TY - JOUR
T1 - Inhibition of NO-induced β-cell death by novel NF-κB inhibitor (-)-DHMEQ via activation of Nrf2-ARE pathway
AU - Ogasawara, Akira
AU - Simizu, Siro
AU - Ito, Ayumi
AU - Kawai, Toshihide
AU - Saisho, Yoshifumi
AU - Takei, Izumi
AU - Umezawa, Kazuo
N1 - Funding Information:
This work was supported in part by grants from the programs Grants-in-Aid for Scientific Research (B) and the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research. This work was also supported in part by MEXT-Supported Program for the Strategic Research Foundation at Private Universities, which is for Aichi Medical University 2011-2015 (S1101027). The first author is also very grateful to Yoshida Scholarship Foundation for its financial support during studies in Master’s course.
PY - 2013/4
Y1 - 2013/4
N2 - Excessive nitric oxide (NO) plays a pivotal role in the progression of β-cell apoptosis in type 1 diabetes mellitus. We used mouse insulinoma Min6 cells as a model of β cells in this research. We found that (-)-DHMEQ, an NF-κB inhibitor, rescued β cells from NO-induced apoptosis, and then studied the mechanism of apoptosis inhibition. (-)-DHMEQ activated Nrf2 and induced transcription of Nrf2-target genes following the increase of antioxidant response element (ARE) reporter activity. Similarly, tert-butyl hydroquinone (tBHQ), a known activator of Nrf2, inhibited NO-induced cell death along with the transcriptional activation of ARE. RNAi-mediated knockdown of Nrf2 lowered the cytoprotective effect of (-)-DHMEQ against NO, suggesting that (-)-DHMEQ inhibited NO-induced cell death via Nrf2 activation. Furthermore, overexpression of Nrf2 rendered cells to be more resistant to NO, indicating that Nrf2 activation provides critical defense function against NO in Min6 cells. Taken together, we conclude that (-)-DHMEQ may be a useful therapeutic agent for type 1 diabetes mellitus in the onset of disease by protecting β cells from apoptosis.
AB - Excessive nitric oxide (NO) plays a pivotal role in the progression of β-cell apoptosis in type 1 diabetes mellitus. We used mouse insulinoma Min6 cells as a model of β cells in this research. We found that (-)-DHMEQ, an NF-κB inhibitor, rescued β cells from NO-induced apoptosis, and then studied the mechanism of apoptosis inhibition. (-)-DHMEQ activated Nrf2 and induced transcription of Nrf2-target genes following the increase of antioxidant response element (ARE) reporter activity. Similarly, tert-butyl hydroquinone (tBHQ), a known activator of Nrf2, inhibited NO-induced cell death along with the transcriptional activation of ARE. RNAi-mediated knockdown of Nrf2 lowered the cytoprotective effect of (-)-DHMEQ against NO, suggesting that (-)-DHMEQ inhibited NO-induced cell death via Nrf2 activation. Furthermore, overexpression of Nrf2 rendered cells to be more resistant to NO, indicating that Nrf2 activation provides critical defense function against NO in Min6 cells. Taken together, we conclude that (-)-DHMEQ may be a useful therapeutic agent for type 1 diabetes mellitus in the onset of disease by protecting β cells from apoptosis.
KW - (-)-DHMEQ
KW - Apoptosis
KW - NF-κB
KW - Nrf2
KW - β Cell
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U2 - 10.1016/j.bbrc.2013.02.062
DO - 10.1016/j.bbrc.2013.02.062
M3 - Article
C2 - 23454127
AN - SCOPUS:84877668193
SN - 0006-291X
VL - 433
SP - 181
EP - 187
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -
