Oxidative Medicine and Cellular Longevity
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2022
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IF 7.31
Xinye Wang,Ran Huo,Zhongjie Liang,Congcong Xu,Tingting Chen,Jingjing Lin,Luyao Li,Wei Lin,Bingting Pan,Xiaoqin Fu,Shangqin Chen
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly found in premature infants. Excessive inflammation and oxidative stress contribute to BPD occurrence and development. Simvastatin, as an inhibitor of HMG-CoA reductase, has been reported to have antioxidative and anti-inflammatory effects. However, its effect and possible mechanisms in hyperoxia-induced lung injury are rarely reported. In this study, in vivo and in vitro experiments were conducted to investigate whether simvastatin could ameliorate hyperoxia-induced lung injury and explore its potential mechanism. For the in vivo study, simvastatin could improve alveolar development after hyperoxic lung injury and reduce hyperoxic stress and inflammation. The in vitro study revealed that simvastatin can reduce inflammation in A549 cells after high-oxygen exposure. Simvastatin suppressed NLRP3 inflammasome activation and played anti-inflammatory and antioxidant roles by increasing KLF2 (Krüppel-like factor 2) expression. In vitro experiments also revealed that these effects of simvastatin were partially reversed by KLF2 shRNA, indicating that KLF2 was involved in simvastatin effects. In summary, our findings indicate that simvastatin could downregulate NLRP3 inflammasome activation and attenuate lung injury in hyperoxia-induced bronchopulmonary dysplasia via KLF2-mediated mechanism.
研究领域:
儿科
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肺科学
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药理学
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炎症
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氧化应激
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
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2023
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IF 3.8
Xiao Ji,Zhenwu Zhao
Background Silencing of miR-92a-3p may be beneficial in relieving depression of chronically stressed rats. The level of kruppel-like factor 2 (KLF2) was increased in the striatum of depressed rats after ketamine treatment. Enriched environment (EE) ameliorated depression-like behaviors in rats. However, the specific mechanism of EE treatment on depression induced by chronic unpredictable mild stress (CUMS) remains unclear. Methods After CUMS-induced male Sprague Dawley rats were treated under EE or/and Adeno-Associated Virus (AAV)-miR-92a-3p, depression-like behaviors, cognitive ability, dendritic spine density, as well as levels of miR-92a-3p and KLF2 were detected by the behavioral tests, morris water maze test, Golgi staining, and quantitative real-time polymerase chain reaction (qRT-PCR) as needed. The body weight of rats was also measured. Next, primary hippocampal neurons were cultivated. The targeting relationship between miR-92a-3p and KLF2 was analyzed by TargetScan v7.2 and dual-luciferase reporter assay. After hippocampal neurons were transfected with miR-92a-3p mimic or/and overexpressed KLF2 vector, the cell viability, and apoptosis, together with the levels of KLF2, brain-derived neurotrophic factor (BDNF), phosphorylated (p)-tropomysin related kinase B (p-TrkB) and TrkB were determined by MTT assay, flow cytometry, qRT-PCR, and western blot as needed. Results EE ameliorated CUMS-induced depression-like behaviors and cognitive ability, and elevated the neuronal dendritic spine density and KLF2 level, but reduced miR-92a-3p level in hippocampal tissues, while the above effects were reversed by AAV-miR-92a-3p. MiR-92a-3p mimic restrained cell viability, along with p-TrkB/ TrkB and BDNF levels, but promoted apoptosis in hippocampal neurons, which were reversed by overexpressed KLF2. Conclusion EE ameliorates CUMS-induced depression-like symptoms in rats via regulating the miR-92a-3p/KLF2 pathway.
研究领域:
神经科学
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分子生物学
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行为科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2023
·Vol. 20
·期 1
·1-15
·
IF 9.3
Zheng Yingxia,Chen Zheyi,Zhou Bingqian,Chen Shiyu,Chen Ningdai,Shen Lisong
Background Protein arginine methyltransferase 5 (Prmt5) is the main type II methyltransferase, catalyzes protein arginine residue symmetric dimethylation, and modulates normal cellular physiology and disease progression. Prmt5 inhibition or deletion in CD4+ T cells has been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), but the detailed molecular mechanisms have not yet been elucidated.Methods EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in T cells Prmt5 conditional knockout (CD4-cre-Prmt5fl/fl, Prmt5cko) and Prmt5fl/fl (WT) mice. Flow cytometry, single-cell RNA sequencing, ATAC sequencing and chromatin immunoprecipitation assay (ChIP) approaches were used to explore the detail mechanisms.Results We find that Prmt5cko mice are resistant to EAE; infiltrating inflammatory CD4+ T cells in the central nervous system (CNS) are greatly reduced. However, in Prmt5cko mice, T cells in the spleen show much more proliferation and activation properties, the total number of CD4+ T cells in the spleen is not reduced, and the percentage of Rora+ CD4+ T cells is elevated. Also, CD4+ T cells express lower levels of S1pr1 and Klf2 than WT mice, which may influence pathogenic CD4+ T-cell egress from the spleen and migration to the CNS. Moreover, the single-cell ATAC sequence and ChIP assay reveal that the transcription factor Klf2 is enriched at the S1pr1 promoter and that Klf2 motif activity is reduced in Prmt5cko mice.Conclusion sOur study delineates the undiscovered role of Prmt5 in T-cell biology in which Prmt5 may inhibit Klf2-S1pr1 pathway to ameliorate EAE disease. Controlling T-cell Prmt5 expression may be helpful for the treatment of autoimmune diseases.
研究领域:
免疫学
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分子生物学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Hao Kan,Yuan Liu,Ka Zhang,Aiqin Mao,Li Geng,Fan Yu,Lei Feng
Background Endothelial dysfunction induced by lipotoxicity is a critical initiating factor in atherosclerosis. Sweroside, a bioactive iridoid glycoside, possesses significant anti-inflammatory activities; however, its therapeutic potential in regulating vascular endothelial inflammation and dysfunction remains unexplored. This study aimed to investigate the protective effects of Sweroside against endothelial injury and to elucidate the underlying molecular mechanisms, specifically focusing on the transcriptional regulation of inflammatory cascades. Methods Human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs) stimulated with palmitic acid (PA), along with C57BL/6J mice fed a high-fat diet (HFD), served as the in vitro and in vivo models, respectively. Transcriptome sequencing (RNA-seq) was employed to screen for potential therapeutic targets. Molecular mechanisms were validated using small interfering RNA (siRNA) knockdown, Western blotting, and dual-luciferase reporter assays. Vascular function was evaluated via wire myograph to assess endothelium-dependent relaxation and pulse wave velocity (PWV) to measure arterial stiffness. Results Sweroside treatment significantly attenuated PA-induced cytotoxicity, oxidative stress, inflammation, and cytoskeletal disruption in ECs. RNA-seq identified Krüppel-like Factor 2 ( KLF2 ) as a core target up-regulated by Sweroside. Mechanistically, Sweroside restored KLF2 expression, which subsequently functioned as a transcriptional repressor by directly binding to the promoter of Fatty Acid Binding Protein 4 ( FABP4 ). This repression reduced FABP4 levels, thereby alleviating the suppression of PPAR-γ and blocking the NF-κB-dependent induction of the downstream chemokine CCL20. In vivo, Sweroside administration effectively improved endothelium-dependent relaxation, and reduced aortic stiffness and vascular inflammation in HFD-fed mice. Conclusions Sweroside ameliorates endothelial dysfunction and vascular remodeling by activating the KLF2-mediated signaling axis to repress FABP4 and the downstream CCL20 inflammatory cascade. These findings highlight Sweroside as a promising therapeutic candidate for the treatment of atherosclerosis and cardiovascular diseases associated with metabolic inflammation.
✓ 已验证
DOI
PubMed
高影响因子
NEUROTOXICITY RESEARCH
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2021
·Vol. 39
·期 6
·1937-1945
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IF 3.911
Wang Guijie,Tian Fang,Li Yu,Liu Yang,Liu Chunfeng
Acute ischemic stroke is a challenging disease that threatens the life of older people. Dysfunction of brain endothelial cells is reported to be involved in the pathogenesis of acute ischemic stroke. Ramelteon is a novel agonist of melatonin receptor developed for the treatment of insomnia. Recently, the promising protective effect of Ramelteon on brain injury has been widely reported. The present study aims to investigate the protective effect of Ramelteon against free fatty acid (FFA)–induced damages in brain vascular endothelial cells and the underlying mechanism. Firstly, we discovered that Ramelteon administration remarkably reversed the decreased cell viability, increased LDH release, activated oxidative stress, and excessive released inflammatory factors caused by FFAs. Secondly, Ramelteon extensively suppressed the attachment of U937 monocytes to bEnd.3 brain endothelial cells induced by FFAs. In addition, the elevated expression of E-selectin and the reduced expression of KLF2 induced by FFAs were pronouncedly alleviated by Ramelteon. Lastly, silencing of KLF2 abolished the protective effects of Ramelteon against FFA-induced expression of E-selectin and the attachment of U937 monocytes to bEnd.3 brain endothelial cells. In conclusion, Ramelteon mitigated FFA-induced attachment of monocytes to brain vascular endothelial cells by increasing the expression of KLF2 and reducing the expression of E-selectin.
研究领域:
神经科学
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药理学
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心血管疾病
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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