Positive Effect of Andrographolide Induced Autophagy on Random-Pattern Skin Flaps Survival

Random-pattern skin flap replantation is generally used in the reconstruction of surgical tissues and covering a series of skin flap defects. However, ischemia often occurs at the flap distal parts, which lead to flap necrosis. Previous studies have shown that andrographolide (Andro) protects against ischemic cardiovascular diseases, but little is known about the effect of Andro on flap viability. Thus, our study aimed to building a model of random-pattern skin flap to understand the mechanism of Andro-induced effects on flap survival. In this study, fifty-four mice were randomly categorized into the control, Andro group, and the Andro+3-methyladenine group. The skin flap samples were obtained on postoperative day 7. Subsequently, the tissue samples were underwent a series of evaluations such as changes in the appearance of flap tissue, the intensity of blood flow, and neovascularization density of skin flap. In our study, the results revealed that Andro enhanced the viability of random skin flaps by enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Furthermore, our results have also demonstrated that the administration of Andro caused an elevation in the autophagy, and these remarkable impact of Andro were reversed by 3-methyladenine (3-MA), the most common autophagy inhibitor. Together, our data proves novel evidence that Andro is a potent modulator of autophagy capable of significantly increasing random-pattern skin flap survival.

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

Cell Death and Disease ◽

10.1038/s41419-019-1704-0 ◽

2019 ◽

Vol 10 (7) ◽

Cited By ~ 6

Author(s):

Hongqiang Wu ◽

Huanwen Chen ◽

Zhilong Zheng ◽

Jiafeng Li ◽

Jian Ding ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Skin Flap ◽

Random Pattern ◽

Skin Flaps ◽

Major Pathway ◽

Flap Survival ◽

Flap Viability ◽

Tissue Edema ◽

Skin Flap Survival

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

Cell Death and Disease ◽

10.1038/s41419-019-2105-0 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 2

Author(s):

Kailiang Zhou ◽

Huanwen Chen ◽

Jinti Lin ◽

Hui Xu ◽

Hongqiang Wu ◽

...

Keyword(s):

Signaling Pathways ◽

Nuclear Translocation ◽

Skin Flap ◽

Therapeutic Benefit ◽

Random Pattern ◽

Skin Flaps ◽

Flap Survival ◽

Ampk Signaling ◽

Flap Viability ◽

Mechanistic Investigation

AbstractRandom-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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The Relationship of Hematocrit Levels to Skin Flap Survival Length in the Pig

Otolaryngology ◽

10.1177/019459988108900511 ◽

1981 ◽

Vol 89 (5) ◽

pp. 750-752 ◽

Cited By ~ 5

Author(s):

Jeffrey B. Alperstein ◽

Howard L. Levine ◽

Harvey M. Tucker

Keyword(s):

Human Skin ◽

Control Animal ◽

Skin Flap ◽

Random Pattern ◽

Skin Flaps ◽

Flap Survival ◽

Significant Difference ◽

Skin Flap Survival ◽

Relationship Of ◽

The Relationship

The work of several investigators suggests that anemia may increase the survival length of skin flaps in the dog and the rabbit. The following experiment was designed to study the survival of standardized skin flaps of varying lengths in normocythemic, polycythemic, and anemic pigs. The pig was chosen because of the similarity of its skin to that of human skin. Twenty-nine standardized random-pattern flaps and six standardized arterial flaps were studied in pigs with varying hematocrits. A statistically significant increase was found in the survival lengths of skin flaps in the polycythemic animal as compared with the anemic one. No significant difference was found when the flap survival lengths of the normocythemic control animal were compared with those of the polycythemic animal or with those of the anemic animal. These findings suggest that relative polycythemia may allow improved flap length-survival and, in contradistinction to the findings of previous investigators, that anemia does not result in improved survival length.

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Liraglutide, a TFEB-Mediated Autophagy Agonist, Promotes the Viability of Random-Pattern Skin Flaps

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6610603 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Xuwei Zhu ◽

Xinli Hu ◽

Junsheng Lou ◽

Jiafeng Li ◽

Yu Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Survival Rate ◽

Skin Flap ◽

Difficult Problem ◽

Signalling Pathway ◽

Random Pattern ◽

Skin Flaps ◽

Flap Viability ◽

Activation Of Transcription ◽

Important Means

Random skin flaps are commonly used in reconstruction surgery. However, distal necrosis of the skin flap remains a difficult problem in plastic surgery. Many studies have shown that activation of autophagy is an important means of maintaining cell homeostasis and can improve the survival rate of flaps. In the current study, we investigated whether liraglutide can promote the survival of random flaps by stimulating autophagy. Our results show that liraglutide can significantly improve flap viability, increase blood flow, and reduce tissue oedema. In addition, we demonstrated that liraglutide can stimulate angiogenesis and reduce pyroptosis and oxidative stress. Through immunohistochemistry analysis and Western blotting, we verified that liraglutide can enhance autophagy, while the 3-methylladenine- (3MA-) mediated inhibition of autophagy enhancement can significantly reduce the benefits of liraglutide described above. Mechanistically, we showed that the ability of liraglutide to enhance autophagy is mediated by the activation of transcription factor EB (TFEB) and its subsequent entry into the nucleus to activate autophagy genes, a phenomenon that may result from AMPK-MCOLN1-calcineurin signalling pathway activation. Taken together, our results show that liraglutide is an effective drug that can significantly improve the survival rate of random flaps by enhancing autophagy, inhibiting oxidative stress in tissues, reducing pyroptosis, and promoting angiogenesis, which may be due to the activation of TFEB via the AMPK-MCOLN1-calcineurin signalling pathway.

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Pseudoginsenoside F11 Enhances the Viability of Random-Pattern Skin Flaps by Promoting TFEB Nuclear Translocation Through AMPK-mTOR Signal Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.667524 ◽

2021 ◽

Vol 12 ◽

Author(s):

Feiya Zhou ◽

Xian Zhang ◽

Liangfu Jiang ◽

Shi Li ◽

Yiheng Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Skin Flap ◽

Signal Pathway ◽

Random Pattern ◽

Panax Quinquefolium ◽

Skin Flaps ◽

Flap Viability ◽

Tissue Edema ◽

Tissue Reconstruction

Random-pattern skin flap is widely used in tissue reconstruction. However, necrosis occurring in the distal part of the flap limits its clinical application to some extent. Activation of autophagy has been considered as an effective approach to enhance the survival of skin flaps. Pseudoginsenoside F11 (PF11), an ocotillol-type saponin, is an important component of Panax quinquefolium which has been shown to confer protection against cerebral ischemia and alleviate oxidative stress. However, it is currently unknown whether PF11 induces autophagy to improve the survival of skin flaps. In this study, we investigated the effects of PF11 on blood flow and tissue edema. The results of histological examination and western blotting showed that PF11 enhanced angiogenesis, alleviated apoptosis and oxidative stress, thereby improving the survival of the flap. Further experiments showed that PF11 promoted nuclear translocation of TFEB and by regulating the phosphorylation of AMPK. In summary, this study demonstrates that PF11 activates autophagy through the AMPK-TFEB signal pathway in skin flaps and it could be a promising strategy for enhancing flap viability.

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