Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model

Fukunaga, Yutaka; Izawa‐Ishizawa, Yuki; Horinouchi, Yuya; Sairyo, Eriko; Ikeda, Yasumasa; Ishizawa, Keisuke; Tsuchiya, Koichiro; Abe, Yoshiro; Hashimoto, Ichiro; Takahashi, Toshiaki

doi:10.1111/wrr.12510

Cited by 18 publications

(10 citation statements)

References 30 publications

(97 reference statements)

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“…While random-pattern skin flaps are convenient tools in tissue reconstruction, distal ischemic necrosis is a common clinical complication, limiting the use of random flaps and reducing the success of surgery 35,36 . The main reasons for ischemic necrosis at the distal flap are insufficient blood supply and ischemia-reperfusion injury 36,37 . Oxidative stress and apoptosis are two important mechanisms of ischemia-reperfusion injury, leading to further damage or necrosis of the tissue 38,39 .…”

Section: Discussionmentioning

confidence: 99%

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

et al. 2019

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Random-pattern skin flap is commonly used for surgical tissue reconstruction due to its ease and lack of axial vascular limitation. However, ischemic necrosis is a common complication, especially in distal parts of skin flaps. Previous studies have shown that FGF21 can promote angiogenesis and protect against ischemic cardiovascular disease, but little is known about the effect of FGF21 on flap survival. In this study, using a rat model of random skin flaps, we found that the expression of FGF21 is significantly increased after establishment skin flaps, suggesting that FGF21 may exert a pivotal effect on flap survival. We conducted experiments to elucidate the role of FGF21 in this model. Our results showed that FGF21 directly increased the survival area of skin flaps, blood flow intensity, and mean blood vessel density through enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Our studies also revealed that FGF21 administration leads to an upregulation of autophagy, and the beneficial effects of FGF21 were reversed by 3-methyladenine (3MA), which is a well-known inhibitor of autophagy, suggesting that autophagy plays a central role in FGF21's therapeutic benefit on skin flap survival. In our mechanistic investigation, we found that FGF21-induced autophagy enhancement is mediated by the dephosphorylation and nuclear translocation of TFEB; this effect was due to activation of AMPK-FoxO3a-SPK2-CARM1 and AMPK-mTOR signaling pathways. Together, our data provides novel evidence that FGF21 is a potent modulator of autophagy capable of significantly increasing random skin flap viability, and thus may serve as a promising therapy for clinical use.

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Section: Discussionmentioning

confidence: 99%

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

et al. 2019

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“…Ischemia is a common complication following skin flap establishment, and with restoration of blood supply, tissue may undergo I/R injury. As a result, excess amounts of reactive oxygen species (ROS) is generated 32 . Trehalose has been reported to respond to high levels of ROS via regulating antioxidant gene expression and the autophagy pathway 33 .…”

Section: Discussionmentioning

confidence: 99%

Trehalose promotes the survival of random-pattern skin flaps by TFEB mediated autophagy enhancement

Chen

Zheng

et al. 2019

Cell Death Dis

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Random-pattern skin flaps are commonly used and valuable tools in reconstructive surgery, however, post-operative random skin flap necrosis remains a major and common complication. Previous studies have suggested that activating autophagy, a major pathway for degradation of intracellular waste, may improve flap survival. In this study, we investigated whether trehalose, a novel and potent autophagy activator, improves random skin flap viability. Our results demonstrated that trehalose significantly improves viability, augments blood flow, and decreases tissue edema. Furthermore, we found that trehalose leads to increased angiogenesis, decreased apoptosis, and reduced oxidative stress. Using immunohistochestry and western blot, we demonstrated that trehalose augments autophagy, and that inhibition of autophagy augmentation using 3MA significantly blunted the aforementioned benefits of trehalose therapy. Mechanistically, we showed that trehalose’s autophagy augmentation is mediated by activation and nuclear translocation of TFEB, which may be due to inhibition of Akt and activation of the AMPK-SKP2-CARM1 signaling pathway. Altogether, our results established that trehalose is a potent agent capable for significantly increasing random-pattern skin flap survival by augmenting autophagy and subsequently promoting angiogenesis, reducing oxidative stress, and inhibiting cell death.

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“…Moreover, random cutaneous flaps are frequently used in reconstructive surgery due to its simplicity, flexibility, and easy-of-use. However, since these flaps do not have specific blood vessels, there remains a risk of ischemia and necrosis 6 . Previous studies have shown that accelerating the angiogenesis in flaps is beneficial to improve the survival of flaps 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

Photocrosslinked gelatin hydrogel improves wound healing and skin flap survival by the sustained release of basic fibroblast growth factor

Kubota

Mayumi

Nakayama

et al. 2021

Sci Rep

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Biomaterials traditionally used for wound healing can act as a temporary barrier to halt bleeding, prevent infection, and enhance regeneration. Hydrogels are among the best candidates for wound healing owing to their moisture retention and drug-releasing properties. Photo-polymerization using visible light irradiation is a promising method for hydrogel preparation since it can easily control spatiotemporal reaction kinetics and rapidly induce a single-step reaction under mild conditions. In this study, photocrosslinked gelatin hydrogels were imparted with properties namely fast wound adherence, strong wet tissue surface adhesion, greater biocompatibility, long-term bFGF release, and importantly, ease of use through the modification and combination of natural bio-macromolecules. The production of a gelatin hydrogel made of natural gelatin (which is superior to chemically modified gelatin), crosslinked by visible light, which is more desirable than UV light irradiation, will enable its prolonged application to uneven wound surfaces. This is due to its flexible shape, along with the administration of cell growth factors, such as bFGF, for tissue regeneration. Further, the sustained release of bFGF enhances wound healing and skin flap survival. The photocrosslinking gelatin hydrogel designed in this study is a potential candidate to enhance wound healing and better skin flap survival.

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Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model

Cited by 18 publications

References 30 publications

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

Trehalose promotes the survival of random-pattern skin flaps by TFEB mediated autophagy enhancement

Photocrosslinked gelatin hydrogel improves wound healing and skin flap survival by the sustained release of basic fibroblast growth factor

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