LIFE SCIENCES
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2020
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IF 3.647
Li Li,Sufang Zhang,Lei Wei,Zhongfu Wang,Wei Ma,Fangying Liu,Yanhua Shen,Shanfang Zhang,Xiulian Zhang,Yu Hang,Yechang Qian
Aims To investigate the effect and underlying mechanism of melittin and tripartite motif (TRIM) family in human embryonic lung fibroblast (HELF). Materials and methods Lentiviral RNA interference vector and lentiviral overexpression vector were constructed and packaged by transfecting 293T cells; the proliferation of HELF was examined using Cell Counting Kit 8; Western blot and qRT-PCR were performed to examine protein and mRNA expression; the interaction with protein phosphatase magnesium-dependent 1A (PPM1A) was examined by Co-immunoprecipitation. Key findings Compared with the control group, the mRNA expression of the TRIM6, TRIM8 and TRIM47 in the IPF group significantly increased. Melittin inhibited the mRNA expression and protein expression levels of TRIM47, the HELF proliferation, the hydroxyproline levels, and the phosphorylation of Smad2/3; the interference of TRIM47 inhibited the protein expression of Vimentin, α-SMA, CTGF, the phosphorylation of Smad2/3 and the synthesis of hydroxyproline; TRIM47 overexpression elevated the phosphorylation of Smad2/3, induced ubiquitination of PPM1A and decreased the expression level of PPM1A, while TRIM47 RNA interference reversed this result. Significance Melittin has anti-fibrotic effect in HELF by directly reducing the phosphorylation of Smad2/3 or indirectly reducing the phosphorylation of Smad2/3 by decreasing the expression levels of TRIM47 whose overexpression induces ubiquitination of PPM1A.
研究领域:
药理学
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分子生物学
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细胞生物学
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肺纤维化
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产品关联
DOI
PubMed
高影响因子
iScience
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2024
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IF 4.6
Changyun Yu,Chen Zhang,Qianqian Zhang,Cai Zhang,Jingjie Han,Jinying Li
Tripartite motif-containing 47 (TRIM47) is a member of the TRIM family, which has E3 ligase activity and has been demonstrated to be involved in tumor development. In this work, we found that TRIM47 is highly expressed in head and neck squamous cell carcinomas (HNSCC) tissues. TRIM47 overexpression promoted HNSCC cell proliferation. Downregulation of TRIM47 suppressed HNSCC cell proliferation and promoted apoptosis and autophagy. TRIM47 suppression caused cell proliferation inhibition and apoptosis promotion could be reversed by 3-MA, an autophagy inhibitor. In mechanism, TRIM47 interacted with XIAP-associated factor 1 (XAF1), promoting its ubiquitination and degradation. XAF1 promoted HNSCC cell apoptosis and autophagy. TRIM47 overexpression caused cell proliferation promotion and autophagy inhibition could be reversed by XAF1 overexpression. Animal experiments confirmed that the knockdown of TRIM47 inhibits tumor growth in vivo . Ultimately, TRIM47 promotes the ubiquitination and degradation of XAF1 and suppresses apoptosis and autophagy to promote the progression of HNSCC.
研究领域:
肿瘤学
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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
Molecular Metabolism
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2026
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IF 6.3
Weiyan Wang,Lingli Xie,Guilan Chen,Xin Zuo,Meiling Zhong,Tong Yang,Weihua Wu
Background Diabetic cardiomyopathy (DCM) is a prevalent and severe cardiovascular complication of diabetes mellitus, characterized by progressive cardiac dysfunction and pathological remodeling driven by myocardial metabolic disturbances. However, the underlying molecular mechanisms remain incompletely elucidated. Methods A type 2 DCM mouse model was established by feeding C57BL/6 mice a high-fat diet combined with streptozotocin injections. Cardiomyocyte-specific TRIM47 knockdown was achieved via AAV9-mediated delivery of a cardiomyocyte-specific cTnT promoter-driven shRNA. In vitro, primary neonatal mouse ventricular cardiomyocytes (NMCMs) were treated with palmitic acid (PA) to model cardiomyocyte injury. Results TRIM47 was significantly upregulated in diabetic hearts. Cardiomyocyte-specific TRIM47 knockdown improved left ventricular ejection fraction and fractional shortening, attenuated chamber dilation, and reduced heart weight-to-tibia length ratio. TRIM47 silencing attenuated cardiomyocyte hypertrophy, interstitial fibrosis, and cardiomyocyte apoptosis, alongside reduced myocardial inflammatory cytokine levels (TNF-α, IL-6, IL-1β). Furthermore, TRIM47 knockdown alleviated myocardial lipid accumulation and reduced triglyceride levels, accompanied by downregulation of the fatty acid translocase CD36. In vitro, PA-treated NMCMs exhibited elevated TRIM47 expression, and its knockdown mitigated PA-induced cardiomyocyte injury, inflammation, apoptosis, and lipid deposition. Mechanistically, the m6A reader YTHDF3 was upregulated under PA conditions and directly bound to m6A-modified TRIM47 mRNA, enhancing its stability. Rescue experiments demonstrated that YTHDF3 overexpression exacerbated PA-induced cardiomyocyte injury, whereas concurrent TRIM47 knockdown largely reversed these deleterious effects. Conclusions Our results revealed that TRIM47 may contribute to the progression of DCM by promoting abnormal cardiac lipid metabolism, exacerbating inflammation and apoptosis, and these effects are partially mediated through the upstream m6A reader YTHDF3.
✓ 已验证
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Zhao Tong,Zhou Zhi-ruo,Wan Hui-qi,Feng Tian,Hu Xu-hui,Li Xiao-qian,Zhao Shi-mei,Li Hong-lin,Hou Ji-wei,Li Wei,Lu Da-yun,Qian Min-yi,Shen Xu
Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC 50 value of 4.23 μM. Treatment with OB (2.5, 5 mg·kg −1 ·d −1 , i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.
研究领域:
药理学
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肺病学
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分子生物学
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
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2025
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IF 3.9
Yanyang Fu,Jixing Wu,Jian Shi,Changjun Jia
To explore potential biomarkers in the progression of intrahepatic cholangiocarcinoma (ICC), the gene expression profiles in ICC and paired normal tissues were analyzed using mRNA-sequencing. E3 ubiquitin ligase tripartite motif containing 47 (TRIM47) was found highly expressed in ICC tissues (Log 2 FC=2.473, p<0.001), which was also observed in seven ICC samples compared with paired normal tissues. Patients with higher TRIM47 expression exhibited shorter disease-free survival period. Functional studies indicated that TRIM47 knockdown in ICC cells suppressed cell growth in vitro and the tumorigenicity of tumor cells in vivo , whereas TRIM47 overexpression of had the opposite effect. Furthermore, after co-culture of TRIM47-silenced ICC cells and macrophages, the macrophages showed a reduction in M2 polarization bias. Cancer cells with TRIM47 downregulation were sensitive to macrophage cytotoxicity. Notably, the secretion of fumarate was reduced in TRIM47-silenced cancer cells, and the treatment of dimethyl fumarate, a derivative of fumarate, reversed the effect of TRIM47 downregulation on M2 polarization in macrophages. Through IP-LC/MS analysis, we obtained 1166 binding partners of TRIM47 in ICC cells. Among those partners, fumarate hydratase (FH), a catalytic enzyme for fumarate metabolism, was bound with TRIM47. Knockdown of TRIM47 increased the protein half-life of FH from 1.33 h to 2.25 h. Overexpression of TRIM47 reduced the protein expression of FH and increased its ubiquitination. FH overexpression restored the effects of TRIM47. Collectively, the observations demonstrate that TRIM47 accelerates the progression of ICC by interacting with FH and ubiquitinating FH, indicating that TRIM47/FH axis may be potential target for ICC treatment.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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免疫学
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泛素-蛋白酶体系统
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产品关联
DOI
PubMed
高影响因子
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