Abstract
NF-kappaB activation has been implicated as a key signaling mechanism for pancreatic beta-cell damage. Sulfuretin is one of the main flavonoids produced by Rhus verniciflua, which is reported to inhibit the inflammatory response by suppressing the NF-kappaB pathway. Therefore, we isolated sulfuretin from Rhus verniciflua and evaluated if sulfuretin could inhibit cytokine- or streptozotocin-induced beta-cell damage. Rat insulinoma RINm5F cells and isolated rat islets were treated with IL-1 beta and IFN-gamma to induce cytotoxicity. Incubation of cells and islets with sulfuretin resulted in a significant reduction of cytokine-induced NF-gamma B activation and its downstream events, iNOS expression, and nitric oxide production. The cytotoxic effects of cytokines were completely abolished when cells or islets were pretreated with sulfuretin. The protective effect of sulfuretin was further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining of islets. However, the diabetogenic effects of streptozotocin were completely prevented when mice were pretreated with sulfuretin. The anti-diabetogenic effects of sulfuretin were also mediated by suppression of NF-kappaB activation. Collectively, these results indicate that sulfuretin may have therapeutic value in preventing beta-cell damage.
Highlights
Type 1 diabetes mellitus is an autoimmune disease that causes selective destruction of insulin-producing β-cells in the islets of Langerhans
Untreated or RINm5F cells pretreated with sulfuretin for 3 h were exposed to cytokine for 48 h, and viability was assessed using an MTT assay
We present, for the first time, a mode of action for sulfuretin protection against the diabetes development
Summary
Type 1 diabetes mellitus is an autoimmune disease that causes selective destruction of insulin-producing β-cells in the islets of Langerhans. In early-stage disease, infiltration of inflammatory cells into the pancreatic islets can be observed histologically (Papaccio, 1993). These inflammatory cells produce and release cytokines, including IL-1β, TNF-α, and IFN-γ (Hanafusa and Imagawa, 2008). Nitric oxide is produced by the oxidation of L-arginine to L-citrulline by nitric oxide synthase, and generation of excess nitric oxide may inhibit mitochondrial metabolism, protein modification, and DNA cleavage, any one of which could lead to impaired insulin secretion and β-cell death (Stadler et al, 1991; Corbett and McDaniel, 1992). Inhibition of iNOS activity by aminoguanidine or Nw-nitro-L-arginine methyl ester protects islets against cytokine toxicity (Corbett and McDaniel, 1996; Kim et al, 2007b). Streptozotocin activates poly-ADP ribose polymerase, depletes cellular NAD and ATP, breaks DNA strands, and initiates β-cell necrosis (Yamamoto et al, 1981)
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