Virulence
·
2022
·
IF 5.428
Qiankun Yang,Jianguo Zhang,Feixue Liu,Huizhen Chen,Wei Zhang,Haitao Yang,Nana He,Jingquan Dong,Panpan Zhao
Aeromonas caviae, an important food-borne pathogen, induces serious invasive infections and inflammation. The pro-inflammatory IL-1β functions against pathogenic infections and is elevated in various Aeromonas infection cases. However, the molecular mechanism of A. caviae-mediated IL-1β secretion remains unknown. In this study, mouse macrophages (PMs) were used to establish A. caviae infection model and multiple strategies were utilized to explore the mechanism of IL-1β secretion. IL-1β was elevated in A. caviae infected murine serum, PMs lysates or supernatants. This process triggered NLRP3 levels upregulation, ASC oligomerization, as well as dot gathering of NLRP3 and speck-like signals of ASC in the cytoplasm. MCC950 blocked A. caviae mediated IL-1β release. Meanwhile, NLRP3 inflammasome mediated the release of IL-1β in dose- and time-dependent manners, and the release of IL-1β was dependent on active caspase-1, as well as NLRP3 inflammasome was activated by potassium efflux and cathepsin B release ways. A. caviae also enhanced TLR2 levels, and deletion of TLR2 obviously decreased IL-1β secretion. What’s more, A. caviae resulted in NF-κB p65 nuclear translocation partly in a TLR2-dependent manner. Blocking NF-κB using BAY 11-7082 almost completely inhibited NLRP3 inflammasome first signal pro-IL-1β expression. Blocking TLR2, NF-κB, NLRP3 inflammasome significantly downregulated IL-1β release and TNF-α and IL-6 levels. These data illustrate that A. caviae caused IL-1β secretion in PMs is controlled by NLRP3 inflammasome, of which is mediated by NF-κB pathway and is partially dependent on TLR2, providing basis for drugs against A. caviae.
研究领域:
免疫学
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微生物学
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传染病学
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细胞生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Anna Gan,Haimiao Chen,Fei Lin,Ruixuan Wang,Bo Wu,Tingxu Yan,Ying Jia
Background Acute lung injury (ALI) is a serious respiratory ailment marked by dysregulation of the immune dysregulation and an inflammatory reaction.Currently, effective treatment options for ALI are limited. Sanzi Yangqin Decoction (SZYQ) is a traditional formula used clinically to treat respiratory diseases, although its effects on ALI have not yet been fully elucidated. Purpose This research seeks to elucidate the pharmacodynamic material basis of SZYQ within the context of lipopolysaccharide (LPS)-induced ALI, thereby establishing a robust foundation for considering SZYQ as a possible intervention for improving ALI. Methods The chemical constituents of SZYQ were identified by UHPLC-QTOF-MS. The pharmacological mechanism of SZYQ on ALI was preliminarily investigated through network pharmacology. An ALI model induced by LPS was employed to evaluate the efficacy of SZYQ via histopathological analysis and other methodologies. Transcriptomic analysis of lung tissue from ALI mice was conducted to uncover the potential mechanisms underlying SZYQ's effects. Additionally, LPS was used to induce murine alveolar macrophages (MH-S), creating an in vitro ALI model; siRNA was introduced to further validate the pharmacological mechanisms of SZYQ's protective effects on ALI. Results This study identified a total of 37 chemical components within SZYQ, and network pharmacology results indicated that these components exert their effects via the Toll-like receptor pathway. The protective effects of SZYQ on ALI are manifested by the modulation of the immune response and the reduction of lung epithelial barrier damage. Transcriptomics, western blot, flow cytometry, and siRNA experiments demonstrated that SZYQ can inhibit levels of TLR2, p-NF-κB/NF-κB, p-IκB/IκB, p-IKKα/IKKα, MyD88, NLRP3, Caspase-1 and ASC. Furthermore, SZYQ was observed to reduce the release of reactive oxygen species (ROS), suppresses inflammasome activation, as well as decrease the incidence of cell pyroptosis. Conclusions This article demonstrated for the first time that SZYQ can enhance ALI through immune regulation. The proposed mechanism of action involved the TLR2-mediated NF-κB/NLRP3 signaling pathway and the inhibition of NLRP3 inflammasome activation.
研究领域:
药理学
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免疫学
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呼吸医学
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传统中医
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Lingdi Niu,Haoyuan Duan,Jiaqing Wang,Zheng Jia,Hai Li,Junjie Guo,Shuhe Zhang,Ning Liu,Yaxin Miao,Junwei Ge,Fang Wang
Trained immunity refers to the ability of trained innate immune cells to generate an immune memory that produces rapid, broad-spectrum, and long-lasting protection against heterologous stimuli. Based on the rapid and broad-spectrum protection that the peptidoglycan backbone from lactic acid bacteria, bacterium-like particles (BLPs), offers, we hypothesized that BLPs enhance protection through trained immunity. Here, we found that combining BLP with a vaccine significantly improves protective efficacy against methicillin-resistant Staphylococcus aureus (MRSA) infection, accompanied by changes in trained immunity markers. We demonstrate that BLP-induced trained immunity macrophages exhibit increased cytokine secretion and phagocytic activity in vitro. In an in vivo model, BLP confers protection against S. aureus 26003 even without specific antigens. In an ex vivo model, BLP induces increased markers of trained immunity. Transcriptome analysis suggests that BLP may induce trained immunity by activating the IL-6-JAK-STAT3 pathway through TLR2 receptor activation, thereby modulating macrophage metabolic reprogramming and function. In summary, our study establishes that BLP induction of trained immunity, along with regulated metabolic reprogramming and macrophage function, may contribute to enhancing vaccine efficacy. Our findings elucidate a novel mechanism for BLP-mediated immune enhancement, critical for the application of BLP as a vaccine vector to construct a vaccine that combines specific immune response with innate immune response.
研究领域:
免疫学
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微生物学
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疫苗学
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分子生物学
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传染病学
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产品关联
DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
·
2023
·
IF 3.8
Shun Wang,Xiaodi Jin,Hao Chen,Mingdong Han,Jiaxin Bao,Dong Niu,Yikang Wang,Rui Li,Zhiyong Wu,Jichang Li
Chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum (MG) in chickens leads to enormous economic damage to the poultry industry yearly. The active components and mechanism of action of the traditional herbal remedy Ephedra houttuynia powder (EHP), which had been approved for clinical treatment against MG infection in China, remain unknown. In this study, the active components of EHP against MG were screened using a network pharmacological method, additionally, we studied the mechanism of action of the screened results (quercetin (QUE)). The findings demonstrated that QUE was an essential element of EHP against MG infection, effectively attenuating MG-induced oxidative stress and activation of the TLR2/MyD88/NF-κB pathway. Following QUE therapy, IL-1, IL-6, and TNF-α content and expression were downregulated, whereas IL-4 and IL-10 expression were upregulated, eventually suppressing the inflammatory response both in vitro and in vivo . Together, this study presents a strong rationale for using QUE as a therapeutic strategy to inhibit MG infection-induced inflammatory damage and oxidative stress.
研究领域:
兽医学
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药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Probiotics and Antimicrobial Proteins
·
2025
·
IF 4.4
Chen Fengming,Wu Shu,Wang Xiaoyu,Li Yinghui,He Binsheng,Fu Yafen,Huang Xingguo,Chen Jiayi
Reducing the negative impact of oxidative stress (OS) on weaned piglets is crucial for the further development of the pig industry. Our previous studies found that Lactobacillus delbrueckii (LAB) can alleviate OS and protect intestinal health by activating TLR2 and TLR4 expressions in weaned piglets. This research aimed to verify whether LAB can alleviate OS and intestinal barrier injuries in IPEC-J2 cells by activating TLR2 and TLR4. IPEC-J2 cells were first pretreated with 10 10 CFU/mL LAB for 12 h, and then were induced to OS by 0.8 mmol/L H 2 O 2 for another 12 h. The results showed that LAB significantly alleviated OS induced by H 2 O 2 , indicated by the downregulation of MDA ( P < 0.05), along with upregulation of GSH-Px, CAT, T-SOD, and T-AOC ( P < 0.05). Besides, LAB significantly alleviated intestinal barrier injuries induced by H 2 O 2 , indicated by the upregulation of Claudin-1, Occludin, and ZO-1 expressions. Subsequently, the IPEC-J2 cells were pretreated with inhibitors of TLR2 (TLR2-IN-C29) and TLR4 (MD2-TLR4-IN-1) in the absence of LAB for 12 h, and then treated with 0.8 mmol/L H 2 O 2 for another 12 h. The results showed that both inhibitors significantly prevented the protection effects of LAB on H 2 O 2 -induced OS, indicated by the downregulation of CAT, SOD1, HO-1, and GSH-Px1 expressions ( P < 0.05). Taken together, LAB treatment can alleviate OS and intestinal injuries induced by H 2 O 2 by activating TLR2 and TLR4 expressions in IPEC-J2 cells, thus providing novel theoretical support for LAB in the prevention and treatment of oxidative damage.
研究领域:
动物科学
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微生物学
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细胞生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Yan Lin,Xing-Jun Chen,Jing-Jing Li,Lei He,Ya-Ru Yang,Fei Zhong,Ming-Hui He,Yi-Tong Shen,Bo Tu,Xu Zhang,Zhu Zeng
Ethnopharmacology relevance Sophora flavescens Aiton, was a crucial source of Traditional Chinese Medicine (TCM) that has benefited human health for hundreds of years. Alkaloids and flavonoids were the major bioactive constituents from S. flavescens , which had been widely used for liver disease treatment in China. However, the liver-protective components of flavonoids from S. flavescens and their mechanism of action were not clear. Aim of the study This work aimed to evaluate the in vitro hepatoprotective activities of 35 flavonoids from S. flavescens and screen active compounds. Furthermore, it was conducted to demonstrate the hepatoprotective effects of a new active compound (kurarinol A, 1 ) was isolated by authors and the ethyl acetate (EtOAc) extract form S. flavescens against carbon tetrachloride (CCl 4 )-induced hepatic injury in Kunming (KM) mice, meanwhile revealed the potential mechanism. Materials and methods The 35 flavonoids from S. flavescens were co-incubated with HepG2 cells and treated with 0.35% CCl 4 for 6 h cell viability was measured by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay. Then, in vivo animal experiments, the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the serum were analyzed, the degree of hepatic injury was examined using hematoxylin-eosin (H&E) staining, the mRNA expression of Superoxide Dismutase 2 (SOD2), Nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), Interleukin 6 (IL-6), Tumor Necrosis Factor-α (TNF-α), interleukin-1β (IL-1β), and the protein levels of nuclear factor-kappa B p65/p-p65 (NF-κB p65/p-p65), toll-like receptor 2 (TLR2), IL-1β and cyclooxygenase-2 (COX2) in hepatic tissues were detected. Results The lavandulyl flavonoid (kurarinol A, 1 ) and the EtOAc extract from S. flavescens showed protective effects on CCl 4 -injured HepG2 cells, increasing cell viability from 24.5% to 61.3% and 91.8%, respectively. What’s more, we found that treatment with kurarinol A ( 1 ) and the EtOAc extract lead to a significant reduction in hepatotoxicity in response to acute CCl 4 exposure. Compared with the model group, experimental results exhibited kurarinol A (10 mg/kg, i.p.) and the EtOAc extract (300 mg/kg, i.p.) could decrease the levels of AST, ALT, ALP and tissue damage. Further mechanistic investigations revealed that up-regulated the mRNA expression of SOD2, Nrf2, OH-1 and down-regulated the IL-1β in liver tissues, respectively. Additionally, Western blot analyses elucidated that inhibition of IL-1β, TLR2, COX-2, NF-κB (p65/p-p65) via TLR2/NF-κB signaling pathway by kurarinol A and the EtOAc extract contribute to its hepatoprotective activity. Conclusion These findings demonstrated that the novel compound (kurarinol A, 1 ) possessed notable hepatoprotective activity against CCl 4 . It was confirmed that kurarinol A had a certain effect on mice with liver damage induced by CCl 4 , and its mechanism could be include inhibiting inflammation and reducing of oxidative stress reaction by regulating expression of related genes and proteins. Thus, kurarinol A could as a novel active agent that contributes to the hepatoprotective activity of S. flavescens for the treatment of live injury.
研究领域:
药理学
·
民族药理学
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分子生物学
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细胞生物学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2026
·
IF 11.2
Luyun Yang,Yingchao Li,Chunyan Yin,Litao Wu,Kexin Cheng,Jiafu Liang,Xiaona Cheng,Quan Zhang,Yakun Huang,Haoyun Bai,Wenlong Wang,Kaikai Lu,Rong Zhao,Zizhen Guo,Mingzhen Zhang,Shengli Han,Dongmin Li
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition resulting from complex interactions. With current clinical treatments showing limited efficacy, IBD poses an increasing global health challenge. Analysis of the GEO database, clinical samples from IBD patients, and a dextran sulfate sodium (DSS)-induced murine colitis model consistently reveal elevated Toll-like receptor 2 (TLR2) expression at both transcriptional and protein levels, implicating it in IBD pathogenesis and highlighting its potential as a therapeutic target. Previous studies have shown that Schisandrin B (SchB) protects DSS-induced colitis, but whether it directly targets an upstream immune receptor such as TLR2, and what additional mechanisms beyond its known anti-inflammatory actions exist, remain to be explored. In this study, SchB is identified as a moderate TLR2 ligand using cell membrane chromatography (CMC). By directly binding to TLR2 and inhibiting its heterodimerization with Toll-like receptor 1 (TLR1) or Toll-like receptor 6 (TLR6), SchB exerts significant anti-inflammatory and therapeutic effects in inflammatory cell models and ameliorates both DSS-induced ulcerative colitis and peptidoglycan (PGN)-induced immune colitis in mice. SchB inhibits TLR2 signaling and activates the sequestosome 1 (p62/SQSTM1)/Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis, concurrently exerting anti-inflammatory, antioxidant, and anti-apoptotic effects and reinforcing intestinal barrier integrity. These findings provide new evidence of molecular mechanisms supporting SchB as a promising therapeutic candidate for IBD.
✓ 已验证
DOI
高影响因子
Food Science and Technology
·
2021
·
IF 1.718
SHI Min,YIN Pengyi,GUO Xiaobo,LI Qian,SUN Lin,CAO Xiaohua
Baicalein has strong anti-inflammatory activity, but its efficacy and mechanism in pneumonia of mice is still unclear. Herein, RAW264.7 cells were infected with M. tuberculosis H37Rv (MOI 1:10) after pre-incubation with 50 μM baicalein, and the result found that baicalein incubation ameliorated the increase of bacterial load, and reduced the levels of ROS, IL-12p40, TLR2 protein, phosphorylated JNK protein and M1 polarization markers (iNOS and CD11c), and increased the levels of IL-10, M2 polarization markers (Arg1, Mrc1 and CD206) and NEDD4L protein in H37Rv infected-RAW264.7 cells. And lentivirus-mediated NEDD4L overexpression vector (LV-NEDD4L) transfection had the same effect as baicalein, while small interfering RNA target NEDD4L (si-NEDD4L) transfection or JNK pathway inhibitor IQ 3 treatment reversed the effects of baicalein, and ubiquitin inhibitor MG132 treatment reversed the effects of LV-NEDD4L. Co-immunoprecipitation (Co-IP) and TLR2 ubiquitination assays found that the binding of NEDD4L and TLR2 promoted the ubiquitination of TLR2. In vivo, C57BL/6 mice were nasal infected with H37Rv (1000 ± 150 CFU/mouse) to establish a mouse pneumonia model, and then administered with baicalein. The result found that baicalein improved H37Rv-induced pneumonia in mice. In conclusion, baicalein increased NEDD4L-mediated ubiquitination of TLR2, promoting macrophage M2 polarization and alleviating H37Rv-induced pneumonia.
研究领域:
免疫学
·
药理学
·
微生物学
·
分子生物学
✓ 已验证
DOI
高影响因子
ACS Nano
·
2025
·
IF 16
Yan Deng,Hao Cheng,Ji Zhu,Yue Jiang,Hongwu Sun,Guocheng Li,Jing Wei,Ruoyi Xue,Rang Feng,Jingwen Cao,Wenkang Yu,Yalan Wang,Mingqi Xu,Quanming Zou,Haibo Li
Parenteral subunit vaccines typically elicit systemic humoral immune responses but often struggle to induce mucosal immunity. Herein, we developed a promising adjuvant system, TB/P2C-NE, a tamibarotene-loaded nanoemulsion incorporating the TLR2/6 agonist Pam2CSK4. Upon intramuscular vaccination, TB/P2C-NE promoted antigen-specific mucosal immune responses in the gastrointestinal tract, accompanied by systemic humoral and cellular response. Mechanistically, tamibarotene upregulated the intestinal homing molecule CCR9 on lymphocytes through dendritic cell modulation, while Pam2CSK4 increased IL-6 secretion at the injection sites, further amplifying CCR9 expression and lymphocyte activation and leading to enhanced lymphocyte homing to the intestinal mucosa and a subsequent boost in mucosal immunity. Notably, TB/P2C-NE induced long-term gastrointestinal mucosal responses, maintaining elevated sIgA levels for up to three months post-immunization, and also induced gastrointestinal mucosal immunity in combination with a polysaccharide conjugate antigen. Immunization with recombinant intimin using TB/P2C-NE as the adjuvant resulted in a robust protective effect against the EHEC O157:H7 challenge. In summary, TB/P2C-NE offers an adjuvant strategy potentially accelerating the development of vaccines targeting gastrointestinal infections.
研究领域:
免疫学
·
疫苗学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 6
·
IF 7.7
Jiarun Xu,Guoyue Wei,Jianfeng Wang,Haoran Wang,Jian He,Jiaqi Xu,Wenguo Cao,Jialin Wang,Qi Shen,Nasi Ai,Yufang Su,Huaxi Yi,Lingjun Tong
Pre-inflammatory bowel disease (pre-IBD) represents a transitional state between irritable bowel syndrome and IBD, characterized by heightened susceptibility to mucosal inflammation driven by chronic high-fat diet intake and antibiotic exposure. However, effective intervention strategies remain poorly defined. Here, we identify milk-derived extracellular vesicles (mEVs) as a potent nanotherapeutic capable of attenuating pre-IBD pathology. Pre-IBD mice displayed marked gut microbiota dysbiosis and mucosal inflammation, both of which were substantially ameliorated by oral mEVs administration. Mechanistically, mEVs restored microbial homeostasis by enriching Lactobacillus murinus ( L. murinus ), which in turn reduced lysophosphatidylcholine (LPC) accumulation, two factors that exerted opposing and functionally instructive effects on intestinal inflammation. LPC activated the TLR2/MAPK axis to promote M1 polarization, whereas L. murinus engaged the TLR2/STAT3 pathway to drive M2 polarization. Collectively, these findings demonstrate that mEVs reprogram TLR2-dependent macrophage responses by modulating LPC and L. murinus , thereby mitigating mucosal inflammation and preventing the progression of pre-IBD.
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Guanghui Jiang,Bulei Wang,Yuwen Wang,Haoyue Kong,Yufei Wang,Peng Gao,Minghao Guo,Wenna Li,Jian Zhang,Zhezhi Wang,Junfeng Niu
Liver fibrosis has proven to be the main predisposing factor for liver cirrhosis and liver cancer; however, an effective treatment remains elusive. Polysaccharides , with low toxicity and a wide range of bioactivities, are strong potential candidates for anti-hepatic fibrosis applications. For this study, a new low molecular weight neutral polysaccharide ( B. striata glucomannan (BSP)) was extracted and purified from Bletilla striata . The structure of BSP was characterized and its activities for alleviating liver fibrosis in vivo were further evaluated. The results revealed that the structural unit of BSP was likely →4)-β-D-Glc p -(1 → 4)-β-D-Man p -(1 → 4)-β-D-2ace-Man p -(1 → 4)-β-D-Man p -(1 → 4)-β-D-Glc p -(1 → 4)-β-D-Man p -(1 → 4)-β-D-Man p -(1 → 4)-β-D-3ace-Man p -(1→, with a molecular weight of only 58.5 kDa. Additionally, BSP was observed to attenuate the passive impacts of liver fibrosis in a manner closely related to TLR2/TLR4-MyD88-NF-κB signaling pathway conduction. In summary, the results of this study provide theoretical foundations for the potential applications of BSP as an anti-liver fibrosis platform.
研究领域:
药理学
·
生物化学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-12
·
IF 39.3
Gu Yangzhuo,Yang Jingyun,He Cai,Zhao Tingmei,Lu Ran,Liu Jian,Mo Xianming,Wen Fuqiang,Shi Huashan
mRNA vaccines have emerged rapidly in recent years as a prophylactic and therapeutic agent against various diseases including cancer and infectious diseases. Improvements of mRNA vaccines have been underway, among which boosting of efficacy is of great importance. Pam2Cys, a simple synthetic metabolizable lipoamino acid that signals through Toll-like receptor (TLR) 2/6 pathway, eliciting both humoral and cellular adaptive immune responses, is an interesting candidate adjuvant. To investigate the enhancement of the efficacies of mRNA vaccines by Pam2Cys, the adjuvant was incorporated into mRNA-lipid nanoparticles (LNPs) to achieve co-delivery with mRNA. Immunization with the resulting mRNA-LNPs (Pam2Cys) shaped up the immune milieu in the draining lymph nodes (dLNs) through the induction of IL-12 and IL-17, among other cytokines. Antigen presentation was carried out mainly by migratory and dLN-resident conventional type 2 DCs (cDC2s) and significantly more potent antitumor responses were triggered in both prophylactic and therapeutic tumor models in a CD4 + and CD8 + T cell-dependent fashion. Accompanying memory antitumor immunity was also established. Moreover, the vaccine also stimulated much more robust humoral and cellular immunity in a surrogate COVID-19 prophylactic model. Last but not the least, the new vaccines exhibited good preliminary safety profiles in murine models. These facts warrant future development of Pam2Cys-incorporated mRNA vaccines or relevant mRNA therapeutics for clinical application.
研究领域:
免疫学
·
肿瘤学
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传染病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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