Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes

Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the protective effect of the soy isoflavone genistein on diabetic wound healing and investigate underlying mechanisms. Streptozotocin (STZ)-induced type 1 diabetic mice with full-thickness excisional wounds received 0.2, 1 or 5mg/kg/day of genistein via subcutaneous injection. Genistein dose-dependently rescued the delay of wound closure in diabetic mice. A dose of 5 mg/kg/day of genistein treatment significantly increased the mean perfusion rate, and in vitro treatment with genistein protected against high glucose-induced impairment of capillary tube formation in cultured endothelial cells. Diabetic conditions significantly increased superoxide anion (O(2)·(-)) production and nitrotyrosine formation, and decreased nitrite levels in wound tissues. Genistein treatment at all doses normalized the elevated O(2)·(-) production and nitrotyrosine formation, and reversed the attenuated nitrite level. In diabetic wound tissues, the inducible nitric oxide synthase (iNOS) was activated, and genistein administration prevented increased iNOS activity. Moreover, genistein attenuated diabetic cutaneous silent information regulator 1 and forkhead box O transcription factor 1 (FoxO1) levels and potentiated ac-FoxO1 in a dose-dependent manner. Genistein rescued the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetes in mice, at least in part, by suppression of FoxO1, iNOS activity and oxidative stress.