Abstract:
: Aims: Endothelial dysfunction appears in early diabetes mellitus partially because of epidermal growth factor receptor (EGFR) abnormal activation and downstream oxidative stress. The aim of this study was to determine whether Y396, a synthesized analog of rhynchophylline, could protect against endothelial dysfunction in diabetes and the underlying molecular mechanism. Results: Y396 could directly target the EGFR and inhibit its phosphorylation induced by high glucose and EGF, downstream translocation to the nucleus of E2F1, and its transcriptional activity and expression of Nox4. Diabetes-induced endothelium malfunction was ameliorated by Y396 treatment through EGFR inhibition. Downstream oxidative stress was decreased by Y396 in the aortas of type 1 diabetes mellitus mice and primary rat aorta endothelial cells (RAECs). Y396 could also ameliorate tunicamycin-induced oxidative stress in the aorta and RAECs. In addition, we again determined the protective effects of Y396 on high-fat diet/streptozotocin-induced type 2 diabetes mellitus. Innovation: This is the first study to demonstrate that Y396, a novel rhynchophylline analog, suppressed high-glucose-induced endothelial malfunction both in vivo and in vitro by inhibiting abnormal phosphorylation of EGFR. Our work uncovered EGFR as a novel therapeutic target and Y396 as a potential therapy against diabetes-induced complication. Conclusion: Y396 could directly bind with EGFR, and inhibit its phosphorylation and downstream E2F1 transcriptional activity. It could also preserve tunicamycin-evoked endothelial dysfunction and oxidative stress. It could protect against diabetes-induced endothelium malfunction in vivo through EGFR inhibition and downstream oxidative stress. Antioxid. Redox Signal. 32, 743-765.
journal_name
Antioxid Redox Signaljournal_title
Antioxidants & redox signalingauthors
Wang ZJ,Chang LL,Wu J,Pan HM,Zhang QY,Wang MJ,Xin XM,Luo SS,Chen JA,Gu XF,Guo W,Zhu YZdoi
10.1089/ars.2018.7721subject
Has Abstractpub_date
2020-04-10 00:00:00pages
743-765issue
11eissn
1523-0864issn
1557-7716journal_volume
32pub_type
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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doi:10.1089/ars.2018.7642
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2016.6885
更新日期:2017-10-10 00:00:00
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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更新日期:2009-09-01 00:00:00
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
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journal_title:Antioxidants & redox signaling
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doi:10.1089/15230860260220085
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journal_title:Antioxidants & redox signaling
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更新日期:2019-01-20 00:00:00
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2010.3877
更新日期:2011-10-15 00:00:00
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
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更新日期:2011-03-15 00:00:00
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2011.3969
更新日期:2011-12-15 00:00:00
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journal_title:Antioxidants & redox signaling
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