Kim Hyo-Jin, Kim Donghee, Yoon Haelim, Choi Cheol Soo, Oh Yoon Sin, Jun Hee-Sook
College of Pharmacy, Gachon University, Incheon 21936, Korea.
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea.
Antioxidants (Basel). 2020 May 10;9(5):406. doi: 10.3390/antiox9050406.
Pancreatic beta cells are vulnerable to oxidative stress, which causes beta cell death and dysfunction in diabetes mellitus. 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.
胰腺β细胞易受氧化应激影响，氧化应激会导致β细胞死亡及功能障碍，进而引发糖尿病。西伯德（BK）是一种广泛使用的草药，但尚未对其预防β细胞死亡所致糖尿病的潜在作用进行研究。因此，我们研究了BK果实乙醇提取物（BKFE）对链脲佐菌素（STZ）诱导的胰腺β细胞毒性的保护作用。给小鼠腹腔注射STZ会导致高血糖；然而，口服BKFE可显著降低血糖水平及糖化血红蛋白（HbA1c）水平。BKFE治疗可改善糖尿病小鼠的糖耐量并增加体重。此外，BKFE治疗可使糖尿病小鼠的血清胰岛素水平升高、胰腺中胰岛素表达增加，同时降低氧化应激诱导的4-羟基壬烯醛水平。STZ处理会降低小鼠胰岛素瘤细胞（MIN6）的细胞活力，而BKFE预处理可阻止这种情况。BKFE可显著抑制凋亡细胞，并降低STZ处理诱导的半胱天冬酶-3（cleaved-caspase-3）和聚（ADP-核糖）聚合酶（PARP）裂解产物的表达水平。BKFE处理还可显著降低STZ处理的MIN6细胞中活性氧的产生。STZ处理的MIN6细胞及注射STZ的小鼠胰腺中，细胞外信号调节激酶（Erk）磷酸化水平和Nox4水平升高，而BKFE治疗可抑制这种升高。用PD98059抑制剂或Erk小干扰RNA（siRNA Erk）处理抑制Erk磷酸化，也可阻断STZ处理诱导的Nox4表达。总之，BKFE可抑制Erk磷酸化，进而预防STZ诱导的氧化应激和β细胞凋亡。这些结果表明，BKFE可用于预防或治疗糖尿病中的β细胞损伤。
