Random Flaps Research Articles

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

BackgroundFlap 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. MethodsThirty-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. ResultsRivaroxaban upregulated VEGF expression, in turn enhancing angiogenesis, and it downregulated IL-1β, 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. ConclusionsRivaroxaban enhanced random flap survival by down-regulating the TLR4/NF-κB/NLRP3 signaling pathway to suppress pyroptosis, promoting vascular regeneration and inhibiting inflammation.

Microenvironment Remodeling Self-Healing Hydrogel for Promoting Flap Survival.

Random flap grafting is a routine procedure used in plastic and reconstructive surgery to repair and reconstruct large tissue defects. Flap necrosis is primarily caused by ischemia-reperfusion injury and inadequate blood supply to the distal flap. Ischemia-reperfusion injury leads to the production of excessive reactive oxygen species, creating a pathological microenvironment that impairs cellular function and angiogenesis. In this study, we developed a microenvironment remodeling self-healing hydrogel [laminarin-chitosan-based hydrogel-loaded extracellular vesicles and ceria nanozymes (LCH@EVs&CNZs)] to improve the flap microenvironment and synergistically promote flap regeneration and survival. The natural self-healing hydrogel (LCH) was created by the oxidation laminarin and carboxymethylated chitosan via a Schiff base reaction. We loaded this hydrogel with CNZs and EVs. CNZs are a class of nanomaterials with enzymatic activity known for their strong scavenging capacity for reactive oxygen species, thus alleviating oxidative stress. EVs are cell-secreted vesicular structures containing thousands of bioactive substances that can promote cell proliferation, migration, differentiation, and angiogenesis. The constructed LCH@EVs&CNZs demonstrated a robust capacity for scavenging excess reactive oxygen species, thereby conferring cellular protection in oxidative stress environments. Moreover, these constructs notably enhance cell migration and angiogenesis. Our results demonstrate that LCH@EVs&CNZs effectively remodel the pathological skin flap microenvironment and marked improve flap survival. This approach introduces a new therapeutic strategy combining microenvironmental remodeling with EV therapy, which holds promise for promoting flap survival.

Systemic allopurinol administration reduces malondialdehyde, interleukin 6, tumor necrosis factor α, and increases vascular endothelial growth factor in random flap Wistar rats exposed to nicotine.

Smoking poses a risk to flap viability, with nicotine being a major contributor to the formation of free radicals. Allopurinol, known for its antioxidant properties, has been shown to enhance tissue survival in ischemic conditions by reducing the production of reactive oxygen species (ROS). This study aims to assess the impact of allopurinol on the viability and success of skin flaps in Wistar rats exposed to nicotine. This study examined skin flap survival in nicotine-exposed rats treated with allopurinol. Twenty-eight rats were separated into two groups. During 1 month of nicotine exposure, the treatment group received systemic allopurinol 7 days before and 2 days after the flap procedure, while the control group received no allopurinol. Pro-angiogenic factors, proinflammatory factors, anti-inflammatory factors, and oxidative markers were assessed on the 7th day after the flap procedure using enzyme-linked immunosorbent assay method. Macroscopic flap viability was evaluated on the 7th day using Image J photos. As an oxidative marker, malondialdehyde levels were significantly lower in rats given allopurinol than in controls (P < 0.001). The levels of interleukin 6 and tumor necrosis factor α, as markers of inflammatory factors, were significantly lower in the group of rats given allopurinol compared to controls (P < 0.001). The level of angiogenesis in rats given allopurinol, measured by vascular endothelial growth factor levels, was also higher in the treatment group compared to controls (P < 0.001). Macroscopically, the percentage of distal flap necrosis in Wistar rats given allopurinol was lower and statistically significant compared to controls (P < 0.001). Xanthine oxidoreductase is part of a group of enzymes involved in reactions that produce ROS. Allopurinol, as an effective inhibitor of the xanthine oxidase enzyme, can reduce oxidative stress by decreasing the formation of ROS. This reduction in oxidative stress mitigates the risk of ischemic-reperfusion injury effects and significantly increases the viability of Wistar rat flaps exposed to nicotine.

Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps

Abstract Background Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death. The epidermal growth factor family member neuregulin-1 (NRG1) reduces cell death by activating the protein kinase B (AKT) signalling pathway. Moreover, AKT signalling negatively regulates STING activity. We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis. Additionally, we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression. Methods A random-pattern skin flap model was generated on the backs of C57BL/6 mice. The skin flap survival area was determined. The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis. Cluster of differentiation 34 immunohistochemistry (IHC) and haematoxylin and eosin (H&E) staining of the flap sections revealed microvessels. Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps. The levels of angiogenesis, oxidative stress, necroptosis, pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC, immunofluorescence and Western blotting. Packaging adeno-associated virus (AAV) was used to activate STING in flaps. Results NRG1 promoted the survival of ischaemic flaps. An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1. Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis, pyroptosis and STING activity were reduced in the NRG1 group. The phosphorylation of AKT and forkhead box O3a (FOXO3a) were increased after NRG1 treatment. The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1. The ability of NRG1 to phosphorylate AKT-FOXO3a, inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206. Conclusions NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.

Flap Survival after Reconstructive Surgery for Pressure Ulcers: A Cohort Study

Background: Pressure ulcers are troublesome for patients and require considerable resources to resolve. Previous studies have focused on recurrence, whereas there are few studies on flap survival. The aim was to describe the group and to analyze possible factors for flap survival. Method: A descriptive retrospective analysis of all operations between 2008 and 2020 was carried out. Flap survival at 40 days was assessed. A flap was classified as a failure if a reoperation with removal or replacement was planned before, or in connection with, the first return visit. Variables of patient demographics, details of the pressure ulcers, and surgical treatment and care were analyzed with multivariable logistic regression for their effect on flap survival. Results: A total of 111 flaps were included [78 (70%) with random blood supply and 33 (30%) with axial or perforator-based blood supply]; 54 (49%) of the flaps were fasciocutaneous. Body mass index was 25 (IQR 22–28). Flap survival rate was 90%. Variables associated with flap failure were higher body mass index, congenital spinal cord injury, type of blood supply to the flap, and the use of methylene blue to guide debridement of the wound. Conclusions: The findings show factors that can be modified to improve future results, including a normalized body mass index and use of methylene blue in surgery to outline wound edges and depth, as this has been shown to protect against flap failure. Our data suggest that random flaps, such as V-Y, are preferable to axial flaps in the studied group.

Random pattern sub-clavicular flap in digital degloving injuries: an alternative in the reconstructive ladder

Degloving soft tissue detachment injuries occur when the skin and subcutaneous tissue detach from the underlying structures, affecting the skin coverage. The hand is usually the most frequent affected site. In digital lesions, the best results are obtained by revascularization; nevertheless, this procedure is challenging for the surgeon. Random pattern flaps represent an effective alternative for the treatment of these devastating lesions. We present two clinical cases with digital degloving injury from the proximal phalanx. Both cases required reconstructive surgery in 2 stages, using a successful random pattern sub-clavicular flap. This article aims to share the results of using this method as another reconstructive option with good results. After an average follow-up of 8 months in both cases, adequate skin coverage and functionality of the finger treated with the described flap was observed. Patient A presents a finger with proper healing and functionality. Patient B at 10 months, presents a thumb with adequate length for clamping and opposition. Sub-clavicular flap is an excellent reconstructive alternative for digital degloving injuries where revascularization is unattainable, providing good skin coverage and functionality and being a reproducible outpatient procedure.

Cadaveric and Computed Tomography Analysis of the Anterior Ethmoidal Artery Flap.

The anterior ethmoidal artery (AEA) flap has been successful in repairing anterior nasal septal perforations and has been presumed to be axially based on AEA branches coursing through or around the cribriform plate (CP). However, limited evidence supports the flap's axial supply. The purposes of this cadaveric and computed tomography (CT) study were to assess the arterial anatomy from the CP to the septum, and to determine AEA flap length to predict ideal flap base width. Ten fresh latex-injected cadavers were utilized for endoscopic dissection to identify arteries traversing the CPs on each side. First, arterial trajectories along the dorsal septum were recorded. Measurements were then made bilaterally along the septum from the middle turbinate (MT) axilla to the nasal branch of the AEA (NBAEA) traversing the CP. Additionally, 100 sinus CTs were reviewed to measure AEA flap lengths bilaterally. From 10 cadavers, 20 sides were utilized for measurements. In all cadavers, the AEA septal branches coursed diagonally or horizontally along the dorsal septum, and never directly vertically. The mean distance from the MT axilla to the NBAEA was 1.24 ± 1.93 cm (range = 1-1.5 cm). Based on CTs, the mean AEA flap length was 6.40 ± 0.60 cm. Based on the non-vertical courses of AEA septal branches, the AEA flap is more likely a random transposition flap than an axial flap. Average AEA flap length ranged from 6.0 to 7.0 cm. Assuming 3:1 length:width ratios, AEA flap base widths should be about 2.0-2.3 cm. NA Laryngoscope, 134:2100-2104, 2024.

Surgical delay increases the survival of expanded random-pattern flap in pediatric patients

Despite the aid of tissue expansion, the ideal design of random pattern flap is not always available in patients with extensive skin lesions. We investigated the effectiveness of surgical delay on expanded flaps in pediatric patients. Retrospective cohort study was performed on patients who underwent tissue expansion surgery for extensive skin lesions at Seoul National University Children’s Hospital. The surgical delay technique was employed for patients with unfavorable flap conditions related to location or transposition angles. The dimensions of skin lesions and flaps were measured based on medical photographs. Fifty patients underwent a total of 66 tissue expansion procedures (49 conventional procedures among 41 patients, 17 surgical delay procedures among 15 patients) from January 2016 to September 2019. Although flaps in the surgical delay group were more narrow-based (p < 0.001), the partial flap loss rate and excised area-to-inflation amount ratio was comparable between the two groups (p = 0.093 and p = 0.194, respectively). Viable flaps, excluding postoperative necrosis, in the surgical delay group were significantly more narrow-based in terms of the length-to-base width ratio and the area-to-base width ratio compared to conventional group (p < 0.01, p < 0.01). Surgical delay can result in outcomes comparable to well-designed random flaps, even in disadvantageous conditions. Patients with large skin lesions but limited areas for expansion may benefit from surgical delay.

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.

Caloric Restriction: A Novel Conditioning Strategy to Improve the Survival of Ischemically Challenged Musculocutaneous Random Pattern Flaps.

Caloric restriction (CR) is a cost-effective and easy-to-perform approach to counteracting surgical stress. The present study therefore evaluates the tissue-protective effects of a 30% CR in musculocutaneous flaps undergoing ischemia. For this purpose, a well-established murine dorsal skinfold chamber model, in combination with random pattern musculocutaneous flaps, was used. C57BL/6N mice were divided at random into a CR group (n = 8) and a control group with unrestricted access to standard chow (n = 8). The CR animals were subjected to a 30% reduction in caloric intake for 10 days before flap elevation. Intravital fluorescence microscopy was carried out on days 1, 3, 5, 7 and 10 after flap elevation to assess the nutritive blood perfusion, angiogenesis and flap necrosis. Subsequently, the flap tissue was harvested for additional histological and immunohistochemical analyses. The CR-treated animals exhibited a significantly higher functional capillary density and more newly formed microvessels within the flap tissue when compared to the controls; this was associated with a significantly higher flap survival rate. Immunohistochemical analyses showed a decreased invasion of myeloperoxidase-positive neutrophilic granulocytes into the flap tissue of the CR-treated mice. Moreover, the detection of cleaved caspase-3 revealed fewer cells undergoing apoptosis in the transition zone between the vital and necrotic tissue in the flaps of the CR-treated mice. These results demonstrate that a CR of 30% effectively prevents flap necrosis by maintaining microperfusion on a capillary level and inhibiting inflammation under ischemic stress. Hence, CR represents a promising novel conditioning strategy for improving the survival of musculocutaneous flaps with random pattern perfusion.

Ulnar nerve anteposition with adipofascial flap, an alternative treatment for severe cubital syndrome

BackgroundUlnar nerve entrapment at the elbow is the second most common cause of nerve entrapment in the upper limb. Surgical techniques mainly include simple decompression, decompression with anterior transposition and medial epicondylectomy.MethodsWe performed decompression with anterior transposition and protected ulnar nerve by adipofascial flap (a random flap with radial based vascularization, harvested through the avascular plane of Scarpa’s fascia. We analyzed patients who underwent ulnar nerve ante-position from 2015 to 2022 according to inclusion and exclusion criteria for a total of 57 patients. All patients included were graded on the McGowan's classification Messina criteria and the British Medical Research Council modified by Mackinnon and Dellon.ResultsThe average McGowan’s score was 2.4 (± 0.6), Messina’s criteria 91.2% indicated a satisfactory or excellent result, sensibility at 6 months was 98.5% S3 or more. A preferential technique has not yet been defined.ConclusionsThe adipofascial flap offers numerous advantages in providing a pliable, vascular fat envelope, which mimics the natural fatty environment of peripheral nerves and creates favorable micro-environmental conditions to contribute to neural regeneration via axon outgrowth.

Correlation between Indocyanine Green Fluorescence Angiography and Laser Speckle Contrast Imaging in a Flap Model.

Indocyanine green fluorescence angiography (ICG-FA) is used to assess tissue intraoperatively in reconstructive surgery. This requires an intra-venous dye injection for each assessment. This is not necessary in laser speckle contrast imaging (LSCI); therefore, this method may be better suited for tissue evaluation. To determine this, we compared the two methods in a porcine flap model. One random and one pedicled flap were raised on each buttock of six animals. They were assessed with LSCI at baseline, when raised (T0), at 30 minutes (T30) and with ICG-FA at T0 and T30. Regions of interest (ROI) were chosen along the flap axis. Perfusion, measured as perfusion units (PU) in the LSCI assessment and pixel-intensity for the ICG-FA video uptake, was calculated in the ROI. Correlation was calculated between PU and pixel-intensity measured as time to peak (TTP) and area under curve for 60 seconds (AUC60). Correlation between LSCI and AUC60 for the ICG-FA in corresponding ROI could be seen in all flaps at all time points. The correlation was higher for T0 (r=0.7 for random flap and r=0.6 for pedicled flap) than for T30 (r=0.57 for random flap and r=0.59 for pedicled flap). Even higher correlation could be seen PU and TTP (T0: random flap r=-0.8 and pedicled flap r=0.76. T30: random flap r=-0.8 and pedicled flap r=0.71). There is a correlation between PU from LSCI and TTP and AUC60 for ICG-FA, indicating that LSCI could be considered for intraoperative tissue assessment.

Meningomyelocele Reconstruction: Comparison of Repair Methods via Systematic Review.

The purpose of this article was to appraise the various methods of reconstruction for meningomyelocele (MMC) defects. A systematic review of the literature was performed to evaluate all reconstructions for MMC. The method of reconstruction was categorized by: primary closure with and without fascial flaps, random pattern flaps, VY advancement flaps (VY), perforator flaps, and myocutaneous flaps. Perforator flaps were subsequently subcategorized based on the type of flap. Upon systematic review, 567 articles were screened with 104 articles assessed for eligibility. Twenty-nine articles were further reviewed and included for qualitative synthesis. Two hundred seventy patients underwent MMC repair. The lowest rates of major wound complications (MWC) were associated with myocutaneous and random pattern flaps. A majority of MWC was in the lumbrosacral/sacral region (87.5% of MWC). In this region, random patterns and perforator flaps demonstrated the lowest rate of MWC (4.5, 8.1%). Plastic surgery consultation should be strongly considered for MMC with defects in the lumbosacral/sacral region. Perforator flaps are excellent options for the reconstruction of these defects.

Is a pedicular flap coupled to the double turnover flaps urethroplasty suitable for urethral–perineal reconstruction? Considerations about a relapsing urethral–cutaneous fistula condition

Background: This study highlights the effectiveness, in one surgical stage, of two combined local techniques for perineal fistula repair in a patient with spinal cord injury: the " Turn over flaps urethroplasty" and the "Pedicular fasciocutaneous flap" from the inferior gluteal fold. Unlike the traditional Perforator flap, we harvested a Pedicular flap; by definition, this is a flap with a narrow diffuse microvascular supply aimed in our case at shielding the neourethra and substituting the remaining scarred perineum. Method: The urethroplasty technique adopted, the 'Double turn over flaps urethroplasty', has been based on sculpting two opposing local cutaneous flaps circumscribing the fistulous cutaneous openings. Eventually, the neourethra continuity has been re-established by turning over both flaps and making them meet medially. The dimension and thickness of the "Pedicular fasciocutaneous flap", have been considered to prevent any damage to the urethroplasty and at the same time to replace all the debrided scarred perineal tissue. Results: The follow-up confirmed a well-consolidated supple perineal area and a competent neourethra. Conclusions: The "Pedicular flap" is by definition a random vascular flap nourished through a narrow pedicle, not based on a single perforator but only on a diffuse, spread micro-perforators. When associated with the double "Turn over flaps urethroplasty", it represents a possible alternative to achieve satisfactory results for those physical and psychological challenges encountered in the treatment of recurrent urethral fistula of the perineum in a patient with spinal cord injury.

Melatonin Enhances the Viability of Random-Pattern Skin Flaps by Activating the NRF2 pathway

IntroductionRandom skin flap transplantation has been widely used in reconstructive and plastic surgery. As a well-known antioxidant, melatonin has the functions of eliminating reactive oxygen species (ROS), promoting angiogenesis, and protecting ischemia-reperfusion injury (IRI). We explored the effects of melatonin on random skin flap survival and the potential molecular mechanisms.Material and methodsA total of 72 rats were randomly assigned to the control group, the melatonin (MEL) group, and MEL + ML385 groups. After the construction of random skin flap model, these groups were treated with physiological saline, melatonin, and melatonin + ML385. The general conditions of random skin flaps were observed daily after the procedure. Laser doppler blood flow imaging was used to evaluate the subcutaneous vascular network. On postoperative day 7, the animals were euthanized to obtain flap specimens. Hematoxylin-Eosin staining was used to evaluate the vessel density. Immunohistochemistry, immunofluorescence staining, and western blotting were used to evaluate the expression of proteins involved in angiogenesis, oxidative stress, and inflammation.ResultsCompared to the control group, the MEL group exhibited lower tissue water, more abundant vascular, and higher vascular density, thereby enhancing the survival of random flaps. Additionally, the MEL group showed increased expression of angiogenesis-related proteins, enhanced expression of antioxidant proteins, and decreased expression of inflammatory factors. Furthermore, ML385, reversed the beneficial effect of melatonin on random skin flaps.ConclusionsThese findings of our present study demonstrated that melatonin promotes angiogenesis, inhibits oxidative stress, and inflammation by activating NRF2 signaling pathway, thus the improving the survival of random skin flaps.

Reconstruction of Foot and Ankle Defects: A Prospective Analysis of Functional and Aesthetic Outcomes.

Reconstruction of foot and ankle defects requires selecting an appropriate durable and aesthetically appealing option. From the different options, the procedure's choice depends on the defect's size, location, and donor area's availability. Patients' main goal is to have an acceptable biomechanical outcome. In this prospective study, we have included patients who had undergone reconstruction of the ankle and foot defects between January 2019 and June 2021. Patient demographics, location and size of the defect, different procedures, complications, sensory recovery, ankle hindfoot score, and satisfaction score were recorded. 50 patients with foot and ankle defects were enrolled in this study. All flaps survived except one free anterolateral thigh flap. Five locoregional flaps developed minor complications, and all skin grafts healed well. The Ankle Hindfoot Score outcome has no significant relation with the anatomical location of the defects and the reconstructive procedure. All patients reconstructed using random local flap and with free flap were satisfied with the aesthetic outcome. Because of limited soft tissue, local flap availability is restricted to small defects. Satisfaction rates are high in local and free flaps and are best suited for reconstructing the weight-bearing part of the foot. Bulky flaps should be avoided over the dorsum and ankle region.

THE EFFECT OF ORALLY ADMINISTERED COENZYME Q10 ON THE VIABILITY OF RANDOM SKIN FLAP IN NICOTINE EXPOSED WISTAR RATS

Introduction : Nicotine was assumed to be the cause of compromised flap. The administration of antioxidants can eliminate such effect, and one of the most promising antioxidants is Coenzyme Q10. The research aims to find the effect of orally administered Coenzyme Q10 on the viability of random skin flaps in nicotine-exposed wistar rats. Method : Twenty-seven white rats (Rattus norvegicus) were assigned in three groups. The first group received no nicotine, while the other two groups were nebulized with nicotine for 4 consecutive weeks, and treated as random skin flaps. In third group, Coenzyme Q10 was administered for 7 days. Then, a standard histopathological staining and vascular endothelial growth factor (VEGF) measurement were performed on flap sample to examine the extent of neovascularization and VEGF cell expression. Result : The average number of capillaries in group I was 5.33 ± 1.323, in group II was 5.89 ± 0.782, and in group III was 7.78 ± 2.587. There was no significant difference (p = 0.317, 95% CI) in groups I and II of VEGF expression. However, significant differences were found in the intensity of VEGF (p = 0.009, 95% CI) in groups I and group III, and in groups II and group III (p = 0.011, 95% CI). Thus, the intensity was stronger on the subject with coenzyme Q10 compared with the other two groups. Conclusion: Coenzyme Q10 increases the viability of random flaps by increasing the number of capillaries and VEGF expression.

Nose tip defect reconstruction with a modified extended Rintala flap: A case report.

Nose tip defect reconstruction with a modified extended Rintala flap: A case report.

Nuciferine improves random skin flap survival via TFEB-mediated activation of autophagy-lysosomal pathway.

Due to their simplicity and reliability, random-pattern skin flaps are commonly utilized in surgical reconstruction to repair cutaneous wounds. However, the post-operative necrosis frequently happens because of the ischemia and high-level of oxidative stress of random skin flaps, which can severely affect the healing outcomes. Earlier evidence has shown promising effect of Nuciferine (NF) on preventing hydrogen peroxide (H2O2)-induced fibroblast senescence and ischemic injury, however, whether it can function on promoting ischemic flap survival remains unknown. In this work, using network pharmacology analysis, it was possible to anticipate the prospective targets of NF in the context of ischemia. The results revealed that NF treatment minimized H2O2-induced cellular dysfunction of human umbilical vein endothelial cells (HUVECs), and also improved flap survival through strengthening angiogenesis and alleviating oxidative stress, inflammation and apoptosis in vivo. These outcomes should be attributed to TFEB-mediated enhancement of autophagy-lysosomal degradation via the AMPK-mTOR signaling pathway, whilst the restriction of autophagy stimulation with 3MA effectively diminished the above advantages of NF treatment. The increased nuclear translocation of TFEB not only restored lysosome function, but also promoted autophagosome-lysosome fusion, eventually restoring the inhibited autophagic flux and filling the high energy levels. The outcomes of our research can provide potent proof for the application of NF in the therapy of vascular insufficiency associated disorders, including random flaps.

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)-1β, 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-1β, and TNF-α were decreased after RXD injection. RXD promoted random flap survival by reinforcing vascular hyperplasia and decreasing inflammation and ischaemia-reperfusion injury.