ß-Caryophyllene promotes the survival of random skin flaps by upregulating the PI3K/AKT signaling pathway.

BACKGROUND: Flap transplantation is a widely used plastic repair technique in surgical procedures, aimed at addressing skin defects resulting from diverse wounds and diseases. However, due to the insufficient blood supply after flap surgery, the occurrence of ischemia-reperfusion injury, and an excessive sterile inflammatory response, flaps frequently develop complications (e.g., partial or complete ischemic necrosis). These complications have adverse effects on wound healing and repair. ß-Caryophyllene (BCP) is a bicyclic sesquiterpene that is widely present in plants. It mitigates oxidative stress and inflammatory responses, demonstrates neuroprotective and analgesic properties, and serves a protective function in organs or tissues subjected to ischemia-reperfusion injury. However, no study has confirmed whether BCP can be used in the field of flap transplantation to improve the flap survival rate. METHODS: To assess the impact of BCP on random flap survival, we constructed a modified McFarlane random flap model on the rat. After 7 consecutive days of gavage with different doses of BCP, we measured the survival area ratio, angiogenesis, blood perfusion, tissue inflammation level, apoptosis-related protein levels, and the PI3K/AKT signaling pathway expression of the random flap. RESULTS: BCP treatment increased the survival area of the flap in a dose-dependent manner after random flap transplantation in rats. BCP mainly promoted the formation of tissue blood vessels, improved flap blood perfusion, limited the local inflammatory response, and reduced apoptosis. In addition, we demonstrated that BCP works primarily by promoting the PI3K/AKT signaling expression while enhancing the phosphorylation of AKT. Administration of wortmannin, a selective inhibitor of PI3K, eliminated the effects of BCP. CONCLUSION: BCP can promote the survival of random flaps by upregulating the PI3K/AKT signaling pathway, increasing tissue blood perfusion, and limiting the inflammatory response and apoptosis.

Tetrahydropalmatine promotes random skin flap survival in rats via the PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Flap necrosis is the most common complication after flap transplantation, but its prevention remains challenging. Tetrahydropalmatine (THP) is the main bioactive component of the traditional Chinese medicine Corydalis yanhusuo, with effects that include the activation of blood circulation, the promotion of qi, and pain relief. Although THP is widely used to treat various pain conditions, its impact on flap survival is unknown. AIM OF THE STUDY: To explore the effect and mechanism of THP on skin flap survival. MATERIALS AND METHODS: In this study, we established a modified McFarlane flap model, and the flap survival rate was calculated after 7 days of THP treatment. Angiogenesis and blood perfusion were evaluated using lead oxide/gelatin angiography and laser Doppler, respectively. Flap tissue obtained from zone II was evaluated histopathologically, by hematoxylin and eosin staining, and in assays for malondialdehyde content and superoxide dismutase activity. Immunofluorescence was performed to detect interleukin (IL)-6, tumor necrosis factor (TNF)-α, hypoxia-inducible factor (HIF)-1α, Bcl-2, Bax, caspase-3, caspase-9, SQSTM1/P62, Beclin-1, and LC3 expression, and Western blot to assess PI3K/AKT signaling pathway activation and Vascular endothelial growth factor (VEGF) expression. The role played by the autophagy pathway in flap necrosis was examined using rapamycin, a specific inhibitor of mTOR. RESULTS: Experimentally, THP improved the survival rate of skin flaps, promoted angiogenesis, and improved blood perfusion. THP administration reduced the inflammatory response, oxidative stress, and apoptosis in addition to inhibiting autophagy via the PI3K/AKT/mTOR pathway. Rapamycin partially reversed these effects. CONCLUSION: THP promotes skin flap survival via the PI3K/AKT signaling pathway.

Rivaroxaban down-regulates pyroptosis and the TLR4/NF-κB/NLRP3 signaling pathway to promote flap survival.

BACKGROUND: Flap placement remains the primary method for wound repair, but postoperative ischemic flap necrosis is of major concern. This study explored whether rivaroxaban, a factor Xa inhibitor, enhanced flap survival. METHODS: Thirty-six rats were randomly divided into control, low-dose rivaroxaban (3 mg/kg/day), and high-dose rivaroxaban (7 mg/kg/day) groups. On postoperative day 7, the flap survival rate was analyzed and the average survival area calculated. After the rats were euthanized, immunological and molecular biological techniques were employed to assess vascular regeneration, pyroptosis, and inflammation. RESULTS: Rivaroxaban upregulated VEGF expression, in turn enhancing angiogenesis, and it downregulated IL-1ß, IL-6, and TNF-α expression, thereby mitigating inflammation. The drug also suppressed TLR4, NF-κB p65, NLRP3, caspase-1, and IL-18 syntheses, thus inhibiting pyroptosis. CONCLUSIONS: Rivaroxaban enhanced random flap survival by down-regulating the TLR4/NF-κB/NLRP3 signaling pathway to suppress pyroptosis, promoting vascular regeneration and inhibiting inflammation.

L-Borneol promotes skin flap survival by regulating HIF-1α/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The clinical application of skin flaps in surgical reconstruction is frequently impeded by the occurrence of distant necrosis. L-Borneol exhibits myogenic properties in traditional Chinese medicine and is used in clinical settings to promote wound healing and conditions such as stroke. Nevertheless, the precise mechanism by which borneol exerts its protective effects on skin flap survival remains unclear. AIM OF THE STUDY: To explore the potential of L-borneol to promote skin flap survival and elucidate the underlying mechanisms. MATERIALS AND METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into three groups: a high-dose (200 mg/kg L-borneol per day), a low-dose (50 mg/kg/day), and control group (same volume of solvent). In each rat, a modified rectangular McFarlane flap model measuring 3 × 9 cm was constructed. Daily intragastric administration of L-borneol or solvent was performed. The flap was divided into three square sections of equal size, namely Zone I (the proximal zone), Zone II (the intermediate zone), and Zone III (the distal zone). The survival rate was quantified, and the histological state of each flap was evaluated on the seventh day following the surgical procedure. The assessment of angiogenesis was conducted using lead oxide/gelatin angiography, whereas the evaluation of blood flow in the free flap was performed using laser Doppler flow imaging. Superoxide dismutase activity was detected using the water-soluble tetrazolium salt-8 method. The quantities of vascular endothelial growth factor, interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α were determined using immunohistochemistry. The levels of nuclear transcription factor-κB, hypoxia-inducible factor-1, B-cell lymphoma-2 (BCL-2), and BCL-2-associated X (BAX) were determined by Western blotting technique. RESULTS: Flap survival rate significantly improved and neutrophil recruitment and release were enhanced after treatment with the compound. Angiogenesis was promoted. L-borneol protected against oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content. It downregulated the hypoxia-inducible factor nuclear transcription factor-κB pathway, leading to the inhibition of several inflammatory factors. Simultaneously, it facilitated the expression of vascular endothelial growth factor and BCL-2. CONCLUSION: The study shows that L-borneol may promote skin flap survival by inhibiting HIF-1α/NF-κB pathway.

Tetrandrine promotes the survival of the random skin flap via the PI3K/AKT signaling pathway.

Flaps are mainly used for wound repair. However, postoperative ischemic necrosis of the distal flap is a major problem, which needs to be addressed urgently. We evaluated whether tetrandrine, a compound found in traditional Chinese medicine, can prolong the survival rate of random skin flaps. Thirty-six rats were randomly divided into control, low-dose tetrandrine (25 mg/kg/day), and high-dose tetrandrine (60 mg/kg/day) groups. On postoperative Day 7, the flap survival and average survival area were determined. After the rats were sacrificed, the levels of angiogenesis, apoptosis, and inflammation in the flap tissue were detected with immunology and molecular biology analyses. Tetrandrine increased vascular endothelial growth factor and Bcl-2 expression, in turn promoting angiogenesis and anti-apoptotic processes, respectively. Additionally, tetrandrine decreased the expression of Bax, which is associated with the induction of apoptosis, and also decreased inflammation in the flap tissue. Tetrandrine improved the survival rate of random flaps by promoting angiogenesis, inhibiting apoptosis, and reducing inflammation in the flap tissue through the modulation of the PI3K/AKT signaling pathway.