JOURNAL OF CONTROLLED RELEASE
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2021
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IF 9.776
Hongyan Cui,Yue Wang,Lili Chen,Ming Qian,Liuwei Zhang,Xiujue Zheng,Xi Yang,Li Chen,Yan Zhao,Qixian Chen,Jingyun Wang
Molecular insights into tumorigenesis have uncovered intimate correlation of SNAI1 with tumor malignancy. Herein, to explore merits of SNAI1-knockdown in tumor therapy, we harnessed RNA interference tool (shSNAI1), together with chemotherapeutic doxorubicin . Owing to abundant hydroxyl groups , pullulan was attempted to be covalently conjugated with a multiple of functional moieties, including positively-charged oligoethylenimine components for electrostatic entrapment of polyanionic shSNAI1 and hydrophobic components for entrapment of lipophilic doxorubicin. Notably, the aforementioned covalent conjugations were tailored to be detachable in response to intracellular reducing microenvironment owing to redox disulfide linkage, thereby accounting for selective intracellular liberation of the therapeutic payloads. Moreover, the surface of nanomedicine was modified with hyaluronic acid , endowing not only excellent biocompatibilities but active tumor-targeting function due to its receptors (CD44) overexpressed on tumor cells. Subsequent investigations approved appreciably targeted co-delivery of shSNAI1 and doxorubicin into solid lung tumors via systemic administration and demonstrated critical contribution of SNAI1-knockdown in amplifying chemotherapeutic potencies.
研究领域:
癌症治疗
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纳米技术
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分子生物学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Nannan Xu,Wenyi Fu,Jiake Wu,Shuai Zhao,Chunyang Tian
Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe 2+ levels, and LDH activity, while reducing GSH-PX and GSH activities. Moreover, TNF-α treatment increased GPX4 and SLC7A11 expression but decreased ACSL4 levels, and TRIM16 overexpression reversed these effects. TRIM16 knockdown reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Furthermore, Fer-1 treatment reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Mechanistically, TRIM16 directly binds to Snai1, promoted its K48-linked ubiquitination, and specifically ubiquitinates Snai1 at the K146 site. Overexpression of Snai1 decreased the lipid ROS levels and increased the GSH content. Our study identifies TRIM16 as a promoter of ferroptosis in TNF-α-induced FLS by enhancing Snai1 ubiquitination and degradation. In summary, our study presented that TRIM16 plays a protective role in RA.
研究领域:
免疫学
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分子生物学
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风湿病学
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细胞死亡机制
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信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2022
·Vol. 28
·期 1
·1-14
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IF 6.376
Zhao Fei,Ke Jinjing,Pan Wensheng,Pan Hanghai,Shen Miao
Background The increasing incidence of non-alcoholic fatty liver disease (NAFLD) has been reported worldwide, which urges understanding of its pathogenesis and development of more effective therapeutical methods for this chronic disease. In this study, we aimed to investigate the effects of a LIM homeodomain transcription factor, islet1 (ISL1) on NAFLD. Methods Male C57BL/6J mice were fed with a diet high in fat content to produce NAFLD models. These models were then treated with overexpressed ISL1 (oe-ISL1), oe-Lysine-specific demethylase 6B (KDM6B), oe-SNAI1, or short hairpin RNA against SNAI1. We assessed triglyceride and cholesterol contents in the plasma and liver tissues and determined the expressions of ISL1, KDM6B and SNAI1 in liver tissues. Moreover, the in vitro model of lipid accumulation was constructed using fatty acids to explore the in vitro effect of ISL1/KDM6B/SNAI1 in NAFLD. Results The results showed that the expressions of ISL1, KDM6B, and SNAI1 where decreased, but contents of triglyceride and cholesterol increased in mice exposed to high-fat diet. ISL1 inhibited lipogenesis and promoted lipolysis and exhibited a synergizing effect with KDM6B to upregulate the expression of SNAI1. Moreover, both KDM6B and SNAI1 could inhibit lipogenesis and induce lipolysis. Importantly, the therapeutic effects of ISL1 on in vitro model of lipid accumulations was also confirmed through the modulation of KDM6B and SNAI1. Conclusions Taken together, these findings highlighted that ISL1 effectively ameliorated NAFLD by inducing the expressions of KDM6B and SNAI1, which might be a promising drug for the treatment of NAFLD.
研究领域:
分子生物学
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肝病学
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转化医学
✓ 已验证
DOI
PubMed
高影响因子
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