Donepezil promotes skin flap survival through activation of the HIF-1α/VEGF signalling pathway.

Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low-dose (3 mg/kg/day), and high-dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia-inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl-2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti-inflammatory effects by reducing the levels of IL-1ß, IL-6, and TNF-α. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF-1α/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue.

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.

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.

Effects of Catalpol from Rehmannia glutinosa Extract on Skin Flaps.

BACKGROUND: Flaps are commonly used for repairing tissues and wounds in surgery. However, various factors can cause postoperative necrosis in these flaps. Catalpol is a bioactive component in extracts from Rehmannia glutinosa , which has pharmacologic characteristics that may improve flap survival. METHODS: The experiments were performed in 36 male Sprague-Dawley rats divided into three groups: control, low-dose catalpol, and high-dose catalpol. The flap survival rate, neutrophil density, microvessel density, superoxide dismutase, and malondialdehyde levels were measured; histopathologic analysis was performed 7 days after surgery. Blood flow was measured by laser Doppler flowmetry and lead oxide-gelatin angiography. The levels of vascular endothelial growth factor, toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, interleukin (IL)-6, nod-like receptor 3, cysteinyl aspartate specific proteinase-1 (caspase-1), IL-1ß, and IL-18 were determined by immunohistochemistry. RESULTS: Catalpol treatment increased flap survival, reduced neutrophil recruitment and release, decreased malondialdehyde levels, and increased superoxide dismutase levels; thus, it effectively reduced oxidative stress, up-regulated the expression of vascular endothelial growth factor, and increased microvessel density. Laser Doppler flowmetry and lead oxide-gelatin angiography showed that catalpol treatment improved angiogenesis. Immunohistochemical analyses showed that catalpol inhibited the production of inflammatory factors, such as tumor necrosis factor-α and IL-6, by down-regulating toll-like receptor 4 and nuclear factor-κB. Furthermore, catalpol reduced cell pyroptosis by inhibiting the production of nod-like receptor 3 inflammasomes, thereby down-regulating the release of IL-1ß and IL-18. CONCLUSION: Catalpol can improve the rate of flap survival. CLINICAL RELEVANCE STATEMENT: The research verified that the Rehmannia extract catalpol, through angiogenesis, inflammatory response, ischemia-reperfusion injury, and pyroptosis-related pathways, effectively improved the flap survival rate, which will provide new ideas for clinical medication.

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.

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.

Nesfatin-1 regulates the HMGB1-TLR4-NF-κB signaling pathway to inhibit inflammation and its effects on the random skin flap survival in rats.

OBJECTIVE: Random skin flaps are often placed by plastic surgeons to treat limb deformities and dysfunction. Nesfatin-1 (NES) is a peptide that exerts angiogenic, anti-inflammatory, and anti-oxidant effects. We assessed the impact of NES on flap survival and the underlying mechanism. METHODS: We modified the McFarlane random skin flap rat model. Thirty-six male Sprague-Dawley rats were randomly divided into a control group (corn oil solution with DMSO), low-dose group (NES-L at 10 µg/kg/day), and high-dose group (NES-H at 20 µg/kg/day). On day 7 after surgery, average flap survival areas were calculated. Laser Doppler blood flow monitoring and lead oxide/gelatin angiography were used to evaluate blood perfusion and neovascularization, respectively. Flap histopathological status was evaluated by hematoxylin and eosin (H&E) staining. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical techniques were used to evaluate the expression of angiogenetic and inflammatory factors. RESULTS: In the experimental groups, the mean skin flap survival areas and blood perfusion increased considerably. The SOD activities in the experimental groups increased and the MDA contents decreased. Immunohistochemically, VEGF expression was upregulated in the experimental groups and the expression levels of inflammatory factors decreased markedly. CONCLUSION: NES inhibited ischemic skin flap necrosis, promoted angiogenesis, and reduced ischemia-reperfusion injury and inflammation. Inhibition of the inflammatory HMGB1-TLR4-NF-κB signal pathway, which reduced flap inflammation and oxidative stress, may explain the enhanced flap survival.

Activation of aldehyde dehydrogenase-2 improves ischemic random skin flap survival in rats.

Objective: Random skin flaps have many applications in plastic and reconstructive surgeries. However, distal flap necrosis restricts wider clinical utility. Mitophagy, a vital form of autophagy for damaged mitochondria, is excessively activated in flap ischemia/reperfusion (I/R) injury, thus inducing cell death. Aldehyde dehydrogenase-2 (ALDH2), an allosteric tetrameric enzyme, plays an important role in regulating mitophagy. We explored whether ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) could reduce the risk of ischemic random skin flap necrosis, and the possible mechanism of action. Methods: Modified McFarlane flap models were established in 36 male Sprague-Dawley rats assigned randomly to three groups: a low-dose Alda-1 group (10 mg/kg/day), a high-dose Alda-1 group (20 mg/kg/day) and a control group. The percentage surviving skin flap area, neutrophil density and microvessel density (MVD) were evaluated on day 7. Oxidative stress was quantitated by measuring the superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Blood perfusion and skin flap angiogenesis were assessed via laser Doppler flow imaging and lead oxide-gelatin angiography, respectively. The expression levels of inflammatory cytokines (IL-1ß, IL-6, and TNF-α), vascular endothelial growth factor (VEGF), ALDH2, PTEN-induced kinase 1 (PINK1), and E3 ubiquitin ligase (Parkin) were immunohistochemically detected. Indicators of mitophagy such as Beclin-1, p62, and microtubule-associated protein light chain 3 (LC3) were evaluated by immunofluorescence. Results: Alda-1 significantly enhanced the survival area of random skin flaps. The SOD activity increased and the MDA level decreased, suggesting that Alda-1 reduced oxidative stress. ALDH2 was upregulated, and mitophagy-related proteins (PINK1, Parkin, Beclin-1, p62, and LC3) were downregulated, indicating that ALDH2 inhibited mitophagy through the PINK1/Parkin signaling pathway. Treatment with Alda-1 reduced neutrophil infiltration and expressions of inflammatory cytokines. Alda-1 significantly upregulated VEGF expression, increased the MVD, promoted angiogenesis, and enhanced blood perfusion. Conclusion: ALDH2 activation can effectively enhance random skin flap viability via inhibiting PINK1/Parkin-dependent mitophagy. Moreover, enhancement of ALDH2 activity also exerts anti-inflammatory and angiogenic properties.

Saxagliptin promotes random skin flap survival.

BACKGROUND: Flap necrosis is a common issue encountered in clinical flap transplantation surgery. Here, we assessed the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on flap survival and explored the underlying mechanisms. METHODS: A dorsal McFarlane flap model was established in 36 rats, which were randomly divided into a high-dose saxagliptin (HS) group (saxagliptin, 30 mg/kg/day, n = 12), low-dose saxagliptin (LS) group (saxagliptin, 10 mg/kg/day, n = 12), and control group (n = 12). On day 7, flap survival was examined by eye in six rats from each group, along with determination of blood perfusion by laser Doppler flowmetry and angiogenesis by angiography. The remaining rats were sacrificed for harvesting of flap tissue. The status of the flap tissue was examined histopathologically by staining with hematoxylin and eosin (H&E). Oxidative stress was evaluated by determination of superoxide dismutase (SOD) activity and malonaldehyde (MDA) content. Gasdermin D (GSDMD), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), NOD-like receptor pyrin domain containing 3 (NLRP3), interleukin (IL)-6, IL-18, Toll-like receptor 4 (TLR4), IL-1ß, caspase-1, and nuclear factor-κB (NF-κB) expression were detected by immunohistochemical analysis. RESULTS: The experimental group exhibited a larger area of flap survival, with more blood perfusion and neovascularization and better histopathological status than the control group. The degree of oxidative stress and the levels of NF-κB, TLR4, proinflammatory cytokines, and pyroptosis-associated protein were decreased in the experimental group, while the VEGF level was increased in a saxagliptin dose-dependent manner. CONCLUSION: Saxagliptin promotes random skin flap survival.

Roxadustat promotes hypoxia-inducible factor-1α/vascular endothelial growth factor signalling to enhance random skin flap survival in rats.

Random skin flaps have limited clinical application as a broad surgical reconstruction treatment because of distal necrosis. The prolyl hydroxylase domain-containing protein inhibitor roxadustat (RXD) enhances angiogenesis and reduces oxidative stress and inflammation. This study explored the function of RXD in the survival of random skin flaps. Thirty-six male Sprague-Dawley rats were randomly divided into low-dose RXD group (L-RXD group, 10 mg/kg/2 day), high-dose RXD group (H-RXD group, 25 mg/kg/2 day), and control group (1 mL of solvent, 1:9 DMSO:corn oil). The proportion of surviving flaps was determined on day 7 after surgery. Angiogenesis was assessed by lead oxide/gelatin angiography, and microcirculation blood perfusion was evaluated by laser Doppler flow imaging. Specimens in zone II were obtained, and the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as indicators of oxidative stress. Histopathological status was evaluated with haematoxylin and eosin staining. The levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and the inflammatory factors interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α (TNF-α) were detected by immunohistochemistry. RXD promoted flap survival and microcirculatory blood perfusion. Angiogenesis was detected distinctly in the experimental group. SOD activity increased and the MDA level decreased in the experimental group. Immunohistochemistry indicated that the expression levels of HIF-1α and VEGF were increased while the levels of IL-6, IL-1ß, and TNF-α were decreased after RXD injection. RXD promoted random flap survival by reinforcing vascular hyperplasia and decreasing inflammation and ischaemia-reperfusion injury.

Berberine promotes the viability of random skin flaps via the PI3K/Akt/eNOS signaling pathway.

Random skin flaps are often used in reconstruction operations. However, flap necrosis is still a common postoperative complication. Here, we investigated whether berberine (C20 H19 NO5 , BBR), a drug with antioxidant activity, improves the survival rate of random flaps. Fifty-four rats were divided into three groups: control, BBR and BBR + L -NAME groups (L -NAME, L -NG -Nitro-arginine methyl ester). The survival condition and the percentage of survival area of the flaps were evaluated on the seventh day after surgery. After animals were sacrificed, angiogenesis, apoptosis, oxidative stress and inflammation levels were assessed by histological and protein analyses. Our findings suggest that berberine promotes flap survival. The level of angiogenesis increased; the levels of oxidative stress, inflammation and apoptosis decreased; the levels of phosphoinositide 3-kinase (PI3K), phospho-Akt (p-Akt) and phospho-endothelial nitric oxide synthase (p-eNOS) increased in the flap tissue; and L -NAME reversed the effects of berberine on random skin flaps. Statistical analysis showed that the BBR group results differed significantly from those of the control and the BBR + L -NAME groups (p < .05). Our results confirm that berberine is an effective drug for significantly improving the survival rate of random skin flaps by promoting angiogenesis, inhibiting inflammation, attenuating oxidative stress, and reducing apoptosis through the PI3K/Akt/eNOS signaling pathway.

Effect of paeoniflorin on distal survival of random flaps.

BACKGROUND: Distal ischemic necrosisis a common complication of orthopedic random skin flaps surgery. Paeoniflorin, a natural compound extracted from Paeonia lactiflora, can enhances angiogenesis and alleviates excessive inflammatory response. We investigated the changes of ischemic extra-long flaps with paeoniflorin and its possible mechanism. METHODS: We raised dorsal McFarlane flaps in 54 Sprague-Dawley rats. We designed three groups of rats: high-paeoniflorin group (HP, 50 mg/kg/d), low-paeoniflorin group (LP, 20 mg/kg/d), and control group. The flap survival rate was calculated, seven days after flap construction.Blood perfusion was detected by laser Doppler flow imaging, and angiogenesis wasdetected by Lead oxide/gelatin angiography.Oxidative stress levels of flaps were determined by detecting superoxide dismutase (SOD) and malondialdehyde (MDA). The histopathological status of flap was evaluated by hematoxylin and eosin (H&E) staining.Immunohistochemistry was used to determine the expression of high mobility group protein B1 (HMGB1), nuclear factor-kappa B (NF-κB), Toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, IL-18, vascular endothelial growth factor (VEGF), cysteine protease-1 (caspase-1) and NLPR3. RESULTS: The flap survival rates and SOD activity in the experimental groups were significantly higher, while MDA activity was lower. Experimental groups showed significantly improved microcirculatory blood flow to the flap and increased angiogenesis. Immunohistochemistry revealed that paeoniflorin was associated with significantly increased VEGF expression, and decreased level of HMGB1, TLR4, TNF-α, NF-κB, IL-6, IL-1ß, caspase-1, NLPR3, and IL-18. CONCLUSIONS: Paeoniflorin effectively enhanced the survival of rat random skin flaps by promoting vascular hyperplasia, inhibiting pyroptosis, and down-regulating inflammation.

Effect of memantine on the survival of an ischemic random skin flap and the underlying mechanism.

BACKGROUND: Skin flap transplantation is a common wound repair method in orthopedic surgery, but skin flap necrosis remains problematic. Memantine, an excitatory amino acid receptor antagonist, is currently used in the treatment of moderate to severe Alzheimer's disease, due to its ability to promote angiogenesis and reduce oxidative stress. This study investigated the effect of memantine on the survival of random skin flaps in Sprague-Dawley (SD) rats. MATERIALS AND METHODS: Thirty six male SD rats were divided into control, high-dose (20 mg/kg per day), and low-dose (10 mg/kg per day) groups and underwent a McFarland flap procedure. Seven days later, the survival of the flap was evaluated, The microvascular density and neutrophil density were measured by hematoxylin and eosin staining. Lead angiography was used to detect angiogenesis, and laser Doppler was used to detect blood perfusion. Expression levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, Toll-like receptor (TLR) 4, nuclear factor kappa B(NF-κB) and Mitogen-activated protein kinase（MAPK）were detected by immunohistochemistry. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA) and superoxide dismutase (SOD). RESULTS: Compared with the control group, the flap survival area of memantine group, especially the high-dose group, was larger, VEGF expression, microvascular density, angiogenesis, blood perfusion, and superoxide dismutase in the flap were higher in the Memantine-H group than in the Memantine-L and control groups (P < 0.01). In addition, levels of neutrophil density, IL-1ß, IL-6, TNF-α, TLR4, NF-κB, MAPK and malondialdehyde decreased significantly in the Memantine-H group (P < 0.01). CONCLUSIONS: Memantine can promote the survival of skin flap in rats by improving the blood supply, promoting angiogenesis, inhibiting the inflammatory response, and reducing ischemia-reperfusion injury.

Effects of Apigenin Treatment on Random Skin Flap Survival in Rats.

Random skin flaps are often used in plastic surgery, but the complications of marginal flap ischemia and necrosis often limit their wider clinical application. Apigenin (Api) is a flavonoid found in various fruits and vegetables. Api has been shown to promote angiogenesis, as well as reduce oxidative stress, membrane damage, and inflammation. In this study, we assessed the effects of Api treatment on random skin flap survival. Dorsal McFarlane skin flaps were transplanted into rats, which were randomly divided into three groups: control (normal saline), low-dose Api (20 mg/kg), and high-dose Api (50 mg/kg). Seven days after the surgery, the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) were measured. Histological analyses were performed to determine flap survival and tissue edema. H&E staining was performed to assess the histopathological changes in skin flaps, and the levels of microvascular density (MVD) were determined. Laser doppler flowmetry was used to assess microcirculation blood flow. Flap angiography was performed by injection of lead oxide/gelatin. The expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interlukin-1ß (IL-lß) were evaluated by immunohistochemistry. Rats in the high-dose Api group exhibited higher average flap survival area, microcirculatory flow, increased SOD activity, and higher VEGF expression levels compared with the other two groups. Furthermore, the levels of MDA and pro-inflammatory cytokines were significantly decreased in rats treated with high-dose Api. Our findings suggest the potential usefulness of Api in preventing skin flap tissue necrosis.

Rivastigmine Regulates the HIF-1α/VEGF Signaling Pathway to Induce Angiogenesis and Improves the Survival of Random Flaps in Rats.

Random skin flaps are frequently used to repair skin damage. However, the ischemic and hypoxic necrosis limits their wider application. Rivastigmine, a carbamate cholinesterase inhibitor (ChEI), has also been shown to reduce ischemia-reperfusion injury (IRI) and inflammation. This study was performed to examine the effect of rivastigmine on flap survival. Sixty male Sprague-Dawley rats with a modified McFarland flap were randomly divided into three groups: control group, 1 ml of solvent (10% DMSO + 90% corn oil); low-dose rivastigmine group (Riv-L), 1.0 mg/kg; and high-dose rivastigmine group (Riv-H), 2.0 mg/kg. All rats were treated once a day. On day 7, the skin flap survival area was measured. After staining with hematoxylin and eosin (H&E), the pathological changes and microvessel density (MVD) were examined. The expression of inflammatory factors IL-1ß and IL-18, CD34, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was examined by immunohistochemical staining. The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were examined to determine the degree of oxidative stress. Lead oxide/gelatin angiography showed neovascularization and laser Doppler blood flowmetry showed the blood filling volume. Rivastigmine significantly increased the flap survival area and improved neovascularization. CD34, VEGF, and HIF-1α expression were increased, These changes were more pronounced in the Riv-H group. Treatment with rivastigmine reduced the level of MDA, improved SOD activity, and reduced expression of IL-1ß and IL-18. Our results indicate that Rivastigmine can increase angiogenesis and significantly improve flap survival.

Effects of Asiaticoside Treatment on the Survival of Random Skin Flaps in Rats.

Background: Asiaticoside (AS) is extracted from the traditional herbal medicine Centella asiatica, and has angiogenic, antioxidant, anti-inflammatory, and wound-healing effects. We investigated the effects of AS on skin flap survival. Methods: Dorsal McFarlane flaps were harvested from 36 rats and divided into two groups: an experimental group treated with 40 mg/kg AS administered orally once daily, and a control group administered normal saline in an identical manner. On day 2, superoxide dismutase (SOD) and malondialdehyde (MDA) levels, and production of the cytokines tumor necrosis factor-α and interleukin (IL)-6 were evaluated. On day 7, tissue slices were stained with hematoxylin and eosin. The expression of vascular endothelial growth factor (VEGF), IL-6, and IL-1ß were immunohistochemically evaluated. Microcirculatory flow was measured using laser Doppler flowmetry. Flap angiography, using the lead oxide-gelatin injection technique, was performed with the aid of a soft X-ray machine. Results: The AS group exhibited greater mean flap survival area, improved microcirculatory flow, and higher expression levels of SOD and VEGF compared with the control group. However, MDA levels and the inflammatory response were significantly reduced. Conclusions: AS exhibits promise as a therapeutic option due to its effects on the viability and function of random skin flaps in rats.

Exenatide inhibits necrosis by enhancing angiogenesis and ameliorating ischemia/reperfusion injury in a random skin flap rat model.

BACKGROUND: Random skin flaps are often used for plastic repair because they are convenient and flexible. However, necrosis of flaps is a common complication that may lead to disastrous consequences. Exenatide, a glucagon-like peptide 1 receptor agonist, can enhance angiogenesis and ameliorate ischemia/reperfusion injury. Our experiments explored random skin flap outcomes after its use. METHODS: We established modified dorsal McFarlane flaps on 54 Sprague-Dawley rats and divided the rats into three groups (control, Exe-I, and Exe-II). We intraperitoneally injected either 4 or 8 µg/kg/day exenatide into the rats of the Exe-I and Exe-II groups, respectively. On the seventh day after the operation, we measured the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Tissue sections were obtained for histopathological and immunohistochemical analyses, and we evaluated the expression of vascular endothelial growth factor (VEGF), interleukin (IL) 6, IL-1ß, nuclear factor kappa beta (NF-κB), Toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNF-α). We measured blood flow reconstruction and angiogenesis using laser Doppler blood flowmetry and lead oxide/gelatin angiography, respectively. RESULTS: Exenatide increased the average survival area of the flap and improved microvascular density and blood flow intensity in a dose-dependent manner. Meanwhile, the SOD level was up-regulated and the MDA level down-regulated. Exenatide also enhanced the expression of VEGF and reduced the expression of inflammatory cytokines (IL-6, IL-1ß, NF-κB, TLR4, and TNF-α), thereby promoting angiogenesis and inhibiting inflammation. CONCLUSIONS: Exenatide potentially inhibits necrosis in our rat random skin flap model.

Angiogenic and anti-inflammatory properties of azadirachtin A improve random skin flap survival in rats.

Random skin flaps are widely used to repair tissue defects. However, the distal flap regions are prone to ischemic necrosis, limiting clinical applications. Azadirachtin A, a fruit extract from the neem, improves tissue blood supply and metabolism, reduces cell swelling, promotes tissue healing, and prevents venous thrombosis. We explored whether it enhances random skin flap survival. Fifty-four Sprague-Dawley rats were divided into control, low-dose, and high-dose Azadirachtin A-treated groups using a random number table. We used an improved version of the McFarlane technique to create flaps. On day 2, superoxide dismutase and malondialdehyde levels were measured. Tissue slices prepared on day 7 were stained with hematoxylin and eosin. The expression levels of vascular endothelial growth factor (VEGF), toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-kB), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were immunohistochemically assayed. Microcirculatory blood flow was measured via laser Doppler blood flowmetry. Flap angiography was performed using the lead-oxide gelatin injection technique. And the azadirachtin A groups exhibited a greater mean flap survival area, an improved mean blood vessel density, a greater blood flow, and higher superoxide dismutase and VEGF levels, especially at the high dose. Azadirachtin A markedly reduced the levels of TNF-α, IL-6, IL-1ß, TLR4, and NF-kB. These findings suggest that azadirachtin A promotes random skin flap survival by improving the blood supply, reducing tissue inflammation, and inhibiting flap ischemia reperfusion injury.

Protective effects of dexmedetomidine on the survival of random flaps.

BACKGROUND: Random flaps can be used to repair wounds and improve shape and functional reconstruction, but inflammation and necrosis limit their application. Modified McFarlane flap models were constructed on the backs of rats. We hypothesized that dexmedetomidine (DEX) could improve the survival rate of ischemic random flaps. METHODS: Sixty rats were randomly divided into three groups: a low-dose DEX group (DEX-L group, 10 µg/kg/D), a high-dose DEX group (DEX-H group, 20 µg/kg/D) and a control group (0.9 % saline equivalent). On day 7 after flap construction, the survival percentage of the flap model was calculated. Hematoxylin and eosin staining (H&E) was used to evaluate the histopathological status of the flaps and microvessel density (MVD). Lead oxide/gelatin angiography was used to detect angiogenesis, and laser Doppler flow imaging (LDF) was used to detect blood perfusion. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in the middle areas of the flaps were measured to show the level of oxidative stress. The expressions of Toll-like receptor (TLR4), nuclear factor-kappa B (NF-κB), interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. RESULTS: DEX significantly increased the average survival percentage of the flaps and reduced ischemia and necrosis of the distal end of the flaps. SOD activity significantly increased, while MDA significantly decreased, indicating that DEX reduces oxidative damage. The expression of inflammatory immunoregulatory proteins (TLR4, NF-κB) was downregulated, and the levels of inflammatory factors (IL-1ß, IL-6 and TNF-α) were lower. In addition, DEX upregulated VEGF expression, promoted angiogenesis, and increased blood perfusion. CONCLUSION: In random flap transplantation, a high dose of DEX is beneficial to flap survival.

The Effect of Shu Xue Tong Treatment on Random Skin Flap Survival via the VEGF-Notch/Dll4 Signaling Pathway.

Objective: To determine the effect of Shu Xue Tong treatment on random skin flap survival. Methods: Twenty-four male Sprague-Dawley (SD) rats were administered Shu Xue Tong or normal saline. On postoperative day 7, flap survival area, flap angiogenesis angiography, blood flow and vascular endothelial growth factor (VEGF), Notch1, and Delta-like ligand 4 (Dll4) expression were assessed. Results: The mean flap survival area, blood vessel regeneration, microcirculatory flow, and expression of VEGF were enhanced with Shu Xue Tong treatment relative to the control. However, in Shu Xue Tong-treated rat flap, Notch1 and Dll4 levels were significantly reduced. Conclusions: These results demonstrate the beneficial action of Shu Xue Tong on random skin flap survival and suggest that its mechanism of action involves the promotion of angiogenesis via the VEGF-Notch1/Dll4 signaling pathway.