Resveratrol attenuates testicular apoptosis in type 1 diabetic mice: Role of Akt-mediated Nrf2 activation and p62-dependent Keap1 degradation

Abstract

Infertility is a common complication in diabetic men, mainly due to the loss of germ cells by apoptotic cell death. However, effective and safe approaches to prevent diabetic induction of testicular apoptosis for diabetic patients have not been available. Resveratrol (RSV), a group of compounds called polyphenols from plants, has been indicated its promising used clinically for cancers and cardiovascular diseases. Therefore, the present study aimed determining whether RSV attenuates type 1 diabetes (T1D)-induced testicular apoptotic cell death in a mouse model. We found that testicular apoptosis and oxidative stress levels were significantly higher in T1D mice than control mice. In addition, the phosphorylation level of metabolism-related Akt and GSK-3β was downregulated and Akt negative regulators PTEN, PTP1B and TRB3 were upregulated in the T1D group. These effects were partially prevented by RSV treatment. Nrf2 and its downstream genes, such as NQO-1, HO-1, SOD, catalase and metallothionein were significantly upregulated by RSV treatment. In addition, RSV-induced Nrf2 activation was found due to Keap1 degradation, mainly reliant on p62 that functions as an adaptor protein during autophagy. These results indicate that the attenuation of T1D-induced testicular oxidative stress and apoptosis by RSV treatment was mainly related to Akt-mediated Nrf2 activation via p62-dependent Keap1 degradation.

hPMSCs protects against aging-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling

“…The mechanism of Nrf2 regulation has been widely studied [42,43]. Several recent studies have suggested that the activition of Nrf2 was regulated by Akt/GSK-3β/Fyn mediated degradation and nuclear export of Nrf2 [22,44]. In this study, we detected signi cantly decreased activation of the Akt/GSK-3β/Fyn pathway in senescent CD4 + T cells.…”

Protective effect of Dioscorea zingiberensis ethanol extract on the disruption of blood–testes barrier in high‐fat diet/streptozotocin‐induced diabetic mice by upregulating ZO‐1 and Nrf2

“…The decreased transcriptional activity of Nrf2 due to hyperglycaemia caused weakened antioxidant defence system and may represent an essential pathological mechanism in diabetic male infertility. Targeting and inducing Nrf2 have become a potential therapeutic strategy in diabetic male infertility (Ma et al, ; Wang et al, ; Zhao et al, ). In our research, we found that DZ could reduce the accumulation of ROS and enhance the expression of antioxidant enzymes in the testis tissue of mice by activating Nrf2.…”

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

“…[32] Moreover, Zhao et al determined that RSV attenuated type 1 diabetes (T1D)-induced apoptosis in testicular apoptotic cells, which was mainly associated with Akt-mediated Nrf2 activation via p62-dependent Keap1 degradation. [33] Current clinical trials have shown resveratrol was well tolerated and beneficial biomarkers for neurological diseases, cardiovascular diseases and diabetes. [71] However, it has a fuzzy or even detrimental effect on certain types of cancer and NAFLD (Nonalcoholic fatty liver disease).…”