CHEMICAL & PHARMACEUTICAL BULLETIN
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2022
·Vol. 70
·期 1
·66-73
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IF 1.903
Li Han,Aimei Chen,Ling Liu,Fang Wang
Despite the precise mechanisms for renal ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) are poorly understood, nuclear factor erythroid 2 related factor 2 (Nrf2) and Toll-like receptor 4 (TLR4) pathways were considered as the important targets. Leonurine (LEO) is a special alkaloid extracted from Chinese motherwort (Leonurus japonicus Houtt), which has an anti-inflammatory effect and reduces oxidative stress. We conducted the study to explore the efficacy of LEO against I/R-induced AKI in rats and further investigated the underlying mechanisms. Ischemic renal injury was induced by temporary vascular clamping for 45 min. We have measured the levels of inflammation-related biomarkers and antioxidative stress markers. Next, Western blot analysis and Real-time PCR were performed to analyze whether the Nrf2 and TLR4/nuclear factor-kappaB (NF-κB) pathways were involved in this process. We found that LEO pretreatment remarkably decreased serum creatinine and blood urea nitrogen (BUN) in I/R rats and attenuated acute tubular damage. In addition, LEO markedly increased the expression of antioxidant proteins and decreased the levels of inflammatory factors. Further study revealed that LEO promoted Nrf2 into the nucleus, promoted the expression of heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1), and suppressed the TLR4/NF-κB signal pathway in kidney tissues of ischemic AKI rats. The study reveals that LEO has a protective effect to prevent ischemic AKI through activation of Nrf2 nuclear translocation resisting oxidative stress injury and inhibition of the TLR4/NF-κB pathway mediated inflammatory gene expression.
研究领域:
药理学
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肾病学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
Microorganisms
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2021
·Vol. 9
·期 9
·1983
·
IF 4.128
Shiyan Chen,Yanan Li,Bingxin Chu,Lanxin Yuan,Ning Liu,Yaohong Zhu,Jiufeng Wang
SalmonellaTyphimurium (S.Typhimurium) is an aggressive zoonotic pathogen that causes enteritis and diarrhea. Antibiotic therapy is still the primary method at present. However, the increasing emergence of multi-drug resistant bacteria weakens the therapeutic efficacy of antibiotics. Probiotics have been widely studied as an alternative antibiotic therapy. In this study, we established an IPEC-J2 cell model ofS.Typhimurium infection, aiming to determine the protective effect ofLactobacillus johnsoniiL531 (L. johnsoniiL531) onS.Typhimurium infection. As our data showed,S.Typhimurium infection resulted in a robust inflammatory response demonstrated by promoted protein levels of the inflammatory-related pathway (TLR4, MyD88, p-IκBα, and p-p65), increased cytokine levels of IL-6, IL-1β, IL-18, and TNF-α, and activated the NLRP3 inflammasome via promoting its assembly. However,L. johnsoniiL531 pre-incubation inhibited the activation of the above inflammatory signaling pathways and reduced the expression levels of pro-inflammatory cytokines. In addition,L. johnsoniiL531 alleviated the damage ofS.Typhimurium to tight junctions ZO-1, Occludin, and Claudin-1. In summary, our findings suggested thatL. johnsoniiL531 alleviatedS.Typhimurium-induced tight junction injury by inhibiting the TLR4/NF-κB/NLRP3 inflammasome signaling pathway.Keywords:SalmonellaTyphimurium;Lactobacillus johnsonii;TLR4;NF-κB;NLRP3 inflammasome;tight junctions
研究领域:
微生物学
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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
BIOMATERIALS
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2023
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IF 14
Li Liu,Shengxiang Fu,Wencheng Zhu,Zhongyuan Cai,Yingzi Cao,Yubing Huang,Li Yang,Xiaomin Fu,Rongrong Jin,Chunchao Xia,Yunjiao Zhang,Su Lui,Qiyong Gong,Bin Song,Longping Wen,James M. Anderson,Hua Ai
Carbohydrates have emerged as promising candidates for immunomodulation , however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles , comparing to mannose and galactose . In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK , and STAT1 signaling pathways . Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy .
研究领域:
癌症免疫疗法
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纳米技术
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免疫学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Sumin Ge,Sihua Wu,Qin Yin,Meng Tan,Sichuan Wang,Yonghao Yang,Zixuan Chen,Lei Xu,Hui Zhang,Chuang Meng,Yufei Xia,Naoki Asakawa,Wenping Wei,Kaizheng Gong,Xin Pan
Ethnopharmacological relevance Eclipta prostrata (Linn.) is a traditional medicinal Chinese herb that displays multiple biological activities, such as encompassing immunomodulatory, anti-inflammatory, anti-tumor, liver-protective, antioxidant, and lipid-lowering effects. Ecliptasaponin A (ESA), a pentacyclic triterpenoid saponin isolated from Eclipta prostrata (Linn.), has been demonstrated to exert superior anti-inflammatory activity against many inflammatory disorders. Aim of the study Inflammation plays a critical role in acute myocardial infarction (AMI). This study aims to explore the treatment effects of ESA in AMI, as well as the underlying mechanism. Methods An AMI mouse model was established in mice via left anterior descending coronary artery (LAD) ligation. After surgery, ESA was injected at doses of 0.5, 1.25, and 2.5 mg/kg, respectively. Myocardial infarction size, cardiomyocyte apoptosis and cardiac echocardiography were studied. The potential mechanism of action of ESA was investigated by RNA-seq, Western blot, surface plasmon resonance (SPR), molecular docking, and immunofluorescence staining. Results ESA treatment not only significantly reduced myocardial infarct size, decreased myocardial cell apoptosis, and inhibited inflammatory cell infiltration, but also facilitated to improve cardiac function. RNA-seq and Western blot analysis proved that ESA treatment-induced differential expression genes mainly enriched in HMGB1/TLR4/NF-κB pathway. Consistently, ESA treatment resulted into the down-regulation of IL-1β, IL-6, and TNF-α levels after AMI. Furthermore, SPR and molecular docking results showed that ESA could bind directly to HMGB1, thereby impeding the activation of the downstream TLR4/NF-κB pathway. The immunofluorescence staining and Western blot results at the cellular level also demonstrated that ESA inhibited the activation of the HMGB1/TLR4/NF-κB pathway in H9C2 cells. Conclusion Our study was the first to demonstrate a cardiac protective role of ESA in AMI. Mechanism study indicated that the treatment effects of ESA are mainly attributed to its anti-inflammatory activity that was mediated by the HMGB1/TLR4/NF-κB pathway.
研究领域:
药理学
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心脏病学
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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
MOLECULES
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2018
·Vol. 23
·期 7
·1788
·
IF 3.098
Hong-Xin Cui,Ji-Hong Chen,Jing-Wan Li,Fang-Rong Cheng,Ke Yuan
Myrica rubra(MR) is rich in anthocyanins, and it has good anti-cancer, anti-aging, antioxidant, and antiviral effects. The proportion of disability and death caused by ischemic stroke gradually increased, becoming a major disease that is harmful to human health. However, research on effects of anthocyanin from MR on cerebral ischemia-reperfusion (I/R) injury is rare. In this study, we prepared eight purified anthocyanin extracts (PAEs) from different types of MR, and examined the amounts of total anthocyanin (TA) and cyanidin-3-O-glucoside (C-3-G). After one week of PAE treatment, the cerebral infarction volume, disease damage, and contents of nitric oxide and malondialdehyde were reduced, while the level of superoxide dismutase was increased in I/R mice. Altogether, our results show that Boqi1MR contained the most TA (22.07%) and C-3-G (21.28%), and that PAE isolated from Dongkui MR can protect the brain from I/R injury in mice, with the mechanism possibly related to the Toll-like receptor 4 (TLR4)/ nuclear factor-κB (NF-κB) and NOD-like receptor pyrin domain-containing 3 protein (NLRP3) pathways.Keywords:Myrica rubra;anthocyanins;cyanidin-3-O-glucoside;cerebral ischemia-reperfusion;TLR4/NF-κB;NLRP3
研究领域:
药理学
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神经科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
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2024
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IF 5.3
Ying Wang,Kunzhan Dong,Yan Zhang,Qi Li,Chang Liu,Shijie Cai,Zhiye Xu,Jingyang Shan,Sen Wang
Excessive inflammation can cause severe damage to biological tissues and organs, and current anti-inflammatory drugs still have certain limitations. This study aims to explore anti-inflammatory strategies. Nanozymes, a class of nanomaterials with enzyme-like catalytic properties, have gained significant attention in recent years. In this study, iron ion integrated coordination polymer nanodots (FNDs) were synthesized. The anti-inflammatory effects of FNDs were investigated from multiple aspects, including material characterization, antioxidant performance testing, in vitro cell experiments, and mouse model experiments. The results demonstrated that FNDs have the characteristics of small size, high stability, and excellent antioxidant capacity. In vitro cell experiments showed that FNDs significantly inhibited the production of LPS-induced TNF-α, IL-1β, and IL-6 in THP-1 macrophages. Further analysis of signaling pathways revealed that FNDs markedly suppressed the NF-κB and MAPK pathways and downregulated the expression of TLR4 and CD14 on the surface of macrophages. Experiments in mouse models indicated that FNDs significantly suppressed inflammation and cellular damage in organs such as the lungs and liver, and reduced the number of inflammatory cells and the concentrations of TNF-α, IL-1β, and IL-6 in peripheral blood. This study demonstrates that FNDs possess excellent antioxidant and anti-inflammatory properties, providing a strategy for the treatment of inflammatory diseases.
研究领域:
纳米技术
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免疫学
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药理学
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生物医学工程
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产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Zhehuan Wang,Huiru Zhang,Caihong Qi,Hui Guo,Xiangyue Jiao,Jia Yan,Yifei Wang,Qiangsheng Li,Mingming Zhao,Xinhao Guo,Baoluo Wan,Xiaotian Li
Background Ursolic acid (UA) is a triterpenoid compound found in natural plants. It has been reported to have anti-inflammatory, antioxidant, and immunomodulatory properties. However, its role in atopic dermatitis (AD) is unknown. This study aimed to evaluate the therapeutic effect of UA in AD mice and explore the underlying mechanisms. Methods Balb/c mice were treated with 2, 4-dinitrochlorobenzene (DNCB) to induce AD-like lesions. During modeling and medication administration, dermatitis scores and ear thickness were measured. Subsequently, histopathological changes, levels of T helper cytokines, and oxidative stress markers levels were evaluated. Immunohistochemistry staining was used to assess changes in the expression of the nuclear factor of kappa B (NF-κB) and NF erythroid 2-related factor 2 (Nrf2). Furthermore, CCK8 assay, reactive oxygen species (ROS) assay, real-time PCR, and western blotting were employed to evaluate the effects of UA on ROS levels, inflammatory mediator production, and the NF-κB and Nrf2 pathways in TNF-α/IFN-γ-stimulated HaCaT cells. Results The results showed that UA significantly reduced dermatitis score and ear thickness, effectively inhibited skin proliferation and mast cell infiltration in AD mice, and decreased the expression level of T helper cytokines. Meanwhile, UA improved oxidative stress in AD mice by regulating lipid peroxidation and increasing the activity of antioxidant enzymes. In addition, UA inhibited ROS accumulation and chemokine secretion in TNF-α/IFN-γ-stimulated HaCaT cells. It might exert anti-dermatitis effects by inhibiting the TLR4/NF-κB pathway and activating the Nrf2/HO-1 pathway. Conclusion Taken together, our results suggest that UA may have potential therapeutic effects on AD and could be further studied as a promising drug for AD treatment.
研究领域:
药理学
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免疫学
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皮肤科
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
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2017
·Vol. 7
·期 1
·1-10
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IF 4.259
Yuan Yi,Han Qiuju,Li Siyu,Tian Zhigang,Zhang Jian
The Wingless-type MMTV integration site family member 2b (Wnt2b) has been found to be a principal mediator of liver development and regeneration. However, the significance of Wnt2b in the pathogenesis of fibrosis-related liver diseases remains undefined. Here, we report that Wnt2b was highly expressed in the fibrotic liver tissues, exhibiting protective effects against activation of hepatic stellate cells (HSCs) and fibrosis progression. We identified a negative regulation of Wnt2b on the toll-like receptor 4 (TLR4) activation-mediated pro-fibrogenic effects. Wnt2b was shown not only to directly suppress LPS-induced HSCs activation, but also to inhibit TLR4-enhanced the sensitivity of HSCs to transforming growth factor beta (TGF-β). Mechanistic study showed that Wnt2b suppresses TLR4 signaling through inhibiting the expression of TLR4 as well as the activation of NF-κB and MAPKs. These findings provided new insights into the pathophysiology of liver fibrosis by characterizing Wnt2b as a novel endogenous suppressor of TLR4 signaling, maintaining tissue homeostasis during the early stage of hepatic fibrosis-associated liver diseases.
研究领域:
肝病学
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分子生物学
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细胞信号传导
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DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
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2024
·
IF 3.3
Zhikun Zhang,Dawei Shi,Haiwei Dou,Ruijie Wan,Qing Yuan,Peng Tu,Deli Xin
In previous study, lower levels of serum GP130 were reported in children with MPP. GP130 is an important signal transducer, the down regulation of which may influence host immune responses. In this study, we aimed to analyze the regulatory mechanism of GP130 during MP infection. Firstly, the mRNA and protein levels of GP130 both decrease and then increase with increasing multiplicity of infection (MOI: 1 to 40) of MP. The lowest levels of GP130 were detected at MOI of 5. Then, heat treated MP but not trypsin treated MP or MP extracted proteins show regulatory effect to the expression of GP130. These indicate that the down regulation of GP130 is related to protein mediate adhesion process of MP. Gene expression analysis revealed that MP affected apoptosis and the TLR4 pathway in infected cells, and the mRNA level of IL-6 was correlated with that of GP130. Further, Z-VAD-FMK (pan-caspase inhibitor) can suppress the apoptosis induced by MP infection and restore GP130 at protein level. Further studies revealed that MP infection promoted TLR4 internalization but did not activate the NF-κB pathway. The levels of surface TLR4 showed correlation with the transcription of IL-6 and GP130. TAK242 (TLR4 inhibitor) and PS341 (proteasome inhibitor) can restore the decreased transcription of GP130, both of which were able to promote NF-κB pathway activation in MP-infected cells. These suggested that the regulation of TLR4/NF-κB pathway and induced apoptosis post MP infection are involved in the down-regulation of GP130 at transcription and protein levels, respectively.
研究领域:
微生物学
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免疫学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Ziyue Wang,Lu Li,Wenliang Li,Haiyang Yan,Yuan Yuan
As a food contaminant that can be quickly absorbed through the gastrointestinal system, furan has been shown to disrupt the intestinal flora and barrier. Investigation of the intestinal toxicity mechanism of furan is of great significance to health. We previously identified the regulatory impact of salidroside (SAL) against furan-provoked intestinal damage, and the present work further explored whether the alleviating effect of SAL against furan-caused intestinal injury was based on the intestinal flora; three models, normal, pseudo-germ-free, and fecal microbiota transplantation (FMT), were established, and the changes in intestinal morphology, barrier, and inflammation were observed. Moreover, 16S rDNA sequencing observed the variation of the fecal flora associated with inflammation and short-chain fatty acids (SCFAs). Results obtained from the LC–MS/MS suggested that SAL increased furan-inhibited SCFA levels, activated the mRNA expressions of SCFA receptors (GPR41, GPR43, and GPR109A), and inhibited the furan-activated TLR4/MyD88/NF-κB signaling. Analysis of protein–protein interaction further confirmed the aforementioned effects of SAL, which inhibited furan-induced barrier damage and intestinal inflammation.
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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毒理学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Xiong Chen,Jinfu Qian,Shiqi Liang,Jianchang Qian,Wu Luo,Yujuan Shi,Hong Zhu,Xiang Hu,Gaojun Wu,Xiaokun Li,Guang Liang
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NF κ B signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
研究领域:
心脏病学
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糖尿病
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
·
IF 5.6
Shuhan Li,Zhanpeng Zhu,Tian Lan,Yuhan Wu,Ye Li,Changmin Wang,Wencheng Jian,Shu Yan Yu
Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, has been reported to have anti-depressive effects. However, the detailed mechanisms underlying these effects are still unclear. This study aimed to investigate the antidepressant mechanisms of levomilnacipran to discover new perspectives on the treatment of depression in male rats. Intraperitoneal injection of lipopolysaccharide (LPS) was used to induce depressive behaviors in rats. Activation of microglia and apoptosis of neurons verified by immunofluorescence. Inflammatory related proteins and neurotrophic related proteins were verified by immunoblotting. The mRNA expression of apoptosis markers was verified by real-time quantitative PCR. Finally, electron microscopy analysis was used to observe the ultrastructural pathology of neuron. Here, we found that the anti-depression and anti-anxiety effects of levomilnacipran in the LPS-induced rat model of depression was resulted from the suppression of neuroinflammation and neuronal apoptosis within prefrontal cortex of rats. Furthermore, we found that levomilnacipran could decrease the number of microglia and suppress its activation in prefrontal cortex of rats. This effect may be mediated by suppressing the TLR4/NF-κB and Ras/p38 signaling pathways. In addition, levomilnacipran plays a neuroprotective role by increasing the expression of neurotrophic factors. Taken together, these results suggest that levomilnacipran exerts antidepressant effects by attenuating neuroinflammation to inhibit the damage in central nervous system and plays a neuroprotective role to improve depressive behaviors. These findings suggest that suppression of neuroinflammation in prefrontal cortex could ameliorate depressive behavioral disorder of rats induced by LPS, which provided a new perspective for the treatment of depression.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）