TY - JOUR
T1 - Modified cell-permeable JNK inhibitors efficiently prevents islet apoptosis and improves the outcome of islet transplantation
AU - Noguchi, Hirofumi
AU - Miyagi-Shiohira, Chika
AU - Nakashima, Yoshiki
AU - Ebi, Nana
AU - Hamada, Eri
AU - Tamaki, Yoshihito
AU - Kuwae, Kazuho
AU - Kobayashi, Naoya
AU - Saitoh, Issei
AU - Watanabe, Masami
N1 - Funding Information:
We thank Ms. Naomi Kakazu (University of the Ryukyus) for the office processing and Ms. Saki Uema, Maki Higa, Yuki Kawahira, and Saori Adaniya (University of the Ryukyus) for technical support. This work was supported in part by JSPS KAKENHI Grant Numbers JP16H05404, JP16K10435, JP18K08545, Japan Agency for Medical Research and Development, Okinawa Science and Technology Innovation System Construction Project, the Waksman Foundation of Japan, Inc., and The Naito Foundation.This work was supported in part by the Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Okinawa Science and Technology Innovation System Construction Project, the Waksman Foundation of Japan, Inc., and The Naito Foundation.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - We previously reported that treatment with a JNK inhibitory peptide (11R-JNKI) prevents islet apoptosis and enhances the islet function in vivo. In the present study, we explored more efficient JNK inhibitors. The inhibition of the JNK activity by five types of deletion peptides in 11R-JNKI was investigated. One of the peptides, 8R-sJNKI(-9), significantly prevented JNK activation. At a concentration of 1 µM, 8R-sJNKI(-9) inhibited JNK activity similarly to 10 µM 11R-JNKI and the inhibition of the JNK activity by 10 µM 8R-sJNKI(-9) was significantly greater than that by 10 µM 11R-JNK. To evaluate the effects of 8R-sJNKI(-9), porcine islets were cultured with 1 µM of 8R-sJNKI(-9) or 8R-mutant sJNKI(-9) (8R-mJNKI(-9)). After 1 day of culture, the numbers of islets in the 8R-sJNKI(-9)-treated group was significantly higher than that in the 8R-mJNKI(-9)-treated group. After islet transplantation, the blood glucose levels reached the normoglycemic range in 58.3% of streptozotocin-induced diabetic mice in the 8R-sJNKI(-9) group and 0% of the mice in the 8R-mJNKI(-9)-treated group. These data suggest that 8R-sJNKI(-9) inhibits islet apoptosis and improves islet function.
AB - We previously reported that treatment with a JNK inhibitory peptide (11R-JNKI) prevents islet apoptosis and enhances the islet function in vivo. In the present study, we explored more efficient JNK inhibitors. The inhibition of the JNK activity by five types of deletion peptides in 11R-JNKI was investigated. One of the peptides, 8R-sJNKI(-9), significantly prevented JNK activation. At a concentration of 1 µM, 8R-sJNKI(-9) inhibited JNK activity similarly to 10 µM 11R-JNKI and the inhibition of the JNK activity by 10 µM 8R-sJNKI(-9) was significantly greater than that by 10 µM 11R-JNK. To evaluate the effects of 8R-sJNKI(-9), porcine islets were cultured with 1 µM of 8R-sJNKI(-9) or 8R-mutant sJNKI(-9) (8R-mJNKI(-9)). After 1 day of culture, the numbers of islets in the 8R-sJNKI(-9)-treated group was significantly higher than that in the 8R-mJNKI(-9)-treated group. After islet transplantation, the blood glucose levels reached the normoglycemic range in 58.3% of streptozotocin-induced diabetic mice in the 8R-sJNKI(-9) group and 0% of the mice in the 8R-mJNKI(-9)-treated group. These data suggest that 8R-sJNKI(-9) inhibits islet apoptosis and improves islet function.
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U2 - 10.1038/s41598-018-29481-9
DO - 10.1038/s41598-018-29481-9
M3 - Article
C2 - 30038242
AN - SCOPUS:85050609226
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 11082
ER -
