Department of Biochemistry, Research Institute for Endocrine Sciences, and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Jeonbuk 561–756, Republic of Korea.
Biol Pharm Bull. 2011;34(7):1026-31. doi: 10.1248/bpb.34.1026.
The generation of nitric oxide (NO) via inducible NO synthase (iNOS) and reactive oxygen species plays a key role in cytokine-mediated pancreatic β-cell damage. Oxidative stress due to reactive oxygen species activates the nuclear factor-κB (NF-κB) transcription factor, which regulates iNOS expression. In this regard, suppression of the NF-κB pathway is a novel strategy for protecting β-cells from damage. This study was performed to explore the effects of kazinol U, a prenylated flavan from Broussonetia kazinoki, on the NF-κB activation pathway in interleukin-1β (IL-1β)- and interferon-γ (IFN-γ)-treated β-cells. The cytotoxic effects of cytokines were completely abolished when RINm5F cells or islets were pretreated with kazinol U. Kazinol U inhibited the nuclear translocation and DNA binding of NF-κB subunits, which correlated with the inhibitory effects on IκB kinase (IKK) phosphorylation and IκBα degradation. In addition, kazinol U suppressed NO and hydrogen peroxide production and apoptotic cell death by cytokines in RINm5F cells. The protective effects of kazinol U were further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Taken together, these results suggest that using kazinol U to block the NF-κB pathway in pancreatic β-cells reduces cell damage. Therefore, kazinol U may have therapeutic value in delaying pancreatic β-cell destruction in type 1 diabetes.
诱导型一氧化氮合酶（iNOS）和活性氧产生的一氧化氮（NO）在细胞因子介导的胰岛β细胞损伤中起关键作用。活性氧引起的氧化应激激活核因子-κB（NF-κB）转录因子，后者调节 iNOS 的表达。在这方面，抑制 NF-κB 途径是保护β细胞免受损伤的一种新策略。本研究旨在探讨来自榕属的一种prenylated flavan kazinol U 对白细胞介素-1β（IL-1β）和干扰素-γ（IFN-γ）处理的β细胞中 NF-κB 激活途径的影响。当用 kazinol U 预处理 RINm5F 细胞或胰岛时，细胞因子的细胞毒性作用完全被消除。kazinol U 抑制 NF-κB 亚基的核易位和 DNA 结合，这与对 IκB 激酶（IKK）磷酸化和 IκBα降解的抑制作用相关。此外，kazinol U 抑制了由细胞因子引起的 RINm5F 细胞中 NO 和过氧化氢的产生以及细胞凋亡。在对葡萄糖的反应中，用细胞因子处理的胰岛中胰岛素正常分泌进一步证明了 kazinol U 的保护作用。综上所述，这些结果表明，用 kazinol U 阻断胰腺β细胞中的 NF-κB 途径可减少细胞损伤。因此，kazinol U 在延迟 1 型糖尿病中胰岛β细胞破坏方面可能具有治疗价值。
