of NADPH oxidase (NOX) activity. Pharmacological inhibitor experiments indicated that autophagy was also required for the NET formation induced by FTY720. Moreover, p38 and AKT inhibitor significantly suppressed the NET formation by FTY720, whereas ERK inhibitor had no effect, suggesting that FTY720-induced NETs depended on the activation of p38 and AKT. We further found that citrullination of histone H3 and peptidylarginine deiminase 4 (PAD4) did not mediated FTY720-induced NET formation. Interestingly, necroptosis signaling activation was involved in the vital NET formation by FTY720, however, plasma membrane rupture resulting from necroptosis was not a major component of NET formation described here. Collectively, these findings indicated that FTY720 could be a potential antibacterial drug to protect host against pathogen infection.
研究领域:
免疫学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
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