Abstract
Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria), and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-κB signaling pathway. In this study, we analyzed the effects of fisetin on proinflammatory cytokine secretion and epigenetic regulation, in human monocytes cultured under hyperglycemic conditions. Human monocytic (THP-1) cells were cultured under control (14.5 mmol/L mannitol), normoglycemic (NG, 5.5 mmol/L glucose), or hyperglycemic (HG, 20 mmol/L glucose) conditions, in the absence or presence of fisetin. Fisetin was added (3–10 μM) for 48 h. While the HG condition significantly induced histone acetylation, NF-κB activation, and proinflammatory cytokine (IL-6 and TNF-α) release from THP-1 cells, fisetin suppressed NF-κB activity and cytokine release. Fisetin treatment also significantly reduced CBP/p300 gene expression, as well as the levels of acetylation and HAT activity of the CBP/p300 protein, which is a known NF-κB coactivator. These results suggest that fisetin inhibits HG-induced cytokine production in monocytes, through epigenetic changes involving NF-κB. We therefore propose that fisetin supplementation be considered for diabetes prevention.
Highlights
Diabetes and its complications are known for their chronic inflammatory properties
We hypothesized that fisetin suppresses proinflammatory cytokine secretion through the NF-κB signaling pathway, by altering the balance between histone acetylation and deacetylation
We investigated the cytotoxic effect of fisetin on high glucoseinduced THP-1 cells, using CCK-8 assay (Figure 1(b))
Summary
Diabetes and its complications are known for their chronic inflammatory properties. Inflammation is a defense reaction of host tissue against diverse insults. Normally a beneficial process, when it occurs over prolonged periods, inflammation can be deleterious to cells [1]. Hyperglycemia has been implicated in diabetes-induced inflammatory disease and several diabetes-related complications [2, 3]. It has been reported to induce oxidative stress [4, 5]. High levels of glucose can activate the proinflammatory transcription factor nuclear κB (NF-κB), resulting in increased inflammatory chemokine and cytokine release [6, 7]
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