FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Yuqian Li,Lijingzhe Hou,Kang Cheng,Guangbo He,Jau-Shyong Hong,Sheng Li,Jie Zhao,Yanjie Guo
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal tract with limited treatment options and no definitive cure. Emerging evidence implicates NADPH oxidase (Nox) in IBD pathogenesis, but the specific subtype involved and its therapeutic potential remain unclear. To assess the efficacy of dextromethorphan (DM), a potent Nox2 inhibitor, we employed a dextran sulfate sodium (DSS)-induced chronic colitis model in mice. Mice exposed to intermittent DSS for 34 days developed IBD-like symptoms, including weight loss, elevated disease activity index (DAI), colon shortening, and epithelial barrier disruption. DM exhibited a bimodal protective effect: both standard-dose DM (10 mg/kg/day) and ultralow-dose DM (ULDM, 10 ng/kg/day) significantly reduced colitis severity, with ULDM proving more effective and selected for further studies. Notably, ULDM remained effective when post-administered after DSS exposure. Histological analyses revealed that ULDM reduced immune cell infiltration, crypt damage, and tissue disruption. It also suppressed pro-inflammatory cytokine expression (MCP-1, IL-6, IL-1β, TNF-α) and oxidative stress markers (myeloperoxidase, malondialdehyde, 8-hydroxydeoxyguanosine), while enhancing anti-inflammatory cytokines (IL-4, IL-10) and antioxidant enzymes (catalase, superoxide dismutase). Importantly, ULDM protected Nox1 KO but not Nox2 KO mice, indicating a Nox2-dependent mechanism. In vitro, ULDM inhibited Nox2 activation in primary macrophages and RAW 264.7 cells by blocking the membrane translocation of p47 phox . Furthermore, our study suggested a feed-forward inflammatory cycle between epithelial cell death and macrophage overactivation that exacerbated colitis. Together, these findings demonstrated that Nox2 played a central role in DSS-induced chronic colitis and identified ultralow-dose dextromethorphan as a promising, mechanism-based therapeutic candidate for IBD.
研究领域:
免疫学
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药理学
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胃肠病学
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分子生物学
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炎症性肠病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2017
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IF 4.593
Shimei Qi,Zunyong Feng,Qiang Li,Zhilin Qi,Yao Zhang
Myricitrin, a naturally occurring polyphenol hydroxy flavonoid, has been reported to possess anti-inflammatory properties. However, the precise molecular mechanism of myricitrin’s effects on LPS-induced inflammation is unclear. In the present study, myricitrin significantly alleviated acute lung injury in mice. Myricitrin also markedly suppressed the production of NO, TNF-α, IL-6, and MCP-1 in RAW264.7 macrophage cells. The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of iNOS. The phosphorylation of JAKs and STAT-1 was abrogated by myricitrin. Furthermore, myricitrin inhibited the nuclear transfer and DNA binding activity of STAT1. The JAK-specific inhibitor ruxolitinib simulated the anti-inflammatory effect of myricitrin. However, myricitrin had no impact on the MAPK signalling pathway. Myricitrin attenuated the generation of intracellular ROS by inhibiting the assembly of components of the gp91phox and p47phox. Suppression of ROS generation using NAC or apocynin or by silencing gp91phox and p47phox all demonstrated that decreasing the level of ROS inhibited the LPS-induced inflammatory response. Collectively, these results confirmed that myricitrin exhibited anti-inflammatory activity by blocking the activation of JAKs and the downstream transcription factor STAT1, which may result from the downregulation of NOX2-dependent ROS production mediated by myricitrin.
研究领域:
药理学
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免疫学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Antioxidants
·
2022
·Vol. 12
·期 1
·74
·
IF 7.675
Wanying Liu,Ke Li,Menglin Zheng,Ling He,Tong Chen
The present study was conducted to evaluate the effect of genipin (GEN) on the microglia of diabetic cognitive impairment and explore its potential mechanism. Diabetic mice were induced by STZ/HFD, while GEN was intragastrically and intraventricularly treated. The human microglia cell HMC3 was induced by LPS/HG/PA. As a result, GEN attenuated diabetic symptoms and diabetic cognitive impairment-related behavior in novel object recognition, Morris water maze and passive avoidance tests. GEN inhibited M1 microglia polarization, lipid accumulation, oxidative stress and promoted mitochondrial fusion via FABP4/Mfn1. FABP4 overexpression, Mfn1 overexpression, selective FABP4 inhibitor BMS, and Mfn1 SiRNA were employed for investigating the mechanism. The inhibitory effect of GEN on ROS may be associated with NOX2 signaling and the translocation of p47phox/p67phox to the cell membrane. With the ROS scavenger NAC, it was proved that ROS participated in GEN-mediated inflammation and lipid accumulation. GEN inhibited the phosphorylation and nucleus translocation of NF-κB. GEN inhibited the ubiquitination of Mfn1, which was mediated by the E3 ligase Hrd1. GEN also enhanced microglia phagocytosis. Molecular docking predicted that GEN may interact with FABP4 by hydrogen bond at the S53 and R78 residues. In conclusion, GEN attenuated diabetic cognitive impairment by inhibiting inflammation, lipid accumulation and promoting mitochondrial fusion via FABP4/Mfn1 signaling.Keywords:diabetic cognitive impairment;genipin;microglia;FABP4;Mfn1
研究领域:
神经科学
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药理学
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糖尿病
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
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2024
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IF 10.7
Jing Xu,Chang He,Yongsong Cai,Xipeng Wang,Jidong Yan,Jing Zhang,Fujun Zhang,Vilma Urbonaviciute,Yuanyuan Cheng,Shemin Lu,Rikard Holmdahl
Autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematous, are regulated by polymorphisms in genes contributing to the NOX2 complex. Mutations in both Ncf1 and Ncf4 affect development of arthritis in experimental models of RA, but the different regulatory pathways mediated by NOX2-derived reactive oxygen species (ROS) have not yet been clarified. Here we address the possibility that intracellular ROS, regulated by the NCF4 protein (earlier often denoted p40phox) which interacts with endosomal membranes, could play an important role in the oxidation of cysteine peptides in mononuclear phagocytic cells, thereby regulating antigen presentation and activation of arthritogenic T cells. To study the role of NCF4 we used mice with an amino acid replacing mutation (NCF4 R58A ), which is known to affect interaction with endosomal membranes, leading to decreased intracellular ROS production. To study the impact of NCF4 on T cell activation, we used the glucose phosphate isomerase peptide GPI 325-339 , which contains two cysteine residues (325-339c-c). Macrophages from mice with the NCF4 58A mutation efficiently presented the peptide when the two cysteines were intact and not crosslinked, leading to a strong arthritogenic T cell response. T cell priming occurred in the draining lymph nodes (LNs) within 8 days after immunization. Clodronate treatment, which depletes antigen-presenting mononuclear phagocytes, ameliorated arthritis severity, whereas treatment with FYT720, which traps activated T cells in LNs, prohibited arthritis. We conclude that NCF4-dependent intracellular ROS maintains cysteine peptides in an oxidized crosslinked state, which prevents presentation of peptides recognized by non-tolerized T cells and thereby protects against autoimmune arthritis.
研究领域:
免疫学
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自身免疫
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Host & Microbe
·
2024
·
IF 20.6
Dongping Li,Meijuan Wan,Lanfeng Xue,Zhelin Zhang,Yifeng Qiu,Fengyi Mei,Niexing Tang,Chunxiao Yu,Yao Yu,Tianqi Chen,Xing Ding,Qin Yang,Qiuyan Liu,Peng Gu,Wei Jia,Yu Chen,Peng Chen
Cholestatic liver disease (CLD) is a common liver disorder with limited treatment options. Here, we demonstrate that zinc (Zn) supplementation can alter the gut microbiome to mitigate cholestatic liver injury. Oral Zn altered the microbiota of mice and humans (this study was registered at clinicaltrials.gov [NCT05597137]), increasing the abundance of Blautia producta ( B. producta ) and promoting the generation of p-coumaric acid. Additionally, p-coumaric acid concentrations were negatively correlated with liver injury parameters in CLD patients. In mice, the protective effects of Zn were partially mediated by p-coumaric acid, which directly bound to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and suppressed the production of reactive oxygen species (ROS) in hepatocytes, thus preventing hepatocyte cell death and liver damage. Additionally, knocking out the histidine ammonia-lyase, which catalyzes the conversion of tyrosine to p-coumaric acid in B. producta , blunted the protective effects of Zn. These findings highlight a host-microbiota interaction that is stimulated by Zn supplementation, providing potential benefits for CLD.
研究领域:
胃肠病学
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微生物学
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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
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