Cyclic helix B peptide promotes random‐pattern skin flap survival via TFE3‐mediated enhancement of autophagy and reduction of ROS levels

Abstract

Background and Purpose Necrosis of random‐pattern skin flaps limits their clinical application. Helix B surface peptide (HBSP) protects tissues from ischaemia–reperfusion injury but its short plasma half‐life limits its applications. Here, we have synthesized cyclic helix B peptide (CHBP) and investigated its role in flap survival and the underlying mechanisms. Experimental Approach Flap viability was evaluated by survival area analysis, laser Doppler blood flow and histological analysis. RNA sequencing was used to identify mechanisms underlying the effects of CHBP. Levels of autophagy, oxidative stress, pyroptosis, necroptosis and molecules related to the AMP‐activated protein kinase (AMPK)–TRPML1–calcineurin signalling pathway were assayed with Western blotting, RT‐qPCR, immunohistochemistry and immunofluorescence. Key Results The results indicated that CHBP promoted the survival of random‐pattern skin flaps. The results of RNA sequencing analysis indicated that autophagy, oxidative stress, pyroptosis and necroptosis were involved in the ability of CHBP to promote skin flap survival. Restoration of autophagy flux and enhanced resistance to oxidative stress contributed to inhibition of pyroptosis and necroptosis. Increased autophagy and inhibition of oxidative stress in the ischaemic flaps were regulated by transcription factor E3 (TFE3). A decrease in the levels of TFE3 caused a reduction in autophagy flux and accumulation of ROS and eliminated the protective effect of CHBP. Moreover, CHBP regulated the activity of TFE3 via the AMPK–TRPML1–calcineurin signalling pathway. Conclusion and Implications CHBP promotes skin flap survival by up‐regulating autophagy and inhibiting oxidative stress in the ischaemic flap and may have potential clinical applications.

Diallyl Trisulfide Enhances the Survival of Multiterritory Perforator Skin Flaps

“…Therefore, autophagy is a double-edged sword and may play different roles in different diseases and disease progress ( Wang et al, 2021 ). Our previous studies have also shown that the effect of autophagy on flap viability is controversial and needs further research ( Li et al, 2020 ; Zhang et al, 2020 ; Chen et al, 2021 ; Zhu et al, 2021 ; Lou et al, 2022 ). Therefore, the present study seeks to explore the effects of DATS and DATS-induced autophagy on the survival of perforator flaps and to reveal its possible regulatory mechanisms.…”

A snake cathelicidin enhances transcription factor EB‐mediated autophagy and alleviates ROS‐induced pyroptosis after ischaemia–reperfusion injury of island skin flaps

“…In addition, apoptosis has been shown in our earlier investigations to play an important function in flap necrosis (Chen et al, 2022). The detection of programmed cell death suggests that necrosis can be interfered with (Harder et al, 2008; Lou, Zhang, et al, 2022). According to our findings, BF‐30 significantly reduced the expression levels of proteins associated with apoptosis and pyroptosis, indicating that it efficiently suppresses these processes in skin flaps with I/R injury, especially in the vascular endothelial cells of the dermis.…”

“…Recent progress in studies of programmed cell death has been encouraging, offering new opportunities for treating I/R‐injured flaps. Pyroptosis is a newly identified form of proinflammatory cell death that affects many tissues (Yu et al, 2021), including the skin, and is regulated by the inflammasome (Lou, Zhang, et al, 2022). NLR family pyrin domain‐containing 3 (NLRP3) inflammasomes are complexes that contain multiple components, including caspase‐1, apoptosis‐associated speck‐like protein containing a caspase recruitment segment (ASC) and NLRP3 (Sharma & Kanneganti, 2021).…”

“…In harsh environments, autophagy and lysosomes cooperate to form autolysosomes, degrading waste and toxins and providing energy and raw materials for homeostasis preservation and cell regeneration (Yu et al, 2018). Previous research studies have demonstrated that autophagy has a protective impact on ischaemic flaps and can promote skin flap survival by enhancing autophagy flux (Lou, Zhang, et al, 2022). Importantly, regulating autophagy flux in I/R‐injured skin flaps might be a promising therapeutic target.…”

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

“…Random flaps are widely applied to repair and reconstruct soft tissue injuries caused due to trauma, congenital diseases, and tumor excision (Khoong et al, 2021; X. Lin et al, 2022; Wang et al, 2022). Despite adequate progress in surgical techniques, random flap necrosis occurs in the distal area of the flap when the ratio exceeds 1.5–2, thus limiting its clinical use (Lou, Zhang, et al, 2022). At present, the prevention and treatment of distal ischemia and necrosis of flaps mainly include pretreatment (Kankam et al, 2020), stem cell transplantation (Pu et al, 2017), and drug therapy (Y. Zheng et al, 2021).…”