Exenatide improves random‐pattern skin flap survival via TFE3 mediated autophagy augment

Abstract

Random‐pattern skin flaps are widely applied to rebuild and restore soft‐tissue damage in reconstructive surgery; however, ischemia and subsequent ischemia‐reperfusion injury lead to flap necrosis and are major complications. Exenatide, a glucagon‐like peptide‐1 analog, exerts therapeutic benefits for diabetic wounds, cardiac injury, and nonalcoholic fatty liver disease. Furthermore, Exenatide is a known activator of autophagy, which is a complex process of subcellular degradation that may enhance the viability of random skin flaps. In this study, we explored whether exenatide can improve skin flap survival. Our results showed that exenatide augments autophagy, increases flap viability, enhances angiogenesis, reduces oxidative stress, and alleviates pyroptosis. Coadministration of exenatide with 3‐methyladenine and chloroquine, potent inhibitors of autophagy, reversed the beneficial effects, suggesting that the therapeutic benefits of exenatide for skin flaps are due largely to autophagy activation. Mechanistically, we identified that exenatide enhanced activation and nuclear translocation of TFE3, which leads to autophagy activation. Furthermore, we found that exenatide activates the AMPK–SKP2–CARM1 and AMPK–mTOR signaling pathways, which likely lead to exenatide's effects on activating TFE3. Overall, our findings suggest that exenatide may be a potent therapy to prevent flap necrosis, and we also reveal novel mechanistic insight into exenatide's effect on flap survival.

Pinocembrin alleviates pyroptosis and apoptosis through ROS elimination in random skin flaps via activation of SIRT3

“…ROS along with induced apoptosis and pyroptosis, are the primary causes of necrosis in random flap tissue (J. Li et al, 2020). We revealed that Pino could alleviate ROS production and lower pyroptosis and apoptosis.…”

“…Genechem (Shanghai, China) synthesized the AAV‐SIRT3 shRNA for this research. The procedure of the construction of adeno‐associated virus (AAV) included the synthesis of the plasmid, and then transfection into AAV‐293 cells as described previously (J. Li et al, 2020).…”

“…The approach described previously was used to measure the flap survival area (J. Li et al, 2020). We observed the color and appearance of random flaps on postoperative day (POD) 7, and calculated the percentage of survival size via Image‐pro Plus imaging (Ver.…”

Sulforaphane protects microvascular endothelial cells in lower limb ischemia/reperfusion injury mice

“…70 Moreover, it has been reported that TFE3-mediated autophagy and anti-oxidative response can markedly improve tissue survival. 71,72 Therefore, we hypothesized that SFN might also activate TFE3 to enhance autophagy and anti-oxidative effects and alleviate EC death in limbs following I/R.…”

Paeoniflorin Suppresses TBHP-Induced Oxidative Stress and Apoptosis in Human Umbilical Vein Endothelial Cells via the Nrf2/HO-1 Signaling Pathway and Improves Skin Flap Survival

“…The microvascular network at the junction of the skin flap and tissue usually supports the survival of the skin flap with nutrition, which is prone to ischemia and necrosis due to insufficient blood supply at distal flaps ( Wang et al, 2017 ). In particular, when the length–width ratio of the flap is greater than 2:1, it often leads to ischemia necrosis ( Li J. et al, 2021 ). This complication significantly limits its clinical application and postoperative efficacy ( Chehelcheraghi et al, 2016 ).…”