BIOCHEMICAL PHARMACOLOGY
·
2023
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IF 5.8
Shanshan Wei,Wanjun Ma,Yuanying Yang,Taoli Sun,Chuanhao Jiang,Jian Liu,Bikui Zhang,Wenqun Li
Trastuzumab (Tra), the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), is commonly used alongside doxorubicin (Dox) as a combination therapy in HER2-positive breast cancer. Unfortunately, this leads to a more severe cardiotoxicity than Dox alone. NLRP3 inflammasome is known to be involved in Dox-induced cardiotoxicity and multiple cardiovascular diseases. However, whether the NLRP3 inflammasome contributes to the synergistic cardiotoxicity of Tra has not been elucidated. In this study, primary neonatal rat cardiomyocyte (PNRC), H9c2 cells and mice were treated with Dox (15 mg/kg in mice or 1 μM in cardiomyocyte) or Tra (15.75 mg/kg in mice or 1 μM in cardiomyocyte), or Dox combined Tra as cardiotoxicity models to investigate this question. Our results demonstrated that Tra significantly potentiated Dox-induced cardiomyocyte apoptosis and cardiac dysfunction. These were accompanied by the increased expressions of NLRP3 inflammasome components (NLRP3, ASC and cleaved caspase-1), the secretion of IL-β and the pronounced production of ROS . Inhibiting the activation of NLRP3 inflammasome by NLRP3 silencing significantly reduced cell apoptosis and ROS production in Dox combined Tra-treated PNRC. Compared with the wild type mice, the systolic dysfunction , myocardial hypertrophy , cardiomyocyte apoptosis and oxidative stress induced by Dox combined Tra were alleviated in NLRP3 gene knockout mice . Our data revealed that the co-activation of NLRP3 inflammasome by Tra promoted the inflammation, oxidative stress and cardiomyocytes apoptosis in Dox combined Tra-induced cardiotoxicity model both in vivo and in vitro . Our results suggest that NLRP3 inhibition is a promising cardioprotective strategy in Dox/Tra combination therapy.
研究领域:
肿瘤学
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心脏病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
International Journal of Ophthalmology
·
2021
·
IF 1.779
Rong Li,Lin Chen,Guo-Min Yao,Hong-Lin Yan,Li Wang
AIM To investigate the effects of quercetin on diabetic retinopathy (DR) and its association with nucleotide-binding oligomerization domain-like receptors 3 (NLRP3) inflammasome and autophagy using retinal endothelial cell as an experimental model. METHODS Human retinal microvascular endothelial cells (HRMECs) were cultured in vitro and assigned into the control group, high-glucose (HG) group, and HG+different concentrations of quercetin groups. Cellular viability, migration, and tube formation in these groups was detected by MTT, transwell and matrigel assay, respectively. Expressions of NLRP3, apoptosis-associated speck-like protein (ASC), cysteiny aspartate-specific protease-1 (Caspase-1) as well as microtubule-related protein 1 light chain 3 (LC3) and Beclin-1 were detected by Western blotting. Expressions of IL-1β and IL-18 were detected by ELISA and cellular autophagy was detected by Cyto-ID ® autophagy detection kit. RESULTS Under an HG condition, the viability, migration, tube formation of HRMECs, and the protein expressions of NLRP3, ASC, Caspase-1, IL-1β, IL-18, LC3, and Beclin-1 as well as autophagy were all increased. Quercetin inhibited angiogenesis of HRMECs as well as the expressions of NLRP3, ASC, Caspase-1, IL-1β, IL-18, LC3, Beclin-1, and autophagy of HRMECs under a HG condition. The inhibitory effects of quercetin on angiogenesis, NLRP3 inflammasome and autophagy increased with the increase of its concentration. CONCLUSION The therapeutic potential of quercetin in retinal neovascularization of DR, and inhibition of NLRP3 inflammasome and autophagy signaling pathway may be involved.
研究领域:
眼科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
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IF 4.932
Zhi Lu,Yiqun Yao,Jinhong Wang,J.-Y. Peng
Dioscin presents extents of pharmacological activities on several diseases, but its effect and mechanism on diabetes cognitive dysfunction (DCD) remains unclear. Herein, we conducted a series of pharmacological evaluation assays of purinergic receptor P2X7 (P2X7R) with dioscin. We uncovered that dioscin presented a clearly protective effect on diabetes cognitive dysfunction via a methylglyoxal-treated PC12 cell model and streptozocin (STZ)-induced rat models. Additionally, it found that P2X7R and NLRP3 inflammasome signals were activated in diabetes cognitive dysfunction via in vivo and in vitro detection. Moreover, it was demonstrated that P2X7R regulated NLRP3 inflammasome signals in methylglyoxal-treated PC12 cells. Meanwhile, it was showed that dioscin-induced anti-diabetes cognitive dysfunction effect was accompanied with an inhibition of P2X7R/NLRP3 signal. A deeper mechanical study indicated that an overexpression of P2X7R further enhanced the protective effect of dioscin. Whilst, an inhibition of P2X7R abolished the protective effect of dioscin. These results suggested that dioscin protected type 2 diabetes cognitive dysfunction through, at least partially, regulating the P2X7R/NLRP3 signal pathway. Our findings further indicate the great value of dioscin on preventing type 2 diabetes cognitive dysfunction.
研究领域:
药理学
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神经科学
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糖尿病
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炎症
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DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
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2025
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IF 3.8
Su Qiyan,Feng Yingyue,Guo Jin,Cui Xi,Zhu Jiarui,Yang Jumei,Zhang Sigong
BackgroundIdiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.MethodsA murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of IL-1β, IL-6 and TNF-α were detected by ELISA. PFD was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot was utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NLRP3 inflammasome markers.ResultsPFD treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. PFD intervention reduced NETs formation in vitro. PFD treatment significantly reduce NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD down-regulated EMT and NLRP3-related proteins in vivo. PFD treatment also notably reduced serum levels of IL-1β, IL-6 and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. PFD attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.ConclusionPFD alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.
研究领域:
免疫学
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呼吸病学
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药理学
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DOI
PubMed
高影响因子
Scientific Reports
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2024
·Vol. 14
·期 1
·1-12
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IF 3.8
Gao Kexin,Liu Yancui,Sun Cheng,Wang Ying,Bao Hongrong,Liu Guoyang,Ou Jinrui,Sun Ping
Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.
研究领域:
肿瘤学
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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
Bioactive Materials
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2025
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IF 20.3
Yi Wang,Xuemei Liao,Qinglong Guo,Heng Zhang,Lei Ye,Liangchen Yu,Xiaoming Kong,Yicheng Jiang,Peng Zhao,Kaiyong Cai,Hongwei Cheng
Parkinson's disease (PD), a progressive neurodegenerative disorder, is marked by the degeneration of dopaminergic neurons. Emerging evidence highlights the critical involvement of neuronal ferroptosis and microglial pyroptosis in PD pathogenesis. In this study, we first characterized systemic inflammatory alterations in the peripheral blood of PD patients compared to healthy controls, revealing distinct pro-inflammatory signatures. Based on these findings, we engineered BV2 microglial membrane-camouflaged biomimetic multienzyme gallic acid-selenium nanoparticles (BM@GA-Se nanosomes) and evaluated their neuroprotective potential. In vitro and in vivo experiments demonstrated that BM@GA-Se nanosomes enhanced neuronal survival by simultaneously suppressing ferroptosis of neurons (via GPX4-mediated lipid peroxide reduction) and pyroptosis of microglia (through inhibition of the HSP90/NLRP3/Caspase-1 signaling pathway). These results position BM@GA-Se nanosome as a new dual-pathway targeting therapeutic strategy, offering a promising translational approach to mitigate PD progression by addressing interdependent inflammatory and oxidative mechanisms.
研究领域:
神经退行性疾病
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免疫炎症调节
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纳米医学
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氧化应激
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Qitao Ye,Bingfeng Lin,Pingcui Xu,Fanxuan Zhang,Nani Wang,Dan Shou
Ethnopharmacological relevance Yunvjian decoction (YNJ) is a traditional Chinese herbal prescription that has been used in the clinical treatment of periodontitis . However, the underlying molecular mechanism of YNJ in the periodontitis treatment is not well understood. Aim of the study The purpose of this study was to evaluate the therapeutic effects of YNJ against periodontitis and its underlying molecular mechanisms. Materials and methods Orthodontic ligation and lipopolysaccharide (LPS)-induced periodontitis rat model was established. YNJ groups were gavaged with YNJ decoction (5 g/kg/d or 10 g/kg/d) for four months. The rats in positive control group were gavaged with metronidazole (MDZ, 100 mg/kg/d) for four months. The maxilla was scanned by micro-computed tomography. The chemical compositions of YNJ were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry. The molecular mechanism of YNJ were predicted using network pharmacological analysis and validated using immune-staining and Western blot . Results YNJ treatment decreased the distance between cementoenamel junction and alveolar bone crest on the sagittal slide of the periodontitis rats. Western blot showed YNJ downregulated the protein levels of the bone resorption marker (receptor activator of nuclear factor-κB ligand), while upregulated the levels of the bone formation markers (bone morphogenetic protein 2, runt-related transcription factor 2, alkaline phosphatase , and osteoprotegerin) in alveolar bone of the periodontitis rats. Hematoxylin and eosin , immunohistochemical staining, and Western blot analysis indicated that YNJ attenuated the inflammation and decreased the levels of interleukin-6 and tumor necrosis factor-α in the alveolar bone. In addition, a total of 61 compounds were identified from YNJ. Network pharmacology indicated that the nucleotide binding oligomerization domain-like receptor signaling pathway was the main pathway for YNJ in the treatment of periodontitis. The experiments confirmed that YNJ administration inhibited LPS induced-pyroptosis in alveolar bone through suppressing the phosphorylation of nuclear factor κB, reduced expression of NOD-like receptor family pyrin domain containing 3, and Caspase-1, subsequently suppressing the interleukin-1β secretion. Conclusion YNJ is an effective therapeutic strategy for periodontitis and acts by inhibiting pyroptosis and NFκB/NLRP3/IL-1β pathway in alveolar bone.
研究领域:
药理学
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牙科学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
POULTRY SCIENCE
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2024
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IF 3.8
Xinzhang Chen,Xu Lin
Trimethyl tin (TMT) is a good stabilizer for plastic products but is also a toxic environmental pollutant. Selenium has good antioxidant and anti-inflammatory properties and has been widely used in the poultry industry. However, it has not been reported whether selenium enrichment can antagonize TMT-induced viral hepatitis in poultry. To fill this gap, AA broiler models exposed to TMT for 42 d were established and fed a Se-enriched diet at the same time. H&E staining showed that selenium could significantly alleviate TMT-induced liver inflammation. Further analysis of the underlying mechanism revealed that TMT induced nitrosation stress (RNS), increased NO content and iNOS expression, which in turn activated the NF-κB/NLRP3 pathway and induced pyroptosis. However, selenium enrichment can reverse this situation, that is, reduce the occurrence of RNS, reduce the degree of pyroptosis, and thus alleviate the occurrence of inflammation. In our study, we demonstrated for the first time that TMT could induce hepatotoxicity other than neurotoxicity in poultry and that selenium could antagonize TMT-induced hepatotoxic hepatitis in chickens through the RNS/NF-κB/NLRP3 pathway.
研究领域:
毒理学
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兽医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2025
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IF 2.9
Leina Jia,Xiaoning Meng,Yu Ma,Jinyu Luo,Xiaoqi Luo,Huifang Yang,Jian Zhou
Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems. Objectives: In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses. Methods: Nthy-ori 3-1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h. Results: CYP treatment enhanced oxidative damage in Nthy-ori 3-1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765+CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level. Conclusion: The results demonstrate that CYP induces pyroptosis in Nthy-ori 3-1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.
研究领域:
毒理学
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内分泌学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
·
2020
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IF 4.133
Yan Wu,Yacheng Zhang,Jie Zhang,Tingting Zhai,Jingping Hu,Hairong Luo,Haiyan Zhou,Qinghai Zhang,Zhiguang Zhou,Feng Liu
Aims The antimicrobial peptide cathelicidin ( Camp ) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. Methods and results In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion . An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils . Knockout of Camp in mice reduced MI/R-induced myocardial inflammation , infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X 7 R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X 7 R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1β (a “first line” pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1β protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1β from human neutrophils via stimulating TLR4 signaling and P2X 7 R/NLRP3 inflammasome. Conclusions Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X 7 R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury .
研究领域:
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
BIOSCIENCE REPORTS
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2020
·Vol. 40
·期 8
·
IF 2.942
Zhu Jialei,Tang Jing
Postpartum depression (PPD) is a kind of mental disorder characterized by persistent low emotions in puerperium. The most significant physiological change in postpartum is lactation which is regulated by oxytocin receptor (OXTR). However, whether OXTR is related to pathological process of PPD and the potential mechanism still remain unclear. In the present study, we prepared hormone-simulated pregnancy (HSP)-induced PPD mouse model and found that the protein level of OXTR in hippocampus of PPD model mice was down-regulated and Nod-like receptor protein 3 (NLRP3) inflammasome was activated. We identified five long non-coding RNAs (lncRNAs) related to PPD by transcriptome sequencing, including three up-regulated and two down-regulated. The five lncRNAs were associated with the signaling pathway of OXTR according to the bioinformatics analysis. Furthermore, we focused on one of the five lncRNAs, Gm14205, and found that it targeted OXTR which inhibited astrocytic NLRP3 inflammasome activation in hippocampal primary astrocytes. These findings illustrate that OXTR has protective effects in PPD by inhibiting NLRP3 inflammasome activation and provides a new strategy for targeting lncRNA Gm14205 in the pathogenesis of PPD.
研究领域:
神经科学
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分子生物学
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药理学
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精神病学
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产品关联
DOI
PubMed
高影响因子
Food & Function
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2020
·Vol. 11
·期 6
·5156-5165
·
IF 4.171
Yu-Sheng Shi,Xiao-Xing Li,Hao-Tian Li,Yan Zhang
Liver fibrosis is a histological change that often occurs due to hepatic stellate cell (HSC) activation and excessive formation of an extracellular matrix in the liver. Pelargonidin (PEL) is a natural anthocyanidin existing in blueberries, berries, strawberries, and red radishes and has been demonstrated to possess health beneficial effects. Herein, we investigated the effect of PEL on liver fibrosis induced by CCl4 and hepatic stellate cells induced by transforming growth factor-β (TGF-β). We found that PEL administration prevented liver injury and liver fibrosis induced by CCl4 in a dose-dependent manner. Further data revealed that PEL increased liver nuclear factor E2-related factor 2 (Nrf2) and reduced liver oxidative stress and the expression levels of NLRP3, caspase-1 and IL-1β. In TGF-β-challenged HSCs (LX-2 cells), PEL effectively inhibited the LX-2 cell activation. In addition, the anti-fibrosis effects of PEL in LX-2 cells were abolished by Nrf2 knockdown. In summary, our study demonstrated that PEL ameliorated CCl4-induced liver fibrosis and HSC activation induced by TGF-β. The possible molecular mechanisms of PEL in liver fibrosis may be attributed to its suppression of ROS-NLRP3-IL-1β signaling by Nrf2 activation.
研究领域:
药理学
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肝病学
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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）