BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Yelin Tang,Wenxin Zhang,Liqin Wu,Bin Bai,Bin Zheng,Mengying Li,Yue Tang,Xiaona Zhu,Yali Zhang,Yi Wang,Bing Zhang
Purpose Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target. Methods In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance , ELISA and immunoprecipitation assay. Results It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines , and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization . Conclusions As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.
研究领域:
药理学
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免疫学
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肺医学
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2025
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IF 4
Rui Ge,Qikai Su,Jian Liang,Lu Zheng,Qing-shan Li,Li Tang
The identification of natural compounds with therapeutic efficacy for acute lung injury has consistently represented a critical area of research. Dulcitol, a natural product isolated from plants, is extensively used in the food and medical industries as a sweetener. Herein, we investigated whether dulcitol exerts an anti-inflammatory effect on LPS-induced acute lung injury (ALI) in mice. In our study, ICR mice were pretreated with dulcitol at dose of 6, 12 and 24 mg/kg for seven consecutive days, followed by intratracheally instilled with LPS (10 mg/kg) to induce acute lung injury. In vitro, RAW264.7 and A549 cells were incubated with LPS in the presence of dulcitol to investigate the anti-inflammatory activity and mechanism. The results demonstrated that dulcitol effectively inhibited the infiltration of inflammatory cells and reduced the excessive production of pro-inflammatory cytokines triggered by LPS to ameliorates acute lung injury in mice. Additionally, in vitro experiments indicated that dulcitol suppressed the release of NO, IL-6 and TNF-α while reducing mRNA expression levels of IL-1β, IL-6, COX-2, iNOS and TNF-α in RAW264.7 and A549 cells in a dose-dependent manner. Furthermore, dulcitol significantly decreased TLR4, MyD88, and TRIF levels and inhibited the translocation of NF-κB from the cytoplasm to the nucleus. Our finding suggested that dulcitol could serve as a protective agent against LPS-induced acute lung injury by inhibiting the TLR-4/NF-κB signaling pathway.
研究领域:
免疫学
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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
高影响因子
Oncotarget
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2016
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IF 5.008
Dong Yang,Xinchuan Zheng,Ning Wang,Shijun Fan,Yongjun Yang,Yongling Lu,Qian Chen,Xin Liu,Jiang Zheng
Free bacterial lipopolysaccharide (LPS) is generally removed from the bloodstream through hepatic uptake via TLR4, the LPS pattern recognition receptor, but mechanisms for internalization and clearance of conjugated LPS are less clear. Kukoamine B (KB) is a novel cationic alkaloid that interferes with LPS binding to TLR4. In this study, KB accelerated blood clearance of LPS. KB also enhanced LPS distribution in the hepatic tissues of C57 BL/6 mice, along with LPS uptake in primary hepatocytes and HepG2 cells. By contrast, KB inhibited LPS internalization in Kupffer and RAW 264.7 cells. Loss of TLR4 did not affect LPS uptake into KB-treated hepatocytes. We also detected selective upregulation of the asialoglycoprotein receptor (ASGPR) upon KB treatment, and ASGPR colocalized with KB in cultured hepatocytes. Molecular docking showed that KB bound to ASGPR in a manner similar to GalNAc, a known ASGPR agonist. GalNAc dose-dependently reduced KB internalization, suggesting it competes with KB for ASGPR binding, and ASGPR knockdown also impaired LPS uptake into hepatocytes. Finally, while KB enhanced LPS uptake, it was protective against LPS-induced inflammation and hepatocyte injury. Our study provides a new mechanism for conjugated LPS hepatic uptake induced by the LPS neutralizer KB and mediated by membrane ASGPR binding.
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
INFLAMMATION
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2015
·Vol. 39
·期 1
·467-472
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IF 2.208
Qiang Li,Yuan Jiang,Shouyin Jiang,Yulin Li,Libing Jiang,Jian-an Wang
Recent studies suggested that TLR4 signaling pathways played an important role in the development of LPS-induced acute lung injury (ALI). Sesamin, a sesame lignan exacted from sesame seeds, has been shown to exhibit significant anti-inflammatory activity. The purpose of this study was to investigate the anti-inflammatory effects of sesamin on LPS-induced ALI in mice. Mice ALI model was induced by intratracheal instillation of LPS. Sesamin was given 1 h after LPS challenge. Our results showed that sesamin inhibited LPS-induced lung pathological change, edema, and myeloperoxidase (MPO) activity. Sesamin suppressed LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1β production. Furthermore, sesamin inhibited LPS-induced TLR4 expression and NF-κB activation. In conclusion, the results of this study indicated that sesamin protected against LPS-induced ALI by inhibition of TLR4 signaling pathways.
研究领域:
免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2023
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IF 3.5
Wenbin Wang,Shiyang Zhou,Wenming Jiang,Guangying Chen
A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro , compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC 50 values of 1.21 ± 0.09 μM, 0.73 ± 0.05 μM and 0.43 ± 0.03 μM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1β and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.
研究领域:
免疫学
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药理学
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医学
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DOI
PubMed
高影响因子
Food Frontiers
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2025
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IF 6.9
Xiaoli Qin,Yan Lu,Yawen Luo,Yafang Cui,Kai Zhao,Yang He,Muhammad Aziz ur Rahman,Shengnan Min,Wenfang Wang,Fuyu Yang,Binghai Cao,Huawei Su
Alfalfa is rich in flavonoid compounds, which are known for their antioxidative and anti-inflammatory properties, suggesting therapeutic potential for alfalfa flavonoids (AF) in inflammation-related diseases. This study investigated the effects of AF on Salmonella -induced colitis, a severe inflammatory bowel disorder characterized by oxidative damage and inflammatory response. In vitro, antioxidant assays revealed AF's concentration-dependent radical scavenging, significantly reducing electron paramagnetic resonance (EPR) signals for HO • and O 2 •− by 42% and 54%, respectively. In vivo, AF treatment significantly mitigated body weight (BW) loss by 6%, increased colon length by 11%, and reduced liver and spleen weights by 19% and 81%, respectively, compared to the colitis group. Mechanistically, AF suppressed inflammation by downregulating the Toll-like receptor 4 (TLR4)/IκB/nuclear factor-κB (NF-κB)/cyclooxygenase-2 (COX-2) pathway and inhibiting nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation, thereby lowering levels of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin 6 [IL-6], interleukin 1 beta [IL-1β]). Concurrently, AF enhanced antioxidant defense via the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels while increasing catalase (CAT) (69%), glutathione peroxidase (GPx) (83%), and superoxide dismutase (SOD) (21%) activities. Moreover, AF preserved epithelial and mucosal barriers by reducing apoptosis and upregulating tight junction proteins (Claudin1, ZO-1, E-cadherin) and goblet cell marker Ulex europaeus (Gorse) Agglutinin I (UEA-1). Microbiota analysis revealed that AF significantly enriched beneficial bacteria, including Akkermansia , Oscillibacter , and butyrate-producing taxa, thereby counteracting Salmonella -induced dysbiosis. Furthermore, AF restored the disrupted profile of short-chain fatty acids (SCFAs), strengthening the relationship between symbiotic microbiota and mucosal defense. Overall, AF exerted multifaced protection against Salmonella -induced colitis by alleviating oxidative stress, stabilizing intestinal homeostasis, and thus attenuating inflammation. These findings make AF a promising phytopharmaceutical for the prevention and treatment of inflammatory diseases.
研究领域:
药理学
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微生物学
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免疫学
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产品关联
DOI
高影响因子
PLACENTA
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2024
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IF 3
Caiqun Huang
Introduction T oxoplasma gondii is an opportunistic intracellular parasite that is a major pathogenic factor in miscarriage, especially when it occurs early in pregnancy. We have previously demonstrated that the regulation of forkhead box transcription factor (Foxp3) is associated with abortion in early pregnancy caused by excretory-secretory antigen (ESA) of strain China 1. We aimed to reveal the underlying mechanism of miscarriage caused by ESA. Methods A TLR4 −/− pregnant mouse model was successfully constructed. Pregnant mice at gestational day 5 (G5) were injected with ESA. All animals were sacrificed on G13, pregnancy outcomes were observed, and abortion rates were calculated. Placental status observed by Hematoxylin-eosin staining; gene expression was measured by IHC; flow cytometry analysis was used to determine the number and function of regulatory T cells. In EL4 cells, real-time PCR and Western blot were used to evaluate gene expression and cytokines assay. Results In vivo studies revealed that ESA injection caused 83% abortion in pregnant mice but only 35% abortion in TLR4−/− pregnant mice. In addition, ESA attenuated the number and function of regulatory T cells, further suppressed Foxp3, FOXO1 levels, and upregulated CD127 expression. TLR4 −/− mice partially reversed this inhibitory effect on regulatory T cells. Furthermore, in vitro studies revealed that ESA inhibited TLR4/NF-κB signaling pathway expression and that TLR4 agonists significantly restored the ESA-induced decrease in Foxp3. Discussion These findings suggest that ESA suppresses Foxp3 expression by blocking TLR4/NF-κB signaling, resulting in miscarriage. More importantly, the results indicated that miscarriage caused by ESA is TLR4 dependent.
研究领域:
免疫学
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寄生虫学
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生殖生物学
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
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2024
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IF 1.4
Chen Xue,Kang Yulai,Tang Chunhua,Zhang Lili,Guo Lu
Foam cells are primarily formed through scavenger receptors that mediate the uptake of various modified low-density lipoproteins (LDL) into cells. In addition to the receptor-dependent pathway, macropinocytosis is an essential non-receptor endocytic pathway for vascular smooth muscle cells (VSMCs) to take up lipids. However, the molecular mechanisms underlying this process remain unclear. Primary cultured VSMCs were stimulated with 200 ng/ml lipopolysaccharide (LPS) and 200 μg/ml native LDL (nLDL). We observed a significant increase in TLR4 protein expression and a significant activation of macropinocytosis, which correlated with the highest uptake of nLDL and intracellular lipid deposition in WT VSMCs. However, macropinocytosis was inhibited and lipid accumulation decreased after treatment with macropinocytosis inhibitors and Syk inhibitors in WT VSMCs. Consistently, TLR4 knockout significantly suppressed macropinocytosis and lipid droplets accumulation in VSMCs. Taken together, our findings suggest a critical role of TLR4/Syk signaling in promoting receptor-independent macropinocytosis leading to VSMC-derived foam cells formation.
研究领域:
心血管生物学
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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
Frontiers in Nutrition
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2022
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IF 6.59
Weifang Wang,Yunfeng Li,Guojing Han,Aimin Li,Xiaomei Kong
Background Asthma is a chronic disease, which is harmful to the health of the body and the quality of life. Supplementation of Lactobacillus can affect the immune environment of the lungs through the gut-lung axis. This study aimed to explore the potential regulatory targets of Lactobacillus to relieve inflammation in asthma and determine a new approach for improving asthma. Methods A mouse ovalbumin (OVA)-induced model was constructed. OVA mice were supplemented with Lactobacillus fermentum CECT5716 by gavage. The gut microbiota composition of normal and OVA mice was analyzed using 16S ribosomal DNA identification. BALF, serum, lung tissues, and duodenal tissues were collected. Wright’s staining was performed to determine the cell content of the alveolar lavage fluid. Hematoxylin-eosin staining, Masson staining, and periodic acid-Schiff staining were performed to observe the improvement in the lungs of OVA mice supplemented with Lactobacillus . Immunofluorescence was performed to measure the severity of the intestinal barrier leakage. Enzyme-linked immunosorbent assay was carried out to determine the expression levels of inflammatory cell factors, while quantitative reverse transcription-polymerase chain reaction and western blotting were performed to detect the levels of toll-like receptor 2 (TLR2)/TLR4 expression and cell adhesion factors. Results Compared with Control mice, OVA mice exhibited malignant conditions, such as intestinal leakage and lung edema. After supplementation with Lactobacillus , the inflammatory cell content in the bronchoalveolar lavage fluid decreased, and the inflammatory response was alleviated. The level of TLR2/TLR4 expression was reduced. The inflammatory cell infiltration in the airway mucosa of OVA mice was improved, alveolar swelling was reduced and the basement membrane appeared thinner. Conclusion The Lactobacillus inhibited the TLR2/TLR4 expression in OVA mice. Supplementation with Lactobacillus can alleviate the inflammatory response in OVA mice, inhibit pulmonary fibrosis, and treat asthma.
研究领域:
免疫学
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微生物学
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呼吸病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Miaomiao Sun,Honghong Zhan,Xiaoliang Long,Ali M. Alsayed,Zhe Wang,Fancheng Meng,Guowei Wang,Jingxin Mao,Zhihua Liao,Min Chen
Background Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. Purpose The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. Methods The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo . And DHL on reducing inflammatory response and regulating TLR4/NF‐κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. Results DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. Conclusion This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11.
研究领域:
药理学
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免疫学
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肿瘤学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
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2024
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IF 3
Lihong Liang,Xue Yang,Hao Zeng,Kai Liao,Runze Zhang,Bowen Wang,Jin Yuan
This research focused on how upregulation of S100A9 contributed to the pathogenesis of the dry eye disease (DED) and whether S100A9 served as a promising therapeutic target in DED. Public single-cell RNA sequencing (scRNA-seq) data of a lacrimal gland excision (LGE) murine DED model was analyzed. LGE model was established and expression of protein was measured through immunofluorescence and western blot. DED-related signs were evaluated through tear secretion and fluorescent staining. TUNEL was performed to detect the level of cell death. Briefly, S100A9 was recognized as a highly variable gene in the DED group. LGE model was successfully established, and S100A9 showed a time-dependent increase in the corneal epithelia. Autophagic blockage was predicted by the scRNA-seq data in DED, and further verified by decrease of LC3B-II/LC3B-I and increase of SQSTM1 and p-mTOR/mTOR, while S100A9 inhibitor paquinimod (PAQ) reversed the changes. PAQ also downregulated TLR4, and inhibition of TLR4 also alleviated autophagic blockage in DED. Finally, signs of DED, chronic corneal inflammation and cell death got a remission after either inhibition of S100A9 or TLR4. In general, we deduced a S100A9-TLR4-Autophagic blockage pathway in the pathogenesis of DED.
研究领域:
眼科
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免疫学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Shanbo Ma,Rui Zhang,Long Li,Jin Wang,Meiling Zheng,Xiaodi Guo,Shan Miao,Wei Quan,Wenjuan Liu,Xiaopeng Shi
The current study isolated a homogeneous polysaccharide (AP) with a molecular weight of 7.9 kDa from the pomace of Fuji apples. AP was found to consists of rhamnose, galactose, arabinose, glucose, and galacturonic acid in a ratio of 4.3:5.2:2.6:1.0:11.9. Ten sugar residues in AP, including T-Ara f , 1,5-Ara f , 1,2-Rha p , 1,3-Rha p , T-Gal p , 1,3,5-Ara f, 1,4-Gal p , 1,4-Gal p A, 1,6-Glc p , and 1,3,6-Glc p were identified using methylation and GC–MS. Combined with 1D and 2D NMR, it was further revealed that AP possesses a backbone of α-Gal p- (1 → [3)-α-Rha p -(1 → 2)-α-Rha p -(1] 2 → [4)-α-Gal p A-(1] 10 → 3,6)-β-Glc p -(1 → 6)-β-Glc p -(1 → 4)-β-Gal p -(1 → 4)-β-Gal p -(1→, with two branches: α-Ara f -(1 → 5)-α-Ara f -(1 → 5)-α-Ara f -(1 → 3,5)-α-Ara f -(1 → 6)-β-Glc p -(1→ and →3)-α-Rha p -(1 → 5)-α-Ara f -(1 → 3,6)-β-Glc p -(1→ bonded to the C-3 of β-1,3,6-Glc p . AP significantly inhibited the release of cytokines and inflammatory mediators, such as TNF-α, IL-1β, IL-6, reactive oxygen species (ROS) and nitric oxide (NO). Western blotting results indicated that AP treatment markedly downregulated iNOS and NF-κB protein expression in LPS-induced RAW264.7 cells, leading to decreased levels of phosphorylated proteins (p-NF-κB and p-ΙκΒα) and preventing the degradation of ΙκΒα. Furthermore, in LPS-induced RAW264.7 macrophages, AP inhibited the expression of TLR4 protein, which in turn inhibited the activity of the NF-κB pathway. The findings demonstrated that AP exhibits anti-inflammatory properties in vitro by targeting the TLR4/NF-κB signaling pathway, thus impeding the nuclear translocation of NF-κBp65, suppressing the expression of related pro-inflammatory factors.
研究领域:
食品科学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）