CELLULAR SIGNALLING
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2023
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IF 4.8
Yingying Chen,Zhong He,Bo Zhao,Rui Zheng
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and a severe form of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is induced in response to epithelial injury, which leads to the accumulation of extracellular matrix in the lung parenchyma and contributes to pulmonary fibrosis. NPAS2 (neuronal PAS domain protein 2) is significantly increased in the lung tissues of IPF patients according to microarray dataset GSE10667 and NPAS2 is downregulated in differentiated human pulmonary type 2 epithelial cells in vitro based on microarray dataset GSE3306 from Gene Expression Omnibus (GEO). In this study, we demonstrated that NPAS2 was increased in bleomycin (BLM)- induced fibrotic lungs in mice. Knockdown of NPAS2 inhibited EMT in primary mouse lung alveolar type 2 epithelial (pmATII) cells and human lung alveolar type 2 epithelial cell line A549 cells under BLM challenge in vitro. Moreover, the silence of NPAS2 alleviated the BLM-induced pulmonary fibrosis in a murine model. Mechanistically, NPAS2 promotes EMT through positively regulating hairy and enhancer of split 1 (HES1) expression. In this study, we present novel findings that have not been previously reported, emphasizing that p53 transcriptionally activates NPAS2 in ATII cells and overexpression of NPAS2 weakens the effects of TP53 knockdown on EMT of pmATII and A549 cells. Our results suggest NPAS2 is a novel target gene of p53 in regulating BLM-mediated EMT in ATII cells and pulmonary fibrosis.
研究领域:
呼吸病学
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分子生物学
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细胞生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2019
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IF 3.499
Ziyue Zhou,Yanke Lin,Lu Gao,Zemin Yang,Shuai Wang,Baojian Wu
Brucine is one of the main bioactive and toxic constituents of the herb drug Semen Strychni . Here we aimed to determine dosing time-dependent hepatotoxicity of brucine, and to investigate the role of metabolism in generation of brucine chronotoxicity. Brucine was administered to wild-type or Npas2 −/− (a clock disrupted model) mice at different circadian time points for toxicity and pharmacokinetic characterization. The hepatotoxicity was evaluated by plasma alanine aminotransferase and aspartate aminotransferase measurements and histopathological analysis. The role of Cyp3a11 in brucine metabolism was determined by chemical inhibition assays and Cyp3a11-overexpressing HEK293 cells. Hepatic circadian Cyp3a11 mRNA and protein levels were determined by qPCR and Western blotting, respectively. The toxicity of brucine was more severe in the light phase [Zeitgeber time (ZT) 2 and ZT8] than in the dark phase (ZT14 and ZT20). Chemical inhibition and substrate metabolism assays suggested Cyp3a11 as a significant contributor to brucine metabolism. The Cyp3a11 mRNA, protein and activity in the livers of wild-type mice displayed significant circadian fluctuations. Npas2 ablation markedly down-regulated Cyp3a11 mRNA, protein and activity, and abrogated their circadian rhythms. The circadian time differences in brucine pharmacokinetics and liver distribution were lost in Npas2 −/− mice, so were the time differences in brucine hepatotoxicity. In conclusion, chronotoxicity of brucine was determined by circadian variations in Cyp3a11 metabolism. The findings have implications in improving brucine (and possibly Semen Strychni ) efficacy via dosing time optimization.
研究领域:
药理学
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毒理学
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生物节律学
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分子生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Zhihong Deng,Lifeng Zhao,Xiuxue Li,Chang-Yun Wang,Yue Zhou,Mengfei Li,Yingfei Li,Xianjun Fu
Appropriate topical dressings for burn treatments are important to accelerate skin wound recovery and prevent external infections. This study aimed to evaluate the effect and investigate the mechanism of folium crataegi ( Crataegus pinnatifida Bge. ) for the treatment of burn wounds, as well as to compare the therapeutic effects of aqueous extracts ( HLW ) and alcoholic extracts ( HLE ) from folium crataegi . The results demonstrated that both HLW and HLE groups exhibited a higher wound contraction rate than the silver sulfadiazine ( SSD ) ointment group. Moreover, HLW showed more significant wound repair effects than HLE . HLW significantly increased levels of EGF and FGF-2 in wound tissue, as well as TGF-β1 , VEGF , CAT and IL-10 in serum. Folium crataegi extract, especially aqueous extracts, exerted good anti-inflammatory, anti-oxidant and anti-bacterial effects by upregulating the expression of lag3 , txn1 and slpi , respectively. Folium crataegi extract significantly inhibits the expression of npas2 , a key gene in the circadian rhythm pathway. In conclusion, this research illustrated that the folium crataegi extract, especially aqueous extracts, had better therapeutic effects on skin burns through multiple ways, possibly including a novel mechanism related to circadian rhythm pathway. These findings suggest that folium crataegi could be a valuable source of compounds for enhancing skin regeneration through multiple ways.
研究领域:
药理学
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烧伤治疗
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伤口愈合
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2023
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IF 3.9
Yingying Chen,Wei Song,He Zhang,Xinping Ji
Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is a vital process in idiopathic pulmonary fibrosis (IPF), which results in the accumulation of fibroblasts and myofibroblasts and excessive extracellular matrix deposition. Based on RNA sequencing analysis and GEO dataset reanalysis, we screened out MICALL2, a gene upregulated in the lungs of IPF mice and alveolar epithelial type II (ATII) cells from IPF patients, and aimed to explore its role in IPF. We validated the expression of MICALL2 in bleomycin (BLM)-induced IPF mice and TGF-β1-stimulated ATII cells (primary murine ATII cells and A549 cells), and explored the role of MICALL2 in IPF by knockdown of MICALL2 in BLM-induced mice and TGF-β1-stimulated ATII cells. We found that MICALL2 was upregulated in the lungs of BLM-induced mice and TGF-β1-stimulated ATII cells. MICALL2-deficient mice had reduced fibrogenesis and restrained EMT upon BLM challenge. Knockdown of MICALL2 restrained the EMT process, in vitro, through impeding β‐catenin nuclear translocation. Mechanistically, we demonstrated that NPAS2 is directly bound to the promoter of MICALL2. Altogether, our data revealed transactivation of MICALL2 induced by NPAS2, contributing to activation of the Wnt/β-catenin pathway in ATII cells, thus leading to the EMT process and subsequent pulmonary fibrosis. Interfering with MICALL2 may represent an innovative therapeutic target to mitigate the extent of IPF.
研究领域:
肺科学
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细胞生物学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
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