Nanomaterials
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2022
·Vol. 12
·期 12
·2072
·
IF 5.719
Tsogzolmaa Ganbold,Qingming Bao,Hai Xiao,Dolgorsuren Zurgaanjin,Caifeng Liu,Shuqin Han,Agula Hasi,Huricha Baigude
Ischemic stroke activates toll-like receptor 4 (TLR4) signaling, resulting in proinflammatory polarization of microglia and secondary neuronal damage. Herein, we report a novel lipid-nanoparticle (LNP)-mediated knockdown of TLR4 in microglia and amelioration of neuroinflammation in a mouse model of transient middle cerebral artery occlusion (tMCAO). siRNA against TLR4 (siTLR4) complexed to the novel LNP (siTLR4/DoGo310), which was based on a dioleoyl-conjugated short peptidomimetic (denote DoGo310), was readily internalized by the oxygen–glucose-deprived (OGD) mouse primary microglia, knocked-down TLR4, and polarized the cell to the anti-inflammatory phenotype in vitro. Systemic administration of siTLR4/DoGo310 LNPs in the tMCAO mice model resulted in the accumulation of siRNA mainly in the Iba1 positive cells in the peri-infarct. Analysis of the peri-infarct brain tissue revealed that a single injection of siTLR4/DoGo310 LNPs led to significant knockdown of TLR4 gene expression, reversing the pattern of cytokines expression, and improving the neurological functions in tMCAO model mice. Our data demonstrate that DoGo310 LNPs could be a promising nanocarrier for CNS-targeted siRNA delivery for the treatment of CNS disorders.Keywords:lipid nanoparticles;siRNA delivery;microglia;neuroinflammation;stroke
研究领域:
神经科学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2015
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IF 5.736
Xiaomin Xia,Juanli Fu,Xiufang Song,Qiong Shi,Chuanyang Su,Erqun Song,Yang Song
Fulminant hepatic failure (FHF) is a lethal clinical syndrome characterized by the activation of macrophages and the increased production of inflammatory mediators . The purpose of this study was to investigate the effects of neohesperidin dihydrochalcone (NHDC), a widely-used low caloric artificial sweetener against FHF. An FHF experimental model was established in mice by intraperitoneal injection of D-galactosamine ( d -GalN) (400 mg/kg)/lipopolysaccharides (LPS) (10 μg/kg). Mice were orally administered NHDC for 6 continuous days and at 1 h before d -GalN/LPS administration. RAW264.7 macrophages were used as an in vitro model. Cells were pre-treated with NHDC for 1 h before stimulation with LPS (10 μg/ml) for 6 h. d -GalN/LPS markedly increased the serum transaminase activities and levels of oxidative and inflammatory markers, which were significantly attenuated by NHDC. Mechanistic analysis indicated that NHDC inhibited LPS-induced myeloid differentiation factor 88 (MyD88) and TIR-containing adapter molecule (TRIF)-dependent signaling. Transient transfection of TLR4 or MyD88 siRNA inhibited the downstream inflammatory signaling. This effect could also be achieved by the pretreatment with NHDC. The fluorescence microscopy and flow cytometry results suggested that NHDC potently inhibited the binding of LPS to TLR4 in RAW264.7 macrophages. In addition, the inhibitory effect of NHDC on LPS-induced translocation of TLR4 into lipid raft domains played an important role in the amelioration of production of downstream pro-inflammatory molecules. Furthermore, the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) by NHDC inhibited TLR4 signaling. In conclusion, our results suggest that NHDC attenuates d -GalN/LPS-induced FHF by inhibiting the TLR4-mediated inflammatory pathway, demonstrating a new application of NHDC as a hepatoprotective agent.
研究领域:
免疫学
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肝病学
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药理学
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产品关联
DOI
PubMed
高影响因子
Cell Host & Microbe
·
2022
·
IF 31.316
Haiyang Lu,Xiaoqiang Xu,Di Fu,Yubei Gu,Rong Fan,Hongmei Yi,Xiangyi He,Chaofu Wang,Binshen Ouyang,Ping Zhao,Li Wang,Pengpeng Xu,Shu Cheng,Zhifeng Wang,Duowu Zou,Lizhong Han,Weili Zhao
Summary Microbiota-induced tumorigenesis is well established in solid tumors of the gastrointestinal tract but rarely explored in hematologic malignancies. To determine the role of gut microbiota in lymphoma progression, we performed metagenomic sequencing on human primary gastrointestinal B cell lymphomas. We identified a distinct microbiota profile of intestinal lymphoma, with significantly decreased symbiotic microbes, particularly the genus Eubacterium and notably butyrate-producing Eubacterium rectale . Transfer of E. rectale -deficit microbiota of intestinal lymphoma patients to mice caused inflammation and tumor necrosis factor (TNF) production. Conversely, E. rectale treatment reduced TNF levels and the incidence of lymphoma in sensitized Eμ-Myc mice. Moreover, lipopolysaccharide from the resident microbiota of lymphoma patients and mice synergizes with TNF signaling and reinforces the NF-κB pathway via the MyD88-dependent TLR4 signaling, amalgamating in enhanced intestinal B cell survival and proliferation. These findings reveal a mechanism of inflammation-associated lymphomagenesis and a potential clinical rationale for therapeutic targeting of gut microbiota.
研究领域:
肿瘤学
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免疫学
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2021
·
IF 2.73
Jinhui Dong,Ou Xu,Jianxing Wang,Chunguang Shan,Xiumin Ren
Objective Luteolin has an anti-allergic effect but its mechanism is not clear. This study attempted to determine the mechanisms of luteolin in rhinitis.Methods Allergic rhinitis rat model was established by ovalbumin (OVA) stimulation. Then, the rats were treated with normal saline, luteolin, or lipopolysaccharide (LPS) for 14 days. Nasal symptoms were scored; the histopathological changes of nasal mucosa were detected by hematoxylin–eosin staining. Serum levels of Th1 type cytokines (IFN-γ, IL-2), Th2 type cytokines (IL-4, IL-5, IL-13), and OVA-specific IgE (sIgE) were determined by ELISA. The expressions of Toll-like receptor 4 (TLR4) and p65 in nasal mucosa were detected by Western blot or immunohistochemistry.Results Luteolin decreased symptom scores, specifically, the scores in control group, model group, model + 0.1 mg/kg luteolin, model + 1 mg/kg luteolin, and model + 10 mg/kg luteolin groups were 0.63 ± 0.52, 7.88 ± 0.83, 1.38 ± 0.52, 2.75 ± 0.46, and 5.00 ± 0.53, respectively. Luteolin ameliorated nasal mucosa inflammation by promoting the down-regulated levels of Th1 type cytokines, and suppressing the up-regulated levels of Th2 type cytokines, OVE-sIgE, TLR4, and p65. LPS further increased symptom scores, aggravated nasal mucosa inflammation, improved the unbalance of Th1/Th2 type cytokines, and lowered the expressions of OVE-sIgE, TLR4, and p65. Moreover, LPS reversed the effect of luteolin on allergic rhinitis rats.Conclusion Luteolin ameliorated inflammation and Th1/Th2 imbalance via regulating the TLR4/NF-κB pathway in allergic rhinitis rats. This study provided novel evidence that luteolin could be used as a candidate drug in allergic rhinitis treatment.
研究领域:
免疫学
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药理学
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过敏
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
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2025
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IF 4
Ping Jiang,Yanfei He,Guangpei Xu,Chuanbo Sun
This study aims to evaluate the mechanism of RCH against CCl 4 -induced liver injury in mice. RCH treatment effectively inhibited CCl 4 -induced liver injury and apoptosis in mice, and reduced liver enzyme activities, blood inflammatory cell and serum inflammatory factor levels. Network pharmacology and machine learning predicted that PI3K-Akt pathway and Met proteins play important roles in RCH anti-CCl 4 -induced liver injury. The results of qRT-PCR and Western blot showed that RCH could down-regulate the expression of the receptor proteins Met, Tlr2, and Tlr4, and inhibit the phosphorylation of Pik3ca and Akt1, and prevent the phosphorylation of NF-κB P65, and decrease cleaved Caspase3 expression. These findings suggest that RCH effectively alleviated liver injury in CCl 4 -induced mice by inhibiting the Met/Tlr2/Tlr4-mediated PI3K-Akt signaling pathway.
研究领域:
药理学
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分子生物学
✓ 已验证
DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2021
·
IF 6.025
Rili Hao,Yang Jiang,Feng Li,Dongxiao Sun-Waterhouse,Dapeng Li
Cadmium (Cd) is a toxic heavy metal pollutant that can be accumulated in organs including the spleen, thereby threatening human health. In this study, the effect of caffeic acid phenethyl ester (CAPE, a bioactive component of honeybee propolis) on CdCl 2 -induced spleen toxicity and underlying mechanisms were examined in mice. Histological examinations revealed that CAPE (10 μmol/kg/day b.w.) could mitigate spleen damage induced by CdCl 2 (1.5 mg/kg/day b.w.) in mice. Compared to the mice treated only by CdCl 2 , CAPE administration increased the body weight while decreasing the spleen weight, spleen Cd content and spleen to body ratio of the CdCl 2 -treated mice. Western blot and ELISA tests revealed that CAPE suppressed CdCl 2 -induced inflammation (indicated by the decreases in the levels of inflammatory indictors). TUNEL and Western blot results showed that CAPE suppressed CdCl 2 -induced apoptosis through reducing the percentage of TUNEL-positive cells and regulating apoptosis factors. The antagonistic effect of CAPE against CdCl 2 -induced spleen toxicity was realized by increasing miR-182–5p expression to regulate the TLR4/NF-κB pathway. Therefore, CAPE could be a food-derived spleen protector to counteract Cd-induced spleen toxicity through alleviating apoptosis and inflammation via the miR-182–5p/TLR4/NF-κB axis.
研究领域:
毒理学
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药理学
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分子生物学
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
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2024
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IF 4.8
Danliangmin Song,Jingqi Cheng,Kai Dong,Shiyu Liu,Chaoxin Man,Shiqian Fu,Xinyan Yang,Qianyu Zhao,Yujun Jiang
Cronobacter sakazakii is a facultative anaerobic gram-negative pathogen that has attracted widespread attention for causing necrotizing enterocolitis in infants (premature and low-weight newborns) by contaminating powdered infant formula. Several studies have found that the antibiotic tolerance of Cronobacter sakazakii isolated from food sources is increasing, thereby markedly increasing the difficulty of clinical treatment of Cronobacter sakazakii infection. At present, most studies are focused on clarifying the pathogenicity of Cronobacter sakazakii , but there is still a gap in the study of necrotizing enterocolitis in neonatal rats caused by Cronobacter sakazakii with different antibiotic tolerance. To fill this gap, we analyzed and compared the ability of Cronobacter sakazakii induced by different classes of antibiotics to induce necrotizing enterocolitis in neonatal rats by mediating TLR4-NLRP3-IL-1β pathway. In the results, Cronobacter sakazakii acquired tolerance to aminoglycosides, quinolones and cephalosporins, and caused more inflammatory damage in neonatal rats, improved the ability of mediating TLR4-NLRP3-IL-1β pathway to induce necrotizing enterocolitis. Compared with the XS001 group, the NEC scores of neonatal rats in XS001-Amp, XS001-Ami, XS001-Ofl and XS001-Ceo groups were increased by 8.3%, 58.3%, 50.0% and 58.3%. The acquisition of penicillin and tetracycline tolerance had little effect on the ability of Cronobacter sakazakii to induce necrotizing enterocolitis in neonatal rats. The ability of Cronobacter sakazakii to induce necrotizing enterocolitis in neonatal rats was significantly different due to the type and tolerance of antibiotics.
研究领域:
微生物学
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免疫学
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儿科
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分子生物学
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DOI
高影响因子
iScience
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2024
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IF 4.6
Kerong Liu,Ying Gu,Xingnan Pan,Sha Chen,Jie Cheng,Le Zhang,Minkai Cao
Gestational diabetes mellitus (GDM) is a distinct form of diabetes that poses a significant threat to the health of both pregnant women and fetuses. The objective of this study was to investigate the impact of behenic acid (BA) on glucose metabolism, inflammation, and insulin resistance in GDM mice, and to elucidate the underlying molecular mechanism. Here, we demonstrated that daily administration of 10 mg/mL BA during pregnancy effectively ameliorated abnormal glucose metabolism in GDM mice and their offspring and improved birth outcomes in the offspring. Moreover, BA promoted the proliferation of islet β cells, restored their normal function, and augmented glucose uptake by skeletal muscle cells. Mechanistically, BA mitigated inflammation and insulin resistance in GDM mice by inhibiting activation of the TLR4/NF-κB signaling pathway. Our study provides compelling evidence supporting the efficacy of BA in improving GDM, suggesting its potential use as a dietary supplement for preventing and treating GDM.
研究领域:
内分泌学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Natural Products and Bioprospecting
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2024
·Vol. 14
·期 1
·1-12
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IF 4.8
Shi Yuru,Zhang Xiaoqian,Pei Shengji,Wang Yuhua
Adenosma buchneroides Bonati, also known as fleagrass, is an important medicinal plant used by the Akha (Hani) people of China for treating inflammation-related skin swelling, acne, and diarrhoea, among other conditions. In this study, we aimed to evaluate the anti-inflammatory activities and explore the molecular mechanisms of fleagrass on treating skin swelling and acne. The results demonstrated that fleagrass inhibited the enzymatic activities of 5-LOX and COX-2 in vitro, and decreased the release of NO, IL-6, TNF-α, and IL-10 in the LPS-induced RAW264.7 macrophages. The levels of proteins associated with the nuclear factor-kappa B (NF-κB) pathway were examined by western blotting and immunofluorescence, demonstrating that fleagrass downregulated the expression of TLR4, MyD88, NF-κB/p65, and iNOS and blocked the nuclear translocation of NF-κB/p65. Furthermore, fleagrass exhibited acute anti-inflammatory activity in paw oedema models. The results confirm that fleagrass exhibits remarkable anti-inflammatory activity and can be used in alleviating inflammation, suggesting that fleagrass has the potential to be a novel anti-inflammatory agent. Graphical Abstract
研究领域:
民族药理学
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药理学
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炎症
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药用植物
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2020
·Vol. 11
·期 9
·7925-7934
·
IF 4.171
Yi-Chao Du,Li Lai,Hao Zhang,Fu-Rui Zhong,Huan-Li Cheng,Bao-Lin Qian,Peng Tan,Xian-Ming Xia,Wen-Guang Fu
Acetaminophen (APAP) is one of the safest and most effective over-the-counter (OTC) analgesics and antipyretics, but excessive doses of APAP will induce hepatotoxicity with high morbidity and mortality worldwide. Kaempferol (KA), a flavonoid compound derived from the medicinal and edible plant of Penthorum chinense Pursh, has been reported to exert a profound anti-inflammatory and antioxidant activity. In this study, we explored the protective effect and novel mechanism of KA against APAP-induced hepatotoxicity. The results revealed that KA pretreatment significantly reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), relieved hepatocellular damage and apoptosis, attenuated the exhaustion of glutathione (GSH) and accumulation of malondialdehyde (MDA), increased the expression of antioxidative enzymes (e.g., heme oxygenase 1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1)), and thus restrained APAP-induced oxidative damage in the liver. KA suppressed the expression of NLRP3 and reduced the levels of pro-inflammatory factors, including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Moreover, KA remarkably inhibited high-mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) expression as well as nuclear factor kappa-B (NF-κB) activation for liver protection against APAP-induced inflammatory responses and apoptosis. Taken together, our findings suggested that KA could effectively protect hepatocytes from APAP hepatotoxicity through the up-regulation of HO-1 and NQO1 expression, the down-regulation of NLRP3 expression, and the inhibition of the HMGB1/TLR4/NF-κB signaling pathway.
研究领域:
药理学
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毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
·
IF 4.8
Jing Guo,Qi-Yun Zhang,Lin Xu,Min Li,Qian-Yun Sun
Acute lung injury (ALI) is an acute respiratory-related progressive disorder, which lacks specific pharmacotherapy. Icariin (ICA) has been shown to be effective in treating ALI. However, the targets and pharmacological mechanisms underlying the effects of ICA in the treatment of ALI are relatively lacking. Based on network pharmacology and molecular docking analyses, the gene functions and potential target pathways of ICA in the treatment of ALI were determined. In addition, the underlying mechanisms of ICA were verified by immunohistochemistry, immunofluorescence, quantitative Real-time PCR, and Western blot in LPS-induced ALI mice. The biological processes targeted by ICA in the treatment of ALI included the pathological changes, inflammatory response, and cell signal transduction. Network pharmacology, molecular docking, and in vivo experimental results revealed that ICA inhibited the complement C5a-C5aR1 axis, TLR4 mediated NF-κB, MAPK, and JAK2-STAT3 signaling pathways related gene and protein expressions, and decreased inflammatory cytokine, chemokine, adhesion molecule expressions, and mitochondrial apoptosis in LPS-induced ALI.
研究领域:
药理学
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免疫学
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分子生物学
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呼吸医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INFLAMMOPHARMACOLOGY
·
2025
·
IF 5.3
Li Lirong,Huang Rui,Li Wenwen,Yao Dengjie,Zhang Beibei,Li Mengna,Luo Shunan,Qin Yu,Zhang Wenwen
Camellia nitidissima Chi (CNC), whose main composition was gallic acid, catechin, procyanidin-gallate, apigenin-pentosyl-glucoside, vitexin, cyanidin-3-o-glucoside, myricitrin-glucoside, gallocatechin-gallate, epicatechin and rutin, posses sound anti-inflammatory and antioxidant effects. This study aimed to explore the protective effects and mechanisms of the alcoholic extract of CNC on dextran sulfate sodium-induced ulcerative colitis. CNC effectively maintained weight and colon length, and significantly ameliorated colonic histopathological damage. Furthermore, CNC mitigated colitis-induced oxidative stress and exhibited anti-inflammatory properties in UC mice by reducing levels of myeloperoxidase (MPO) and malondialdehyde (MDA), decreasing the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, CNC downregulated the protein expression levels of TLR4, p-NF-κBP65, and p-IκBα of the inflammation-related TLR4/NF-κB signaling pathways. Validation of the molecular docking results also revealed that rutin, the most abundant compound in CNC, interacts with TLR4 and NF-κB protein mainly through hydrogen bonds. CNC also promoted the proliferation of Lactobacillus and Bifidobacterium while reducing the number of Enterococcus , E. coli , Bacteroides, and Peptococcus in mice to improve the intestinal environment and alleviate colitis. CNC inhibited TLR4/NF-κB signaling pathways to relieve inflammation and oxidative damage on UC, is a potential development of natural medicine for UC.
研究领域:
药理学
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免疫学
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消化病学
✓ 已验证
DOI
PubMed
高影响因子
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