BackgroundThe mechanism of Nicotinamide Adenine Dinucleotide (NAD+) metabolism-related genes (NMRGs) in diabetic peripheral neuropathy (DPN) is unclear. This study aimed to find new NMRGs biomarkers in DPN.MethodsDPN related datasets GSE95849 and GSE185011 were acquired from the Gene Expression Omnibus (GEO) database. 51 NMRGs were collected from a previous article. To explore NMRGs expression in DPN and control samples, differential expression analysis was completed in GSE95849 to obtain differentially expressed genes (DEGs), and the intersection of DEGs and NMRGs was regarded as DE-NMRGs. Next, a protein-protein interaction (PPI) network based on DE-NMRGs was constructed and biomarkers were screened by eight algorithms. Additionally, Gene Set Enrichment Analysis (GSEA) enrichment analysis was completed, biomarker-based column line graphs were constructed, lncRNA-miRNA-mRNA and competing endogenouse (ce) RNA networks were constructed, and drug prediction was completed. Finally, biomarkers expression validation was completed in GSE95849 and GSE185011.Results5217 DEGs were obtained from GSE95849 and 21 overlapping genes of DEGs and NMRGs were DE-NMRGs. Functional enrichment analysis revealed that DE-NMRGs were associated with glycosyl compound metabolic process. The PPI network contained 93 protein-interaction pairs and 21 nodes, with strong interactions between NMNAT1 and NAMPT, NADK and NMNAT3, ENPP3 and NUDT12 as biomarkers based on 8 algorithms. Expression validation suggested that ENPP3 and NUDT12 were upregulated in DPN samples (P < 0.05). Moreover, an alignment diagram with good diagnostic efficacy based on ENPP3 and NUDT12 were identified was constructed. GSEA suggested that ENPP3 was enriched in Toll like receptor (TLR) pathway, NUDT12 was enriched in maturity onset diabetes of the young and insulin pathway. Furthermore, 18 potential miRNAs and 36 Transcription factors (TFs) were predicted and the miRNA-mRNA-TF networks were constructed, suggesting that ENPP3 might regulate hsa-miR-34a-5p by affecting MYNN. The ceRNA network suggested that XLOC_013024 might regulate hsa-let-7b-5p by affecting NUDT12. 15 drugs were predicted, with 8 drugs affecting NUDT12 such as resveratrol, and 13 drugs affecting ENPP3 such as troglitazone.ConclusionENPP3 and NUDT12 might play key roles in DPN, which provides reference for further research on DPN.

Background How to improve flap necrosis in distal flaps is still a popular topic in clinical flap research. Zingerone (ZIN), as a plant extract, has therapeutic effects on many diseases. The purpose of our study was to explore whether ZIN can promote the survival of ischaemic skin flaps and its specific mechanism. Methods An ischemic flap model was established in the dorsal region of mice. The changes of angiogenesis, oxidative stress, apoptosis and Keap1-Nrf2 related proteins in the skin flap were detected by immunofluorescence, western blot and qPCR. Overexpression of Keap1 by adeno-associated virus (AAV) was used to study the specific pathway and mechanism. Results The results showed that ZIN can induce angiogenesis and reduce oxidative stress and apoptosis to promote flap survival. Increased expression of Keap1 reversed the therapeutic effect of ZIN. Conclusion ZIN activates Nrf2 by inhibiting Keap1 activation, thus promoting angiogenesis and inhibiting oxidative stress and apoptosis.

Purpose: To describe and evaluate the anatomical skin shape of the first web space in cadavers and to guide flap design for this area. Methods: Twelve cadavers (24 hands on both sides) were selected. Marker points were chosen based on the characteristics of the first web for morphological measurement and observation. The morphological characteristics of the first web under the radial or palmar abduction position of the thumb were measured and compared. The best morphologic features and parameters of the first web repairing flap were obtained. Results: When the thumb was in the palmar abduction position, the maximum distance a(p) was 6.78 +/- 0.72 cm and the skin area s(p) was 20.09 +/- 2.63 cm(2), both of which were significantly greater than the distance a(r) of 5.86 +/- 0.74 cm and the skin area s(r) of 17.39 +/- 2.15 cm(2) when the thumb was in the radial abduction position (P < 0.05). There was no significant difference in the length b(r) and b(p) of the long axis of the flap between two different abduction positions (P > 0.05). It is found that the shape of the first web area was not a symmetrical spindle but an irregular quadrilateral inclined to the index finger side. Conclusion: The flap design and measurement for the first web space covering should take the maximum palmar abduction position of the thumb as a reference. The asymmetric quadrilateral flap design is more in line with the anatomical and morphological characteristics of the region. (c) 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Random-pattern skin flaps are important method for skin reconstruction after defect; however, the distal end of flaps is not easily viable due to inadequate nutrient supply. Erastin is a well-established ferroptosis inducer, but our study found that low-dose of erastin (2 μM) may reduce nutrient deficiency induced cell death in human umbilical vein endothelial cells (HUVECs). RNA-seq analysis suggested that its role was related to autophagy regulation. Follow-up studies have shown that the use of autophagy inhibitors or the knockdown of TFEB in HUVECs can both reduce the anti-apoptotic effect of erastin in HUVECs. Mechanism study demonstrated that erastin can suppress mTORC1 and promote TFEB activity in HUVECs, suggesting that the effect of erastin on the survival of HUVECs under nutrient deprivation conditions is regulated by mTORC1/TFEB. Subsequently, we evaluated the effect of erastin on the survival of random-pattern skin flaps in mice in vivo. On the postoperative day 7, we observed a significant increase in flap survival area, blood perfusion, and microvascular density after erastin treatment; also, erastin treatment showed enhanced autophagy within the ischemic region. In summary, our study demonstrates that low-dose of erastin may suppress cell death in endothelial cells under nutrient deficiency condition, and its effects may relate to the mTORC1-TFEB medicated autophagy regulation, erastin treatment may be a potential therapy for random-pattern skin flaps.

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.

目的:介绍应用彩色多普勒在术前对股前外侧皮瓣穿支血管进行精准定位后，切取不携带主干血管的短蒂单穿支股前外侧皮瓣游离移植修复四肢中小面积皮肤缺损的手术方法和临床效果。方法:自2017年12月至2019年9月，我科对15例四肢中小面积皮肤缺损患者应用短蒂股前外侧单穿支皮瓣游离移植修复，皮瓣供养动脉与受区动脉端侧吻合，皮瓣静脉与受区静脉端端吻合。皮瓣切取面积6 cm×5 cm~11 cm×7 cm，所有皮肤缺损创面均伴有肌腱或骨外露，皮瓣均为单穿支皮瓣，皮瓣的游离时间为30~40 min，平均切取时间为35 min。皮瓣供区一期缝合。结果:术后15例皮瓣全部存活，随访时间3~12个月，平均7.2个月，皮瓣外形满意，供区创面Ⅰ期愈合。结论:利用彩色多普勒在股前外侧的近中段对皮瓣穿支入皮点及穿支血管在皮下和肌肉内的行径进行精确定位，选择合适的穿支作为皮瓣的供养血管，应用"Free-style"理念切取短蒂股前外侧皮瓣，对供区损伤小，切取较传统方式简便，手术时间短，供区能直接缝合，是一种理想的应对血管变异的手术方法。对显微外科技术和彩色多普勒操作技术和要求较高。

A diabetic wound is a refractory disease that afflicts patients globally. MicroRNA-146a-5p (miR-146a-5p) is reported to represent a potential therapeutic target for diabetic wounds. However, microRNA easily degrades in the wound microenvironment. This study extracted bone marrow mesenchymal stem cell (BMSC)-derived exosomes (EXO). Electroporation technology was used to load miR-146a-5p into EXO (labeled as EXO-miR-146a). The endothelial cells (human umbilical vein endothelial cells [HUVECs]) and macrophages were cocultured in transwell chambers in the presence of high glucose. Cell proliferation, migration, and angiogenesis were measured with cell counting kit 8, scratch, and tube forming assays, respectively. Flow cytometry was introduced to validate the biomarker of macrophages and BMSCs. The expression level of macrophage polarization-related proteins and tumor necrosis factor receptor-associated factor 6 (TRAF6) was assessed with western blotting analysis. The full-thickness skin wound model was developed to verify the in vitro results. EXO-miR-146a promoted the proliferation, migration, and angiogenesis of HUVECs in the hyperglycemic state by suppressing the TRAF6 expression in vitro. Additionally, EXO-miR-146a treatment facilitated M2 but inhibited M1 macrophage polarization. Furthermore, EXO-miR-146a enhances reepithelialization, angiogenesis, and M2 macrophage polarization, thereby accelerating diabetic wound healing in vivo. The EXO-miR-146a facilitated M2 macrophage polarization, proliferation, migration, and angiogenesis of HUVECs through TRAF6, thereby ameliorating intractable diabetic wound healing. These results established the basis for using EXO to deliver drugs and revealed mediators for diabetic wound treatment.

Necrosis that appears at the ischemic distal end of random-pattern skin flaps increases the pain and economic burden of patients. Necroptosis is thought to contribute to flap necrosis. Lysosomal membrane permeabilization (LMP) plays an indispensable role in the regulation of necroptosis. Nonetheless, the mechanisms by which lysosomal membranes become leaky and the relationship between necroptosis and lysosomes are still unclear in ischemic flaps. Based on Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, and liquid chromatography-mass spectrometry (LC-MS) analysis results, we found that LMP was presented in the ischemic distal portion of random-pattern skin flaps, which leads to disruption of lysosomal function and macroautophagic/autophagic flux, increased necroptosis, and aggravated necrosis of the ischemic flaps. Moreover, bioinformatics analysis of the LC-MS results enabled us to focus on the role of PLA2G4E/cPLA2 (phospholipase A2, group IVE) in LMP of the ischemic flaps. In vivo inhibition of PLA2G4E with an adeno-associated virus vector attenuated LMP and necroptosis, and promoted flap survival. In addition, microRNA-seq helped us determine that Mir504-5p was differentially expressed in ischemic flaps. A string of in vitro and in vivo tests was employed to verify the inhibitory effect of Mir504-5p on PLA2G4E, LMP and necroptosis. Finally, we concluded that the inhibition of PLA2G4E by Mir504-5p reduced LMP-induced necroptosis, thereby promoting the survival of random-pattern skin flaps.

Human malignant melanoma (MM), is a type of skin cancer with high morbidity and mortality. In this study, we investigated the role of miR-383-5p in human MM cells in vitro. miR-383-5p expression was downregulated in MM cell lines compared with the human normal melanocyte cell line, and miR-383-5p overexpression inhibited the proliferation, migration, and invasion of M14 and A375 cells. Furthermore, miR-383-5p was able to effectively bind to the 3'UTR of CENPF mRNA. miR-383-5p expression was negatively correlated with CENPF expression and miR-383-5p overexpression inhibited CENPF protein expression in M14 and A375 cells. The overexpression of CENPF could effectively rescue the inhibitory effect on proliferation and invasion caused by miR-383-5p. Additionally, using publicly available databases, we showed that CENPF expression was upregulated in human MM tissues and could predict the prognosis of MM. In conclusion, miR-383-5p acts as a tumor suppressor in human MM by targeting CENPF, suggesting CENPF as a potential therapeutic target for human MM.

Increasing evidence indicates that pyroptosis, a new type of programmed cell death, may participate in random flap necrosis and play an important role. ROS-induced lysosome malfunction is an important inducement of pyroptosis. Transcription factor E3 (TFE3) exerts a decisive effect in oxidative metabolism and lysosomal homeostasis. We explored the effect of pyroptosis in random flap necrosis and discussed the effect of TFE3 in modulating pyroptosis. Histological analysis via hematoxylin-eosin staining, immunohistochemistry, general evaluation of flaps, evaluation of tissue edema, and laser Doppler blood flow were employed to determine the survival of the skin flaps. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were used to calculate the expressions of pyroptosis, oxidative stress, lysosome function, and the AMPK-MCOLN1 signaling pathway. In cell experiments, HUVEC cells were utilized to ensure the relationship between TFE3, reactive oxygen species (ROS)-induced lysosome malfunction and cell pyroptosis. Our results indicate that pyroptosis exists in the random skin flap model and oxygen and glucose deprivation/reperfusion cell model. In addition, NLRP3-mediated pyroptosis leads to necrosis of the flaps. Moreover, we also found that ischemic flaps can augment the accumulation of ROS, thereby inducing lysosomal malfunction and finally initiating pyroptosis. Meanwhile, we observed that TFE3 levels are interrelated with ROS levels, and overexpression and low expression of TFE3 levels can, respectively, inhibit and promote ROS-induced lysosomal dysfunction and pyroptosis during in vivo and in vitro experiments. In conclusion, we found the activation of TFE3 in random flaps is partially regulated by the AMPK-MCOLN1 signal pathway. Taken together, TFE3 is a key regulator of ROS-induced pyroptosis in random skin flaps, and TFE3 may be a promising therapeutic target for improving random flap survival.

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.

The purpose of this study is to investigate the efficacy of fractional ablative carbon dioxide laser (AFXL) surgery in patients with pediatric hand scars. This study enrolled hand scar patients who received treatment in our hospital between May 2018 and April 2019. Patients were assigned to undergo AFXL surgery based on their personal intents and condition, whereas the fractional laser was used for stiffness and abnormal texture. Outcomes were as follows: hand function was evaluated using the Michigan hand outcomes questionnaire; scar condition was evaluated using the Vancouver scar scale and UNC4P scar scale. Total 30 pediatric patients (mean age, 11.4 years) were eligible for the study and laser-treated scars were significantly improved in Michigan hand outcomes questionnaire from 52.30 ± 6.14 to 66.91 ± 6.43 (p < 0.001). Provider-rated Vancouver scar scale dropped from 8.80 ± 2.75 to 6.73 ± 2.52 (p < 0.001). Patient-reported UNC4P scar scale declined from7.07 ± 2.02 to 4.73 ± 1.31 (p < 0.001). AFXL surgery can significantly improve hand function and appearance of pediatric hand scars, suggesting its advantages over traditional methods of operative intervention.

Objective To compare the clinical effects of proximal phalangeal base fractures treated by closed reduction and percutaneous reduction by leverage, and discuss the pathogenesis, radiological characteristics and percutaneous reduction by leverage of irreducible proximal phalangeal base fractures in adults.Methods From February 2012 to March 2015, a total of 61 cases (84 fingers) of comminuted proximal phalangeal base fractures were treated by closed reduction or percutaneous reduction by leverage and fixation by Kirschner wire.The clinical effects were analyzed.Results Closed reduction was successful in 60 fingers with a success rate of 71％.Failure of reduction occurred in 24 fingers and the deformity was aggravated after closed reduction in 6 fingers.All the 24 fingers obtained successful reduction using percutaneous leverage.The incidence of irreducible proximal phalangeal base fractures was 29％.The incidence of iatrogenic deformity was 25％.All the patients were follow-up from 9 to 27 months with an average of 12.8 months.Complete healing achieved in all the cases.According to TAM evaluation criteria, for closed reduction group the results were excellent in 35 fingers, good in 16 fingers, fair in 6 fingers and poor in 3 fingers with the excellent and good rate being 85.0％;for percutaneous reduction by leverage group the results were excellent in 12 fingers,good in 7 fingers, fair in 3 fingers and poor in 2 fingers with the excellent and good rate being 79.2％.There was no significant difference between the two groups (P＞0.05).Conclusion The failure of closed reduction for the irreducible proximal phalangeal base fractures is often caused by comminuted fracture.Application of percutaneous reduction by leverage for deformity correction and Kirschner wire for fracture fixation can achieve good clinical results.