CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
·
2021
·Vol. 99
·期 12
·
IF 2.273
Dongdong Zhang,Dongxu Qi,Yi Xu,Chunhe Hu,Xiao Zhang,Qingjian Yang,Zikun Shang,Guisheng Zhang
Skin flap transfer is an important method to repair and reconstruct various tissue defects; however, avascular necrosis largely affects the success of flap transfer. The sphingosine 1-phosphate receptor 1 (S1PR1) agonist SEW2871 has been proven to ameliorate ischemic injury; however, its effect on flap survival has not been reported. In this study, an experimental skin flap model was established in rats to investigate the roles of SEW2871. The results indicated that SEW2871 greatly increased the survival of the skin flap, alleviated pathological injury, promoted the angiogenesis, and inhibited cells apoptosis in skin flap tissues. SEW2871 activated S1PR1 downstream signaling pathways, including heat shock protein 27 (HSP27), extracellular regulated protein kinases (ERK), and protein kinase B (Akt). In addition, SEW2871 promoted the expression of S1PR1. These findings may provide novel insights for skin flap transfer.
研究领域:
药理学
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外科手术
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分子生物学
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DOI
PubMed
高影响因子
Autophagy
·
2021
·
IF 16.016
Junsheng Lou,Xiangyang Wang,Haojie Zhang,Gaoxiang Yu,Jian Ding,Xuwei Zhu,Yao Li,Yaosen Wu,Hui Xu,Huazi Xu,Weiyang Gao,Jian Xiao,Kailiang Zhou
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.Abbreviations: AAV: adeno-associated virus; ACTA2/α;-SMA: actin alpha 2, smooth muscle, aorta; ALOX15/12/15-LOX: arachidonate 15- lipoxygenase; c-CASP8: cleaved caspase; c-CASP3: cleaved caspase 3; CTSD: cathepsin D; CTSB: cathepsin B; CTSL: cathepsin L; DMECs: primary mouse dermal microvascular endothelial cells; ELISA: enzyme-linked immunosorbent assay; F-CHP: 5-FAM-conjugated collagen hybridizing peptide; FISH: fluorescence in situ hybridization; HUVECs: human umbilical vein endothelial cells; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; LC-MS: liquid chromatography-mass spectrometry; LDBF: laser doppler blood flow; LMP: lysosomal membrane permeabilization; LPE: lysophosphatidylethanolamine; LPC: lysophosphatidylcholine; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MLKL: mixed lineage kinase domain-like; NDI: N-dodecylimidazole; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; PLA2G4A/cPLA2: phospholipase A2, group IVA (cytosolic, calcium-dependent); PLA2G4E/cPLA2: phospholipase A2, group IVE; qPCR: quantitative real-time polymerase chain reaction; RIPK1: receptor (TNFRSF)-interacting serine-threonine kinase 1; RIPK3: receptor-interacting serine-threonine kinase 3; RISC: RNA-induced silencing complex; ROS: reactive oxygen species; shRNA: short hairpin RNA; SQSTM1: sequestosome 1; TBHP: tert-butyl hydroperoxide; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labelling.
研究领域:
医学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-22
·
IF 12.6
Yang Ningning,Hua Rongrong,Lai Yingying,Zhu Peijun,Ding Jian,Ma Xianhui,Yu Gaoxiang,Xia Yiheng,Liang Chao,Gao Weiyang,Wang Zhouguang,Zhang Hongyu,Yang Liangliang,Zhou Kailiang,Ge Lu
In the field of large-area trauma flap transplantation, preventing avascular necrosis remains a critical challenge. Key mechanisms for improving flap viability include angiogenesis promotion, oxidative stress inhibition, and cell death prevention. Recently, two-dimensional ultrathin Ti 3 C 2 T X (MXene) nanosheets have gained attention for their potential contributions to these processes, though MXene’s physiological impact on flap survival had not been previously investigated. This study is the first to confirm MXene's biological effects on the ischaemic microenvironment post-skin flap transplantation. Findings indicated that MXene significantly decreased the necrotic area in ischaemic flaps (37.96% ± 2.00%), with reductions of 30.40% ± 1.86% at 1 mg/mL and 20.19% ± 2.11% at 2 mg/mL in a concentration-dependent manner. Mechanistically, MXene facilitated in situ angiogenesis, mitigated oxidative stress, suppressed pro-inflammatory pyroptosis, and activated the PI3K-Akt pathway, particularly influencing vascular endothelial cells. Comparative transcriptome analysis of skin tissues with and without MXene treatment provided additional evidence, highlighting mechanisms such as pro-inflammatory pyroptosis, ROS metabolic processes, endothelial cell proliferation regulation, and PI3K-Akt signaling pathway activation. Overall, MXene demonstrated biological activity, effectively promoting ischaemic flaps survival and presenting a novel strategy for addressing ischaemic necrosis in skin flaps. Graphical abstract
研究领域:
医学
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生物材料学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Chengji Dong,Gaoxiang Yu,Xianhui Ma,Zhuliu Chen,Ningning Yang,Xuankuai Chen,Yingying Lai,Jiayi Zhao,Yanlan Gu,Kailiang Zhou,Weiyang Gao,Jian Ding,Xuwei Zhu
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.
研究领域:
外科手术
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
·
IF 19
Junwei Su,Xianzhen Dong,Chao Xu,Zheng Wang,Changjiang Liu,Hongjun Yang,Dong Zhang,Aixi Yu
The multi-territory perforator flap is a widely used microsurgical technique for repairing skin and tissue defects in diabetes. In the diabetic microenvironment, oxidative stress and inflammation from reactive oxygen species (ROS) lead to compromised blood supply to the flap, resulting in challenges for survival. The common complication of multi-territory perforator flap is distal necrosis, which is primarily attributed to the Choke zone, the critical location characterized by delayed blood supply and inadequate neovascularization. To address this issue, a ROS-responsive MSL@Z/G hydrogel is developed by encapsulating metformin-Sr-L-Arg@ZIF-90 (MSL@Z) nanoparticles into gelatine methacrylamide (GelMA), enabling the release of metformin, Sr ions and NO. The enhanced deformation resistance and compressive strength properties of the MSL@Z/G hydrogel make it suitable for tissue reconstruction and drug delivery. Additionally, the MSL@Z/G hydrogel exhibits antioxidant and anti-inflammatory effects, thereby modulating the vascular microenvironment. In the dorsal multi-territory perforated flap model of type 2 diabetic rats, the MSL@Z/G hydrogel demonstrates the ability to alleviate inflammation and promote neovascularization of the Choke zone, reducing distal necrosis, which holds great promise for improving flap survival in diabetes.
研究领域:
生物材料学
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组织工程学
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糖尿病研究
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Cheng Lu,Miao Chen,Yuanyuan Zhao,Yongxin Zhan,Xin Wei,Laijin Lu,Mingxi Yang,Xu Gong
Avoiding ischemic necrosis after flap transplantation remains a significant clinical challenge. Developing an effective pretreatment method to promote flap survival postoperatively is crucial. Cobalt chloride (CoCl 2 ) can increase cell tolerance to ischemia and hypoxia condition by stimulating hypoxia-inducible factor-1 (HIF-1) expression. However, the considerable toxic effects severely limit the clinical application of CoCl 2 . In this study, cobalt-based metal-organic frameworks (Co-MOF) encapsulated in a microneedle patch (Co-MOF@MN) was developed to facilitate the transdermal sustained release of Co 2+ for rapid, minimally invasive rapid pretreatment of flap transplantation. The MN patch was composed of a fully methanol-based two-component cross-linked polymer formula, with a pyramid structure and high mechanical strength, which satisfied the purpose of penetrating the skin stratum corneum of rat back to achieve subcutaneous vascular area administration. Benefiting from the water-triggered disintegration of Co-MOF and the transdermal delivery via the MN patch, preoperative damage and side effects were effectively mitigated. Moreover, in both the oxygen-glucose deprivation/recovery (OGD/R) cell model and the rat dorsal perforator flap model, Co-MOF@MN activated the HIF-1α pathway and its associated downstream proteins, which reduced reperfusion oxidative damage, improved blood supply in choke areas, and increased flap survival rates post-transplantation. This preprotection strategy, combining MOF nanoparticles and the MN patch, meets the clinical demands for trauma minimization and uniform administration in flap transplantation. Statement of significance Cobalt chloride (CoCl 2 ) can stimulate the expression of hypoxia-inducible factor (HIF-1) and improve the tolerance of cells to ischemia and hypoxia conditions. However, the toxicity and narrow therapeutic window of CoCl 2 severely limit its clinical application. Herein, we explored the role of Co-MOF as a biocompatible nanocage for sustained release of Co 2+ , showing the protective effect on vascular endothelial cells in the stress model of oxygen-glucose deprivation. To fit the clinical needs of minimal trauma in flap transplantation, a Co-MOF@MN system was developed to achieve local transdermal delivery at the choke area, significantly improving blood supply opening and flap survival rate. This strategy of two-step delivery of Co 2+ realized the enhancement of biological functions while ensuring the biosafety.
研究领域:
生物医学工程
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药学
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组织工程
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再生医学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
WOUND REPAIR AND REGENERATION
·
2025
·Vol. 33
·期 2
·e70028
·
IF 3.4
Junyan Liang,Yang Zou,Haiyan Ju,Yonggang Lv
Random skin flaps are commonly used to cover thick skin wounds. However, necrosis frequently occurs when the flap's aspect ratio exceeds 2:1. Promoting angiogenesis and regulating inflammation are essential for treating ischemia–reperfusion injury in random flaps. In this study, calcium-doped silica nanoparticles loaded with deferoxamine (CD) were created through physical adsorption by rapidly mixing biodegradable calcium-doped silica nanoparticles (CS) with deferoxamine (DFO). A gelatin methacryloyl (GM) hydrogel nanofiber scaffold containing 1% (w/v) CD (GM/CD-1) was subsequently produced using electrospinning technology. The GM/CD-1 scaffold showed excellent biocompatibility and significantly promoted flap regeneration in mice, achieving a 96.17 ± 3.17% flap survival rate at 14 days. Additionally, it effectively stimulated hair follicle growth and exhibited an inflammatory-modulating effect. These features suggest that the GM/CD-1 scaffold could be valuable for clinical applications in flap regeneration and other tissue engineering fields.
研究领域:
生物医学工程
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组织工程
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再生医学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Sizhe Song,Jiahui Guo,Bin Kong,Rui Liu,Jinglin Wang,Ling Lu,Yuanjin Zhao
Electrospun nanofibers have been showing their estimable values as tissue engineering scaffolds. Notably, the oriented structure and intelligent responsiveness are significant directions to enhance the application value of the nanofibrous scaffolds. Here, we present a novel 3D anisotropic and responsive nanofiber sponge scaffolds (ARNFSs) loaded with black phosphorus (BP) and vascular endothelial growth factors (VEGF) for random skin flaps regeneration. Aligned polycaprolactone (PCL) nanofibrous mat prepared by electrospinning technology acted as host materials of sponge scaffolds, which were foamed by soaking in sodium borohydride (NaBH 4 ) solution and filled with poly(N-isopropylacrylamide) (pNIPAM) hydrogel. The highly oriented 3D nanofiber sponge scaffolds can guide the growth of cells along the fibers. Utilizing the superior photothermal conversion properties of BP and thermal responsive ability of pNIPAM, VEGF could be controllably released with the irradiation of near-infrared (NIR) light, thus promoting the angiogenesis of random skin flaps. Notably, in vivo experiments have further proved that our 3D ARNFSs have remarkable performance in enhancing the survival of random skin flaps, indicating their significant value in clinical tissue regeneration and other correlative biomedical fields.
研究领域:
组织工程
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生物材料
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再生医学
✓ 已验证
产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Rui Chang,Pei Wang,Hongrui Chen,Shih-Jen Chang,Qianyi Chen,Lei Chang,Yajing Qiu,Xiansong Wang,Xiaoxi Lin
Diabetes-associated skin defects represent a significant global health challenge. While flap grafts have been a preferred treatment for soft-tissue injuries in diabetic patients, their survival is often compromised by impaired vascularization, infection, and the adverse diabetic pathological microenvironment. To address these limitations, a hybrid photo-crosslinkable hydrogel (HPC) integrated hemangioma stem cell-derived nanovesicle (HemV)-loaded dual-metal-polyphenol network (dMPN) (HemV@dMPN/HPC) is developed. HemVs, derived from highly vascularized infantile hemangioma tissues, play a key role in promoting cell proliferation and angiogenesis. The dMPN facilitates the gradual release of copper (Cu 2+ ) and magnesium ions (Mg 2+ ), stimulating angiogenesis and mitigating inflammation. The HPC further sustains ion release while preserving the therapeutic efficacy of HemVs. Moreover, both HPC and Cu 2+ act to confer antibacterial properties, further accelerating wound healing. This multifunctional HemV@dMPN/HPC platform offers a promising therapeutic strategy for treating large diabetic skin defects and can potentially improve flap graft survival.
研究领域:
生物医学工程
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再生医学
·
糖尿病治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2024
·
IF 3.5
Xianyao Tao,Xiaoyun Pan,Gang Zhao,Mingyu Xue,Yongjun Rui
In clinical flap practice, there are a lot of studies being done on how to promote the survival of distal random flap necrosis in the hypoxic and ischemic state. As a traditional Chinese medicine, dihydromyricetin (DHM) is crucial in preventing oxidative stress and apoptosis in a number of disorders. In this work, we examined the impact of DHM on the ability to survive of ischemia flaps and looked into its fundamental mechanism. Our results showed that DHM significantly increased the ischemic flaps' survival area, encouraged angiogenesis and blood flow, reduced oxidative stress and apoptosis, and stimulated KEAP1-Nrf2 (Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor) signaling pathways. Adeno-associated virus (AAV) upregulation of KEAP1 expression also negated the favorable effects of DHM on flap survival. By activating KEAP1-Nrf2 signaling pathways, DHM therapy promotes angiogenesis while reducing oxidative stress and apoptosis.
研究领域:
药理学
·
外科手术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Tingxiang Chen,Hongyu Chen,Yuedong Fu,Xuao Liu,Haosheng Huang,Zhijie Li,Shi Li
In reconstructive and plastic surgery, random skin flaps are commonly utilized to treat skin abnormalities produced by a variety of factors. Flap delay procedure is commonly used to reduce flap necrosis. Due to the limitations of various conditions, the traditional surgical improvement can’t effectively alleviate the skin flap necrosis. And leonurine (Leo) has antioxidant and anti-inflammatory effects. In this study, we researched the mechanism underlying the influences of varied Leo concentrations on the survival rate of random skin flaps. Our results showed that after Leo treatment, tissue edema and necrosis of the flap were significantly reduced, while angiogenesis and flap perfusion were significantly increased. Through immunohistochemistry and Western blot, we proved that Leo treatment can upregulate the level of angiogenesis, while Leo treatment significantly reduced the expression levels of oxidative stress, apoptosis and inflammation. As a result, it can significantly improve the overall viability of the random skin flaps through the increase of angiogenesis, restriction of inflammation, attenuation of oxidative stress, and reduction of apoptosis. And this protective function was inhibited by LY294002 (a broad-spectrum inhibitor of PI3K) and L-NAME (NG- nitro-L-arginine methyl ester, a non-selective NOS inhibitor). All in all, Leo is an effective drug that can activate the eNOS via the PI3K/Akt pathway. By encouraging angiogenesis, preventing inflammation, minimizing oxidative stress, and lowering apoptosis, Leo can raise the survival rate of random skin flaps. The recommended concentration of Leo in this study was 30 mg/kg.
研究领域:
整形与重建外科
·
药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Yan Chen,Ruxin Cheng,Wenyan Lu,Yonghao Fan,Ye Yu,Ling Huang,Zhenling Wan,Shaojiang Zheng
The random flap is one of the commonly used techniques for tissue defect repair in surgery and orthopaedics, however the risk of ischaemic necrosis at the distal end of the flap limits its size and clinical application. Metformin (Met) is a first-line medication in the treatment of type 2 diabetes, with additional effects such as anti-tumor, anti-aging, and neuroprotective properties. In this study, we aimed to investigate the biological effects and potential mechanisms of Met in improving the survival of random skin flaps. Twenty-four male Sprague-Dawley rats and 12 male C57BL/6J mice underwent McFarlane flap surgery and divided into control (Ctrl) and Met groups (100 mg/kg). The survival rate of the flap were evaluated on day 7. Angiography, Laser doppler blood flow imaging, and H&E staining were used to assess blood flow supply and the levels of microvascular density. Then, reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured by test kits. Immunohistochemistry analysis was conducted to evaluate the expression of Vascular Endothelial Growth Factor A (VEGFA), Vascular endothelial cadherin (VE-cadherin) and CD31. Rats and mice in the Met group exhibited higher flap survival rate, microcirculatory flow, and higher expression levels of VEGFA and VE-cadherin compared with the Ctrl group. In addition, the level of oxidative stress was significantly lower in the met group. And then we demonstrated that the human umbilical vein endothelial cells (HUVECs) treated with Met can alleviate tert -butyl hydroperoxide (TBHP)-stimulated cellular dysfunction and oxidative stress injury. Mechanistically, Met markedly stimulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and promoted Nrf2 nuclear translocation. Silencing of Nrf2 partially abolished the antioxidant and therapeutic effects of Met. In summary, our data have confirmed that Met has a positive effect on flap survival and reduces necrosis. The mechanism of action involves the regulation of the Nrf2/HO-1 signaling pathway to combat oxidative stress and reduce damage.
研究领域:
外科手术
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骨科
·
药理学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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