Heliyon
·
2024
·
IF 3.4
Bin Hu,Gongwen Du
Osteoarthritis (OA) is an age-related joint disease characterized by progressive heterogeneous changes in articular cartilage and subchondral bone. Osteoclast stimulating factor 1 (OSTF1) is a small intracellular protein involved in bone formation and bone resorption. However, to our best knowledge, its role in OA is still unclear. In this study, an OA rat model was established by anterior cruciate ligament transection (ALCT). OSTF1 was increased in the cartilage tissues of OA patients and OA rats. Next, the role of OSTF1 in interleukin-1β (IL-1β)-induced chondrocyte apoptosis, inflammation and extracellular matrix degradation was explored through loss of function assays. Strikingly, OSTF1 knockdown relieved IL-1β-induced chondrocyte apoptosis, with decreased cleaved caspase-3 and cleaved PARP levels. Besides, OSTF1 knockdown restrained IL-1β-induced inflammation and degradation of extracellular matrix of chondrocytes. Subsequently, the molecular mechanism of OSTF1 was explored. Transcriptomic analysis revealed the potential gene network map regulated by OSTF1 knockdown. Some differentially expressed genes (DEGs) were involved in regulating the NF-κB signaling pathway. Furthermore, our results demonstrated that OSTF1 knockdown inhibited IL-1β-activated the NF-κB signaling pathway. Ultimately, we analyzed the potential gene network map regulated by OSTF1 and its downstream NF-κB. Bioinformatics analysis showed that 18 DEGs in OSTF1-silenced chondrocytes overlapped with the NF-κB downstream targets. Collectively, our findings indicate that OSTF1 knockdown mitigates IL-1β-induced chondrocyte injury via inhibiting the NF-κB signaling pathway.
研究领域:
医学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Chuanlong Wang,Qingyi Chen,Siyuan Chen,Lijuan Fan,Zhending Gan,Muyang Zhao,Lexuan Shi,Peng Bin,Guan Yang,Xihong Zhou,Wenkai Ren
Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1β production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1β expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1β maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1β production, providing a potential inflammatory disease target.
研究领域:
免疫学
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代谢
·
炎症
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
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
·
免疫学
·
分子生物学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2022
·
IF 5.168
Rongrong Zhao,Huajun Zhao,Quanjuan Guo,Yongliang Mu,Jian Zhang,Yuhang Su,Qiuju Han
Edaravone (EDA), a strong novel free radical scavenger, have been demonstrated to exert neurovascular protective effects clinically. Furthermore, EDA can suppress the lung injury, pulmonary fibrosis and skin fibrosis , while the precise effects and mechanisms of EDA on liver injury and fibrosis remain unclear. The effects of EDA on the Thioacetamide (TAA)-induced liver fibrosis were evaluated by sirius red staining, α-SMA immunohistochemistry. The percentages of immune cell subsets were analyzed by flow cytometry. Immunofluorescence assay was performed to identify the fibrotic properties of hepatic stellate cells (HSCs). Western blot and qPCR were used to detect the levels of liver fibrosis-related molecules and IL-1β. EDA displayed a hepatic protective role in TAA-induced chronic liver fibrosis via inhibiting monocyte/macrophages recruitment and IL-1β production of macrophages. Mechanically, EDA inhibited of NF-κB signal pathway and reactive oxygen species (ROS) production in macrophages. Moreover, EDA treatment indirectly suppressed the activation of HSCs by decreasing the IL-1β secretion of macrophages. Together, EDA protects against TAA-induced liver fibrosis via decreasing the IL-1β production of macrophages, thereby providing a feasible solution for clinical treatment of liver fibrosis.
研究领域:
药理学
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肝病学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
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
·
肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2019
·Vol. 459
·期 1
·205-214
·
IF 2.884
Duan Liang,Duan Dapeng,Wei Wenbo,Sun Zhengming,Xu Honghai,Guo Lipeng,Wu Xuanhui
Osteoarthritis (OA) is characterized by degradation of articular cartilage. MiRNAs are involved in the regulation of chondrogenesis and OA. We aimed to investigate effects and mechanisms of miR-19b-3p in regulating chondrocytes viability, cartilage degradation and inflammatory response. Primary chondrocytes were isolated from cartilages in control subjects and patients with OA. Murine ATDC5 cells were pre-conditioned with IL-1β in vitro. Expressions and interaction of miR-19b-3p with G protein-coupled receptor kinase 6 (GRK6), and their effects on inflammation, chondrocytes viability and cartilage degradation were determined after miR-19b-3p mimic or GRK6 siRNA transfection. MiR-19b-3p was significantly decreased in OA chondrocytes and IL-1β-stimulated ATDC5 cells, in paralleled with the elevated type-II-collagen, aggrecan, MMP13 and GRK6 expression. MiR-19b-3p mimic dramatically increased the viability of chondrocytes and suppressed cell apoptosis. It also increased type-II-collagen, aggrecan expression and glycosaminoglycan (sGAG) content, and decreased the expression of MMP-1 and MMP-13 that controlled by IL-1β. Overexpression of miR-19b-3p inhibited the production of IL-6 and IL-8 in ATDC5 cells. However, the protective effects of miR-19b-3p mimic on IL-1β induced cell death; IL-8 production and sGAG decrease were greatly discounted by GRK6 lentiviral vectors. Luciferase reporter assay confirmed that GRK6 gene was a direct target ofmiR-19b-3p. GRK6 siRNA transfection antagonized the IL-1β-induced chondrocytes injury, extracellular matrix degradation and inflammatory response. MiR-19b-3p mimic and GRK6 siRNA showed comparable inhibitory effect on IL-1β-provoked NF-κB as reflected by the expression of p-p65. NF-κB translocation inhibition with PS1154 reversed the effects of IL-1β on IL-8 and sGAG. Collectively, miR-19b-3p attenuated OA by targeting GRK6-NF-κB pathway.
研究领域:
骨科
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2020
·
IF 6.551
Haiyang Zhang,Mian Wei,Xiangyu Lu,Qinghong Sun,Chuqiao Wang,Jiuyan Zhang,Honggang Fan
Aluminum (Al) is an inorganic pollutant that induces nerve cells apoptosis and necroptosis, thereby causing depression and neurodegenerative diseases. IL-1β/JNK signaling pathway can regulate apoptosis and necroptosis. However, it remains unclear whether IL-1β/JNK signaling pathway is involving in the regulation of Al-induced hippocampal neural cells apoptosis and necroptosis. To investigate the mechanism of Al on neural cells apoptosis and necroptosis, rats were orally exposed to different doses of AlCl 3 for 90 days. The open-field test results showed that AlCl 3 caused depressive behavior in rats. Histopathological evidence showed that AlCl 3 induced hippocampal neural cells apoptosis and necrosis. Moreover, Bax/Bcl-2 mRNA expression ratio, caspase-3 activity and mRNA expression and TUNEL positive rates were upregulated, meanwhile, TNF-α mRNA and protein expression levels, TNFR1, RIP1, RIP3 and MLKL proteins levels were increased, while caspase-8 protein level was decreased in the hippocampus of Al-exposed groups. These results proved that AlCl 3 induced hippocampal neural cells apoptosis and necroptosis. Combined with histopathology and correlation analysis, we deduced that hippocampal neural cells were more likely to undergo necroptosis at high doses (450 mg/kg) of AlCl 3 , while <150 mg/kg AlCl 3 tended to induce apoptosis. Finally, AlCl 3 increased the proteins level of IL-1β, IL-1RI, IL-1RAcP, JNK and p-JNK, indicating that AlCl 3 activated IL-1β/JNK signaling pathway. However, the application of IL-1 receptor antagonist (IL-1Ra) inhibited the phosphorylation of JNK and the related genes expression of apoptosis and necroptosis caused by AlCl 3 . Thus, we concluded that AlCl 3 induced hippocampal neural cells death and depression-like behavior in rats by activating IL-1β/JNK signaling pathway.
研究领域:
神经科学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
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
·
儿科
·
分子生物学
✓ 已验证
DOI
高影响因子
CHEMOSPHERE
·
2018
·
IF 4.427
Feibo Xu,Qiang Ji,Jian Zhang,Wanyue Huang,Zheng Cao,Yanfei Li
Aluminum (Al), a common environmental pollutant, has been reported to inhibit the immune functions of macrophage. However, the mechanisms involved remain unclear. In this study, murine peritoneal macrophages were exposed to 0, 0.27, 0.54, and 1.08 mg/mL of aluminium chloride (AlCl 3 ) for 24 h, and then treated with 1 μg/mL lipopolysaccharide (LPS) for another 6 h. No addition of both AlCl 3 and LPS serviced as control group. We observed that AlCl 3 has cytotoxicity in murine peritoneal macrophages, showing a decrease in cell viability and an increase in lactate dehydrogenase release. Besides, AlCl 3 exposure restrained the LPS-induced NLR pyrin domain containing 3 (NLRP3) inflammasome activation presented as NLRP3 expressions reduction, caspase-1 cleavage inhibition and interleukin 1 beta (IL-1β) maturation lessened. Meanwhile, AlCl 3 exposure decreased LPS-induced IKKβ activity, IκBα phosphorylation, the phosphorylation and mRNA expression of NF-κB p65, as well the genes expression and concentration in medium supernatant of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). The results suggested that AlCl 3 inhibited the activation of NF-κB signaling pathway induced by LPS, which maybe one of the upstream signals involved in the inhibition of NLRP3 inflammasome activation by AlCl 3 . This research can provide theoretical basis for understanding the immune toxicity of Al, and deepening the cognition of Al exposure hazards to immune response.
研究领域:
免疫学
·
毒理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2016
·
IF 3.025
Xiaomin Xia,Qiong Shi,Xiufang Song,Juanli Fu,Zixuan Liu,Yawen Wang,Yuxin Wang,Chuanyang Su,Erqun Song,Yang Song
Our previous studies suggested that tetrachlorobenzoquinone (TCBQ) elicits pro-inflammatory activities; however, the mechanism of its toxicity toward vascular endothelial cell has not been characterized. Although TCBQ has been shown to stimulate interleukin-1 beta (IL-1β) expression, it is unknown whether TCBQ regulates post-translational IL-1β activation. Using human umbilical vein endothelial cells, we discovered that TCBQ not only promotes the expression of NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) components [composed of NLRP3, adaptor molecule apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC), and pro-caspase 1] but also participates in priming the NLRP3 inflammasome. Activation of the NLRP3 inflammasome results in the maturation and release of IL-1β. Further experiments showed that K+ efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage may be involved in NLRP3 inflammasome activation mediated by TCBQ. Moreover, TCBQ downregulates the ubiquitination of NLRP3, further facilitating the activation of the NLRP3 inflammasome. These results suggest that the NLRP3/IL-1β signaling pathway plays an important role in TCBQ-induced endothelial cell pro-inflammatory responses, which may point to potential therapeutic approaches against TCBQ-mediated toxicity.
研究领域:
毒理学
·
免疫学
·
细胞生物学
·
血管生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 43
·期 9
·2289-2301
·
IF 7.169
Su Xue-ling,Wang Shu-hui,Komal Sumra,Cui Liu-gen,Ni Rui-cong,Zhang Li-rong,Han Sheng-na
Connexin 43 (Cx43) is the most important protein in the gap junction channel between cardiomyocytes. Abnormalities of Cx43 change the conduction velocity and direction of cardiomyocytes, leading to reentry and conduction block of the myocardium, thereby causing arrhythmia. It has been shown that IL-1β reduces the expression of Cx43 in astrocytes and cardiomyocytes in vitro. However, whether caspase-1 and IL-1β affect connexin 43 after myocardial infarction (MI) is uncertain. In this study we investigated the effects of VX765, a caspase-1 inhibitor, on the expression of Cx43 and cell-to-cell communication after MI. Rats were treated with VX765 (16 mg/kg, i.v.) 1 h before the left anterior descending artery (LAD) ligation, and then once daily for 7 days. The ischemic heart was collected for histochemical analysis and Western blot analysis. We showed that VX765 treatment significantly decreased the infarct area, and alleviated cardiac dysfunction and remodeling by suppressing the NLRP3 inflammasome/caspase-1/IL-1β expression in the heart after MI. In addition, VX765 treatment markedly raised Cx43 levels in the heart after MI. In vitro experiments were conducted in rat cardiac myocytes (RCMs) stimulated with the supernatant from LPS/ATP-treated rat cardiac fibroblasts (RCFs). Pretreatment of the RCFs with VX765 (25 μM) reversed the downregulation of Cx43 expression in RCMs and significantly improved intercellular communication detected using a scrape-loading/dye transfer assay. We revealed that VX765 suppressed the activation of p38 MAPK signaling in the heart tissue after MI as well as in RCMs stimulated with the supernatant from LPS/ATP-treated RCFs. Taken together, these data show that the caspase-1 inhibitor VX765 upregulates Cx43 expression and improves cell-to-cell communication in rat heart after MI via suppressing the IL-1β/p38 MAPK pathway.
研究领域:
心脏病学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Mengyuan Qian,Min Ge,Shanshan Liu,Xin Wen,Ning Liu,Qianqian Wang,Jiaxu Cao,Xiuyan Jiang,Yan Zhang,Jun Yang,Lingyun Sun
Inflammatory bowel disease (IBD) is an incurable condition driven by chronic inflammatory dysregulation. Human mesenchymal stem cells (hMSCs) offer therapeutic promise, but limited persistence and functional heterogeneity constrain their clinical efficacy. Here, we present a bio-inspired priming platform built on poly(lactic- co -glycolic acid)/chitosan-heparin microparticles, engineered to display E/N-cadherin motifs and to enable controlled interleukin-1β release through PLGA biodegradation. These functionalized microparticles (hE/N-cad@P/C-h-IL-1β) assemble with hMSCs into hybrid aggregates that enhance cell survival under stress and improve adaptability to microenvironment cues. The priming process upregulates endogenous cadherin expression and modulates AKT/STAT signaling, conferring stimulus- and dose-responsive immune activity. In vitro , hybrid aggregates polarize macrophages toward an anti-inflammatory phenotype, expand regulatory T cells, and suppress pathogenic lymphocyte activation. In a dextran sulfate sodium (DSS) colitis model, intraperitoneal delivery of hybrid aggregates restores intestinal immune homeostasis, accelerates epithelial repair, and reduces disease severity to near baseline within fourteen days. By integrating cell-adhesive and cytokine signals within a modular platform, this strategy overcomes critical translational barriers in hMSC therapy and provides a blueprint for precisely targeted treatment of IBD and related inflammatory disorders.
研究领域:
再生医学
·
免疫学
·
生物材料
·
干细胞治疗
·
炎症性疾病
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）