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Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

by Hyo-Jin Kim 1,†, Donghee Kim 2,†, Haelim Yoon 2, Cheol Soo Choi 2,3,4, Yoon Sin Oh 5,* and Hee-Sook Jun 1,2,6,*
1
College of Pharmacy, Gachon University, Incheon 21936, Korea
2
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
3
Department of Medicine, College of Medicine, Gachon University, Incheon 21565, Korea
4
Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
5
Department of Food and Nutrition, Eulji University, Seongnam 13135, Korea
6
Gachon Medical and Convergence Institute, Gachon Gil Medical Center, Incheon 21565, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Antioxidants 2020, 9(5), 406; https://doi.org/10.3390/antiox9050406
Received: 24 March 2020 / Revised: 1 May 2020 / Accepted: 4 May 2020 / Published: 10 May 2020
(This article belongs to the Special Issue Anti-inflammatory and Antioxidant Properties of Plant Extracts)
Pancreatic beta cells are vulnerable to oxidative stress, which causes beta cell death and dysfunction in diabetes mellitus. Broussonetia kazinoki Siebold (BK) is a widely used herbal medicine, but its potential effects against beta cell death-induced diabetes have not been studied. Therefore, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against streptozotocin (STZ)-induced toxicity in pancreatic beta cells. Intraperitoneal injection of STZ in mice induced hyperglycemia; however, oral administration of BKFE significantly decreased the blood glucose level as well as HbA1c levels. BKFE treatment improved glucose tolerance and increased body weight in diabetic mice. Moreover, BKFE treatment resulted in increased serum insulin levels and insulin expression in the pancreas as well as decreased 4-hydroxynonenal levels induced by oxidative stress. Treatment with STZ decreased cell viability of mouse insulinoma cells (MIN6), which was blocked by BKFE pretreatment. BKFE significantly inhibited apoptotic cells and decreased the expression levels of cleaved-caspase-3 and cleaved-poly (ADP-ribose) polymerase (PARP) induced by STZ treatment. Production of reactive oxygen species in STZ-treated MIN6 cells was also significantly decreased by treatment with BKFE. Erk phosphorylation and Nox4 levels increased in STZ-treated MIN6 cells and the pancreas of mice injected with STZ and this increase was inhibited by treatment with BKFE. Inhibition of Erk phosphorylation by treatment with the PD98059 inhibitor or siRNA Erk also blocked the expression of Nox4 induced by STZ treatment. In conclusion, BKFE inhibits Erk phosphorylation, which in turn prevents STZ-induced oxidative stress and beta cell apoptosis. These results suggested that BKFE can be used to prevent or treat beta cell damage in diabetes. View Full-Text
Keywords: Broussonetia kazinoki Siebold fruit extract; diabetes; pancreatic beta cell; oxidative stress; apoptosis Broussonetia kazinoki Siebold fruit extract; diabetes; pancreatic beta cell; oxidative stress; apoptosis
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Kim, H.-J.; Kim, D.; Yoon, H.; Choi, C.S.; Oh, Y.S.; Jun, H.-S. Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway. Antioxidants 2020, 9, 406.

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