Search

Overexposure to ultraviolet light (UV) has become a major dermatological problem since the intensity of ultraviolet radiation is increasing. As an adaption to outside environments, amphibians gained an excellent peptide‐based defense system in their naked skin from secular evolution. Here, we first determined the adaptation and resistance of the dark‐spotted frogs (Pelophylax nigromaculatus) to constant ultraviolet B (UVB) exposure. Subsequently, peptidomics of frog skin identified a series of novel peptides in response to UVB. These UV‐induced frog skin peptides (UIFSPs) conferred significant protection against UVB‐induced death and senescence in skin cells. Moreover, the protective effects of UIFSPs were boosted by coupling with the transcription trans‐activating (TAT) protein transduction domain. In vivo, TAT‐conjugated UIFSPs mitigated skin photodamage and accelerated wound healing. Transcriptomic profiling revealed that multiple pathways were modulated by TAT‐conjugated UIFSPs, including small GTPase/Ras signaling and MAPK signaling. Importantly, pharmacological activation of MAPK kinases counteracted UIFSP‐induced decrease in cell death after UVB exposure. Taken together, our findings provide evidence for the potential preventive and therapeutic significance of UIFSPs in UV‐induced skin damage by antagonizing MAPK signaling pathways. In addition, these results suggest a practicable alternative in which potential therapeutic agents can be mined from organisms with a fascinating ability to adapt. [ABSTRACT FROM AUTHOR]

The extensive application of nuclear technology has increased the potential of uncontrolled radiation exposure to the public. Since skin is the largest organ, radiation‐induced skin injury remains a serious medical concern. Organisms evolutionally develop distinct strategies to protect against environment insults and the related research may bring novel insights into therapeutics development. Here, 26 increased peptides are identified in skin tissues of frogs (Pelophylax nigromaculatus) exposed to electron beams, among which four promoted the wound healing of irradiated skin in rats. Specifically, radiation‐induced frog skin peptide‐2 (RIFSP‐2), from histone proteolysis exerted membrane permeability property, maintained cellular homeostasis, and reduced pyroptosis of irradiated cells with decreased TBK1 phosphorylation. Subsequently, stearyl‐CoA desaturase 1 (SCD1) is identified, a critical enzyme in biogenesis of monounsaturated fatty acids (MUFAs) as a direct target of RIFSP‐2 based on streptavidin‐biotin system. The lipidomic analysis further assured the restrain of MUFAs biogenesis by RIFSP‐2 following radiation. Moreover, the decreased MUFA limited radiation‐induced and STING‐mediated inflammation response. In addition, genetic depletion or pharmacological inhibition of STING counteracted the decreased pyroptosis by RIFSP‐2 and retarded tissue repair process. Altogether, RIFSP‐2 restrains radiation‐induced activation of SCD1‐MUFA‐STING axis. Thus, the stress‐induced amphibian peptides can be a bountiful source of novel radiation mitigators. [ABSTRACT FROM AUTHOR]

Radiogenic skin injury (RSI) is a common complication during cancer radiotherapy or accidental exposure to radiation. The aim of this study is to investigate the metabolism of bile acids (BAs) and their derivatives during RSI. Rat skin tissues were irradiated by an X-ray linear accelerator. The quantification of BAs and their derivatives were performed by liquid chromatography–mass spectrometry (LC–MS)-based quantitative analysis. Key enzymes in BA biosynthesis were analyzed from single-cell RNA sequencing (scRNA-Seq) data of RSI in the human patient and animal models. The in vivo radioprotective effect of deoxycholic acid (DCA) was detected in irradiated SD rats. Twelve BA metabolites showed significant differences during the progression of RSI. Among them, the levels of cholic acid (CA), DCA, muricholic acid (MCA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), glycohyodeoxycholic acid (GHCA), 12-ketolithocholic acid (12-ketoLCA) and ursodeoxycholic acid (UDCA) were significantly elevated in irradiated skin, whereas lithocholic acid (LCA), tauro-β-muricholic acid (Tβ-MCA) and taurocholic acid (TCA) were significantly decreased. Additionally, the results of scRNA-Seq indicated that genes involved in 7a-hydroxylation process, the first step in BA synthesis, showed pronounced alterations in skin fibroblasts or keratinocytes. The alternative pathway of BA synthesis is more actively altered than the classical pathway after ionizing radiation. In the model of rat radiogenic skin damage, DCA promoted wound healing and attenuated epidermal hyperplasia. Ionizing radiation modulates the metabolism of BAs. DCA is a prospective therapeutic agent for the treatment of RSI. [ABSTRACT FROM AUTHOR]

Severe burns often have a high mortality rate due to sepsis, but the genetic and immune crosstalk between them remains unclear. In the present study, the GSE77791 and GSE95233 datasets were analysed to identify immune‐related differentially expressed genes (DEGs) involved in disease progression in both burns and sepsis. Subsequently, weighted gene coexpression network analysis (WGCNA), gene enrichment analysis, protein–protein interaction (PPI) network construction, immune cell infiltration analysis, core gene identification, coexpression network analysis and clinical correlation analysis were performed. A total of 282 common DEGs associated with burns and sepsis were identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified the following enriched pathways in burns and sepsis: metabolic pathways; complement and coagulation cascades; legionellosis; starch and sucrose metabolism; and ferroptosis. Finally, six core DEGs were identified, namely, IL10, RETN, THBS1, FGF13, LCN2 and MMP9. Correlation analysis showed that some core DEGs were significantly associated with simultaneous dysregulation of immune cells. Of these, RETN upregulation was associated with a worse prognosis. The immune‐related genes and dysregulated immune cells in severe burns and sepsis provide potential research directions for diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies. Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes. We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation. Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids. [ABSTRACT FROM AUTHOR]

Background. Cutaneous squamous cell carcinoma (cSCC) is the leading cause of death in patients with nonmelanoma skin cancers (NMSC). However, the unclear pathogenesis of cSCC limits the application of molecular targeted therapy. Methods. Three microarray datasets (GSE2503, GSE45164, and GSE66359) were downloaded from the Gene Expression Omnibus (GEO). After identifying the differentially expressed genes (DEGs) in tumor and nontumor tissues, five kinds of analyses, namely, functional annotation, protein-protein interaction (PPI) network, hub gene selection, TF-miRNA-mRNA regulatory network analysis, and ferroptosis mechanism, were performed. Results. A total of 146 DEGs were identified with significant differences, including 113 upregulated genes and 33 downregulated genes. The enriched functions and pathways of the DEGs included microtubule-based movement, ATP binding, cell cycle, P53 signaling pathway, oocyte meiosis, and PLK1 signaling events. Nine hub genes were identified (CDK1, AURKA, RRM2, CENPE, CCNB1, KIAA0101, ZWINT, TOP2A, and ASPM). Finally, RRM2, AURKA, and SAT1 were identified as significant ferroptosis-related genes in cSCC. The differential expression of these genes has been verified in two other independent datasets. Conclusions. By integrated bioinformatic analysis, the hub genes identified in this study elucidated the molecular mechanism of the pathogenesis and progression of cSCC and are expected to become future biomarkers or therapeutic targets. [ABSTRACT FROM AUTHOR]

Severe radiation-induced skin injury is a complication of tumor radiotherapy and nuclear accidents. Cell therapy is a potential treatment for radiation-induced skin injury. The stromal vascular fraction (SVF) is a newer material in stem cell therapy that is made up of stem cells harvested from adipose tissue, which has been shown to promote the healing of refractory wounds of different causes. In this study, SVF was isolated from patients with radiation-induced skin injury. Adipose-derived stem cells (ADSCs) accounted for approximately 10% of the SVF by flow cytometry. Compared with the control group of rats, administration with SVF attenuated the skin injury induced by electron beam radiation. The effect of SVF on the human skin fibroblast microenvironment was determined by proteomic profiling of secreted proteins in SVF-co-cultured human skin fibroblast WS1 cells. Results revealed 293 upregulated and 1,481 downregulated proteins in the supernatant of SVF-co-cultured WS1 cells. WS1 co-culture with SVF induced secretion of multiple proteins including collagen and MMP-1. In the clinic, five patients with radiation-induced skin injury were recruited to receive SVF transfer-based therapy, either alone or combined with flap transplantation. Autogenous SVF was isolated and introduced into a multi-needle precision electronic injection device, which automatically and aseptically distributed the SVF to the exact layer of the wound in an accurate amount. After SVF transfer, wound healing clearly improved and pain was significantly relieved. The patients' skin showed satisfactory texture and shape with no further wound recurrence. Our findings suggest that transplantation of SVF could be an effective countermeasure against severe radiation-induced skin injury. [ABSTRACT FROM AUTHOR]

Radiation-induced acute skin injury and consequent fibrosis are common complications of cancer radiotherapy and radiation accidents. Stromal cell-derived factor-1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4) have been shown to be involved in multiple cellular events. However, the role of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin has not been reported. In this study, we found that the expression of SDF-1α and CXCR4 was significantly increased in irradiated skin tissues of humans, monkeys and rats, compared to their nonirradiated counterparts. Mice with keratinocyte-specific ablation of CXCR4 showed less severe skin damage than wild-type mice after receiving a 35 Gy dose of radiation. Consistently, subcutaneous injection of AMD3100, an FDA approved SDF-1α/CXCR4 inhibitor, attenuated skin injury and fibrosis induced by exposure to radiation in a rat model. Mechanically, the SDF-1α/CXCR4 axis promotes pro-fibrotic TGF-b/Smad signaling through the PI3K-MAPK signaling cascade in human keratinocyte HaCaT cells and skin fibroblast WS1 cells. AMD3100 inhibited Smad2 nuclear translocation and transcriptional activity of Smad2/3 induced by radiation, which suppressed the pro-fibrotic TGF-b/Smad signaling pathway activated by exposure. Taken together, these findings demonstrate the involvement of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin, and indicate that AMD3100 would be an effective countermeasure against these diseases. [ABSTRACT FROM AUTHOR]

Irradiation-induced skin ulcers can be resultant from nuclear accident or reaction to radiation therapy of tumor and is intractable for healing. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been considered to be the potential therapeutic tools for tissue regeneration. However, the underlying mechanisms are still not well understood. This study aims to investigate the effects of hUC-MSCs on irradiation-induced skin ulcers healing and the related mechanisms. The ulcers were induced by irradiating the skin of adult SD rats. The ulcers of SD rats were treated with vehicle or hUC-MSCs donated from mother giving birth. The ulcer healing was measured by imaging the healing rate and the H&E staining. CD31 and VEGF expression was measured with immunohistochemistry assay. iTRAQ proteomics analysis was used to analyze the signaling pathway. The results showed that hUC-MSCs improved healing of irradiation-induced skin ulcers in vivo using a rat model of skin ulcer. Transplantation of hUC-MSCs promoted keratin generation and keratinocytes proliferation of ulcer areas. Furthermore, the results demonstrated that hUC-MSCs increased expression of CD31 and VEGF in ulcers and promoted neovascularization. iTRAQ proteomics analysis results indicated that PI3K/Akt signaling pathway involved in hUC-MSCs-mediated repairing of irradiation-induced skin ulcer. In conclusion, human umbilical cord mesenchymal stem cells promoted neovascularization and re-epithelization, and improved healing of irradiation-induced skin ulcers. This healing improvement may be conducted through activating the PI3K/Akt signaling pathway, however, which needs to be proven by the further investigations. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the dynamic change of CD34 level during the survival process of narrow pedicle flaps. Methods: Twenty-five white pigs were randomly and equally divided into 5 experimental groups. Five different type of narrow pedicle with different length-to-width ratio were employed, and each type of narrow pedicle was covered with 5 different size random flaps and which was classified into A, B, C, D and E for 5 groups. Group A was control group. Each type narrow pedicle with 5 different skin flaps were implanted onto the back of the pigs along the midline of back with a reverse direction. A 0.3 cm×0.3 cm full thickness skin flap in the middle of distal segment was collected and on 3rd, 5th, 7th and 14th days of post-operation. The expression of CD34 was measured by immunohistochemistry and enzyme-linked immunosorbent (ELISA). Results: Histological examination showed that with the increasing of length-to-width ratio of the narrow pedicle skin flaps, the expression of CD34 increased in the skin flaps. Increased level of CD34 was found on 3rd day post-operation, and the peak expression was found on 7th day. Persistent high level of CD34 was found until 14th day. Conclusion: Increased CD34 level in the distal skin flap, there is the association between CD34 level and ischemia injury. Moreover, CD34 expression plays an important role during the repair processes of pedicle flaps. [ABSTRACT FROM AUTHOR]

The skin is the largest outermost organ of the human body. It is vulnerable to various damages, such as ionizing radiation. Exploration of proliferation, senescence and radiosensitivity of skin cells contributes to the development of medical and cosmetic countermeasures against skin aging and toward injury protection. Human antigen R (HuR) is one of the most widely studied RNA-binding proteins and serves an important role in stabilization of mRNA and regulation of the expression of the target genes. To investigate the role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells, the present study performed an in vitro study using lentivirus-mediated overexpression or silencing of HuR in human keratinocyte HaCaT cells and human skin fibroblast WS1 cells. The results indicated that overexpression of HuR promoted proliferation, whereas downregulation of HuR inhibited proliferation of HaCaT and WS1 cells. Overexpression of HuR reduced apoptosis and senescence in skin cells. RNA-Seq of skin cells with HuR overexpression or knockdown identified 77 mRNAs positively or negatively correlated with HuR expression levels. In addition, silencing of HuR induced a significant increase in radiogenic reactive oxygen species after irradiation. Overexpression of HuR increased radiotolerance of HaCaT and WS1 cells. RNA immunoprecipitation coupled with RNA-Seq identified 14 mRNAs interacting with HuR upon radiation exposure. Overall, the findings of the present study illustrated the key role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells providing a new therapeutic strategy for cosmetic treatments and to combat skin injury. [ABSTRACT FROM AUTHOR]

AU-rich element RNA-binding factor 1 (AUF1) is a classical RNA-binding protein. AUF1 influences the process of development, apoptosis and tumorigenesis by interacting with adenylate-uridylate rich element-bearing mRNAs. Human skin is the largest organ of the body and acts as a protective barrier against pathogens and injuries. The aim of the present study was to explore the function and potential molecular pathways of AUF1 in human skin cells. AUF1 was overexpressed in human keratinocyte HaCaT cells and human skin fibroblast WS1 cells using adenoviruses and silenced using lentiviruses. AUF1 overexpression facilitated cell proliferation, whereas AUF1 knockdown induced the opposite effect. AUF1 reduced apoptosis but did not affect cell cycle progression. Forced AUF1 expression promoted the migration of human skin cells, as demonstrated by a scratch wound healing assay. Cell senescence was alleviated in AUF1-overexpressing skin cells, while AUF1 knockdown increased cell senescence. WS1 cells with AUF1 overexpression and silencing were used for RNA-sequencing and Kyoto Encyclopedia of Genes and Genomes-based pathway analysis to identify AUF1-affected mRNAs. A total of 18 mRNAs (eight mRNAs with positive associations and 10 mRNAs with negative associations) revealed consistent associations with both AUF1 overexpression and silencing. Enriched pathways associated with AUF1 expression included 'MAPK', 'cell adhesion molecules', 'proteasome', 'cellular senescence' and 'TGF-β signaling', indicating a complex regulatory network. Overall, the results of the present study revealed that AUF1 is involved in the proliferation, migration and senescence of skin cells in vitro and may be a potential target for cosmetic and disease treatment of skin. [ABSTRACT FROM AUTHOR]

B7-H3 is a type I membrane protein that has contradictory co-stimulatory and co-inhibitory effects in adaptive and anti-tumour immunity. B7-H3 is up-regulated in many malignant tumours, including breast cancer. Therefore, we hypothesise that B7-H3, which has an immunosuppressive role, suppresses anti-tumour immunity. The aim of this study was to clarify the role of B7-H3 in the tumor microenvironment in breast cancer, explore the possibility of B7-H3 as a target for clinical immunotherapy, and provide reference for clinical work. We knocked down B7-H3 with siRNA in MCF7 breast cancer cells, which we termed MCF7-B7-H3-KD cells, and the expression of B7-H3 was assessed by flow cytometry. GAPDH (glyceraldehyde-3-phosphate dehydrogenase) knockdown was used as a control (MCF7-Gapdh). MCF7-B7-H3-KD and MCF7-Gapdh cells were co-cultured with peripheral blood mononuclear cells (PBMCs) and CD3+ T cells from healthy donors to assess the effect of B7-H3 loss. PBMCs cultured with MCF7-Gapdh cells showed decreased activation, proliferation, and function of CD8+ T cells, but there was no effect on the proliferation of CD4+ T cells. However, when MCF7-B7-H3-KD cells were co-cultured with PBMCs, the proliferation ability of CD4+ T cells and CD8+ T cells was significantly higher than that observed in MCF7-Gapdh cell co-culture. Additionally, co-culture with MCF7-Gapdh cells decreased the expression of IFN-γ (Interferon-γ). However, after co-culture with MCF7-B7-H3-KD cells, there was an increase in IFN-γ. We further found that this inhibitory effect on IFN-γ was because of decreased mTOR (the mammalian target of rapamycin) phosphorylation in T cells. Treatment of T cells co-cultured with MCF7-B7-H3-KD cells with an mTOR inhibitor blocked the secretion of IFN-γ. B7-H3 on tumour cells inhibits the proliferation of CD4+ and CD8+ T cells and inhibits the release of IFN-γ by decreasing mTOR signalling. A better understanding of these complex immune regulatory mechanisms should facilitate the generation of more powerful and selective tools to manipulate cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease. Pigmented villonodular synovitis (PVNS) is a tenosynovial giant cell tumor that can involve joints. The mechanisms of co-morbidity between the two diseases have not been thoroughly explored. Therefore, this study focused on investigating the functions, immunological differences, and potential therapeutic targets of common genes between RA and PVNS. Methods: Through the dataset GSE3698 obtained from the Gene Expression Omnibus (GEO) database, the differentially expressed genes (DEGs) were screened by R software, and weighted gene coexpression network analysis (WGCNA) was performed to discover the modules most relevant to the clinical features. The common genes between the two diseases were identified. The molecular functions and biological processes of the common genes were analyzed. The protein-protein interaction (PPI) network was constructed using the STRING database, and the results were visualized in Cytoscape software. Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) logistic regression and random forest (RF) were utilized to identify hub genes and predict the diagnostic efficiency of hub genes as well as the correlation between immune infiltrating cells. Results: We obtained a total of 107 DEGs, a module (containing 250 genes) with the highest correlation with clinical characteristics, and 36 common genes after taking the intersection. Moreover, using two machine learning algorithms, we identified three hub genes (PLIN, PPAP2A, and TYROBP) between RA and PVNS and demonstrated good diagnostic performance using ROC curve and nomogram plots. Single sample Gene Set Enrichment Analysis (ssGSEA) was used to analyze the biological functions in which three genes were mostly engaged. Finally, three hub genes showed a substantial association with 28 immune infiltrating cells. Conclusion: PLIN, PPAP2A, and TYROBP may influence RA and PVNS by modulating immunity and contribute to the diagnosis and therapy of the two diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Heng, Li, Su, Liu, Yu, Bian and Li.)

Skin cutaneous melanoma is one of the deadly diseases, and more than 50% of the patients have BRAF gene mutations. Evidence suggests that oncogenic BRAF modulates the immune system's ability to recognize SKCM cells. Due to the complexity of the tumor microenvironment (TME) and a lack of a rational mechanistic basis, it is urgent to investigate the immune infiltration and identify prognostic biomarkers in BRAF mutated SKCM patients. Multiple methods including ESTIMATE algorithm, differential gene analysis, prognostic analysis and immune infiltration analysis were performed to investigate the tumor microenvironment. Based on the patient's immune score and stromal score, immune-related genes DEGs were identified. Functional analysis revealed that these genes were mainly enriched in biological processes such as immune response, defense response and positive regulation of immune system. Furthermore, we analyzed the immune infiltrating cell components of BRAF mutated patients and revealed 4 hub genes associated with overall survival time. Several cells (Monocyte, Macrophage and Gamma delta cells) have been found to be significantly decreased in immune-high BRAF mutated SKCM group. While CD4 + T, CD8 + T, CD4 naïve, Tr1, Th2 and many T cell subsets were significantly increased in immune-high group. These immune cells and genes were closely related to each other. This study revealed that the dysregulation of immune function and immune cells may contribute to the poor outcomes of BRAF mutated patients. It is of great significance to our further understanding of the TME and immune dysfunction in BRAF mutated SKCM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Su and Yu.)

Objective: To reveal the potential targets and signaling pathways of dasatinib in the treatment of radiation ulcers through network pharmacology and molecular docking technology., Methods: Pathological targets of radiation ulcers were screened using GeneCards database. At the same time, the pharmacological targets of dasatinib were obtained through SwissTargetPrediction (STP), Binding DB and Drugbank databases. Subsequently, the potential targets of dasatinib for anti-radiation ulcers were obtained after intersection by Venn diagram. Next, a protein-protein interaction (PPI) network was constructed through the STRING database and core targets were screened. Finally, the identified core targets were subjected to GO and KEGG enrichment analysis, co-expression network analysis, and molecular docking technology to verify the reliability of the core targets., Results: A total of 76 potential targets for anti-radiation ulcer with dasatinib were obtained, and 6 core targets were screened, including EGFR, ERBB2, FYN, JAK2, KIT, and SRC. These genes were mainly enriched in Adherens junction, EGFR tyrosine kinase inhibitor resistance, Focal adhesion, Bladder cancer and PI3K-Akt signaling pathway. Molecular docking results showed that dasatinib binds well to the core target., Conclusion: Dasatinib may play a role in the treatment of radiation ulcers by regulating EGFR, ERBB2, FYN, JAK2, KIT, and SRC. These core targets may provide new insights for follow-up studies of radiation ulcers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Su, Chen, Zhang, Li, Chen and Yu.)

Objective: Through network pharmacology and molecular docking technology, the hub genes, biological functions, and signaling pathways of 4-Octyl itaconate (4-OI) against sepsis were revealed. Methods: Pathological targets of sepsis were screened using GeneCards and GEO databases. Similarly, the pharmacological targets of 4-OI were obtained through Swiss TargetPrediction (STP), Similarity ensemble approach (SEA), and TargetNet databases. Then, all the potential targets of 4-OI anti-sepsis were screened by the online platform Draw Venn diagram, and the hub genes were screened by Cytoscape software. The identified hub genes were analyzed by GO and KEGG enrichment analysis, protein interaction (PPI) network, and molecular and docking technology to verify the reliability of hub gene prediction, further confirming the target and mechanism of 4-OI in the treatment of sepsis. Results: After the target screening of 4-OI and sepsis, 264 pharmacological targets, 1953 pathological targets, and 72 genes related to 4-OI anti-sepsis were obtained, and eight hub genes were screened, namely MMP9, MMP2, SIRT1, PPARA, PTPRC, NOS3, TLR2, and HSP90AA1. The enrichment analysis results indicated that 4-OI might be involved in regulating inflammatory imbalance, immunosuppression, and oxidative stress in developing sepsis. 4-OI protects multiple organ dysfunction in sepsis by acting on hub genes, and MMP9 is a reliable gene for the prognosis and diagnosis of sepsis. The molecular docking results showed that 4-OI binds well to the hub target of sepsis. Conclusion: 4-OI plays an antiseptic role by regulating MMP9, MMP2, SIRT1, PPARA, PTPRC, NOS3, TLR2 and HSP90AA1. These Hub genes may provide new insights into follow-up research on the target of sepsis treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Su, Chen, Lai, Liu and Yu.)

Background: Severe burns and blunt trauma can lead to multiple organ dysfunction syndrome, the leading cause of death in intensive care units. In addition to infection, the degree of immune inflammatory response also affects prognosis. However, the characteristics and clinical relevance of the common mechanisms of these major diseases are still underexplored. Methods: In the present study, we performed microarray data analysis to identify immune-related differentially expressed genes (DEGs) involved in both disease progression in burns and blunt trauma. Six analyses were subsequently performed, including gene enrichment analysis, protein-protein interaction (PPI) network construction, immune cell infiltration analysis, core gene identification, co-expression network analysis, and clinical correlation analysis. Results: A total of 117 common immune-related DEGs was selected for subsequent analyses. Functional analysis emphasizes the important role of Th17 cell differentiation, Th1 and Th2 cell differentiation, Cytokine-cytokine receptor interaction and T cell receptor signaling pathway in these two diseases. Finally, eight core DEGs were identified using cytoHubba, including CD8A, IL10, CCL5, CD28, LCK, CCL4, IL2RB, and STAT1. The correlation analysis showed that the identified core DEGs were more or less significantly associated with simultaneous dysregulation of immune cells in blunt trauma and sepsis patients. Of these, the downregulation of CD8A and CD28 had a worse prognosis. Conclusion: Our analysis lays the groundwork for future studies to elucidate molecular mechanisms shared in burns and blunt trauma. The functional roles of identified core immune-related DEGs and dysregulated immune cell subsets warrant further in-depth study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Wang, Li, Zhao, Huang, Su and Yu.)

Background: Diabetic foot ulcer (DFU) and peripheral artery disease (PAD) are common diseases that seriously affect the quality of life and bring a huge economic burden to society. Although mounting evidence supports a close link between the two disorders, the mechanisms of comorbidity remain to be fully elucidated., Methods: The gene expression profiles of DFU (GSE80178) and PAD (GSE100927) were downloaded from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) performed pathway enrichment analysis for common differentially expressed genes (DEGs) present in DFU and PAD. Subsequently, we constructed a protein-protein interaction (PPI) network using the STRING database and detected core modules and hub genes in the network. Finally, we analyzed the co-expression network and the TF-miRNA-mRNA regulatory network of hub genes., Results: A total of 167 common DEGs (91 up-regulated genes and 76 down-regulated genes) was selected for subsequent analyses. Functional analysis emphasizes the important role of chemokines and cytokines in these two diseases. Finally, six hub genes were identified using cytoHubba, including CXCL8, IL1RN, MMP1, CD68, CCR7 and CCL3., Conclusions: The hub genes and signaling pathways involved can regulate both diseases simultaneously, suggesting a close relationship between the molecular mechanisms of the two diseases and possible targets for drugs that intervene in both diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zou, Zhang, Chen, Su and Yu.)

Background: Radiation facilities and radioactive materials have been widely used in military, industry, medicine, science and nuclear facilities, which has significantly increased the potential of large-scale, uncontrolled exposure to radiation. The skin is one of the radiosensitive organ systems and radiation-induced skin injury remains a serious concern after ionizing radiation exposure. Our previous report indicates the involvement of the peroxisome proliferator-activated receptor pathway in the response of skin tissues to ionizing radiation. PPARα is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. However, the protection of fenofibrate against ionizing radiation in skin keratinocytes and fibroblasts has not been described., Methods: The PPARα mRNA levels in irradiated and nonirradiated skin tissues of rats were determined by real-time assay. The expression of PPARα, and FABP4 were evaluated by western blot and IHC assay. The cell proliferation was detected by colony formation. The γH2AX foci and ROS levels in irradiated WS1 cells with FABP4 overexpression than in control cells were performed by Immunofluorescence assay., Results: We found that PPARα expression was lower in the irradiated skin tissues of mouse, rat, monkey, and human patients than in their nonirradiated counterparts. PPARα fenofibrate significantly decreased radiation-induced ROS and apoptosis in a dose-dependent manner in human keratinocyte HaCaT and skin fibroblast WS1 cells. Moreover, fenofibrate significantly decreased radiation-induced ROS and malondialdehyde (MDA) levels in electron beam irradiated skin tissues of rats. Mechanistically, the proximal promoter of fatty acid binding protein 4 (FABP4) harbored three binding sites of PPARα and fenofibrate stimulated the transcription of FABP4 in skin cells. FABP4 overexpression decreased radiation-induced ROS and γH2AX foci. FABP4 inhibitor BMS309403 abrogated the ROS-eliminating activity as well as the lipid-accumulating role of fenofibrate, indicating that FABP4 mediates the radioprotective role of fenofibrate. In addition, FABP4 overexpression significantly decreased radiation-induced oxidative damage in vivo ., Conclusions: These results confirm that fenofibrate attenuated radiation-induced oxidative damage to the skin by stimulating FABP4., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Background: Decubitus ulcers are common skin injuries in plastic and burn surgery departments, usually occur in patients with a long disease course and poor underlying health. Designing a reconstruction procedure with safety blood supply to a large volume soft tissue and resulting in minimal trauma is a priority for surgeons., Methods: The free-style perforators on the potential donor sites surrounding the ulcers were detected by Doppler, and the area of the ulcer was divided into several sections based on the location of pre-design perforator flaps. According to the insertion point of the perforators, small V-Y advancement flaps, propeller flaps and rotation flaps pedicled with freestyle perforators were formed and moderately modified during surgery. All of the small flaps were transplanted from donor sites to the defect and reassembled into a new composite flap to repair the ulcer. The donor sites were directly closed. The area of the flaps ranged from 7.0 × 10.5 cm to 8.0 × 22.0 cm and the diameter of the pedicle perforators ranged from 0.5 to 4.0 mm., Results: In 30 patients, 65 flaps were constructed, and all of the flaps survived with direct closure of all donor sites. One case with effusion healed 1 month postoperatively through draining and application of a mild pressure dressing. After a 3-24 months follow-up period, all of the patients were satisfied with post-operative function and appearance, and only one case had a local recurrence 6 months postoperatively., Conclusion: The jigsaw puzzle flap based on freestyle perforators can repair the large skin and soft tissue defects caused by decubitus ulcers on the buttocks, with direct donor flap area closure. This method is easy to perform with a safe blood supply and minimal trauma resulting from the avoidance of microvascular anastomosis and the conventional myocutaneous flap., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Huang, Xiao, An, Su and Yu.)

Non-alcoholic fatty liver disease (NAFLD) held a high global prevalence in recent decades. Hepatic lipid deposition is the major characteristic of NAFLD. We aim to explore the mechanisms of psoralen on lipid deposition in NAFLD. The effects of psoralen on insulin resistance, lipid deposition, the expression and membrane translocation of glucose transporter type 4 (GLUT4), autophagy, and lipogenesis enzymes were determined on sodium oleate-induced L02 cells. Chloroquine and 3-MA were employed. The AMP-activated protein kinase alpha (AMPKα) was knocked down by siRNA. Psoralen alleviated insulin resistance in sodium oleate-induced L02 hepatocytes by upregulating the expression and membrane translocation of GLUT4. Psoralen inhibited lipid accumulation by decreasing the expression of key lipogenesis enzymes. Psoralen promotes autophagy and the autophagic flux to enhance lipolysis. Psoralen promoted the fusion of the autophagosome with the lysosome. Both chloroquine and 3-MA blocked the effects of psoralen on autophagy and lipid accumulation. The AMPKα deficiency attenuated the effects of psoralen on autophagy and lipid accumulation. Our study demonstrated that as an antioxidant, psoralen attenuates NAFLD by alleviating insulin resistance and promoting autophagy via AMPK, suggesting psoralen to be a promising candidate for NAFLD.

As a matrix metalloproteinase, the abnormal expression of MMP2 is associated with multiple biological processes, including tissue remodeling and cancer progression. Therefore, spatial analysis of MMP2 protein in tissues can be used as an important approach to evaluate the expression distribution of MMP2 in complex tissue environments, which will help the diagnosis and treatment of various diseases, including tissue or organ injuries. Moreover, this analysis will also help the evaluation of prognoses. However, MMP2 is difficult to be spatially determined by MALDI TOF mass spectrometry due to its large molecular weight (over 72 KD) and low content. Therefore, a new method should be developed to help this detection. Here, we have designed a specific MMP2 probe that closely binds to MMP2 protein in tissue. This probe has a Cl on Tyr at the terminal, which can provide two isotope peaks to help the accuracy quantitative of MMP2 protein. Based on this, we used the probe to determine the spatial expression of MMP2 in the tissues based on MALDI TOF mass spectrometry. This approach may help to study the influence of multifunctional proteases on the degree of malignancy in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yu, Lai, Yan, Fang, Chen and Zhang.)

Objective: To investigate the effectiveness of free-style perforator flap in repairing the soft tissue defect of knee., Methods: Between December 2011 and October 2017, 13 patients with the soft tissue defects of knees were repaired with the free-style perforator flaps. There were 9 males and 4 females, with an average age of 40 years (range, 14-65 years). The injuries were caused by traffic accident in 7 cases, crushing in 4 cases, and falling from height in 2 cases. The soft tissue defects in 9 cases formed after 2 weeks-2 months (mean, 1 month) of lower extremity fractures fixation. The other 4 cases were urgently admitted to the hospital after injury, and the time from injury to admission was 0.5-18.0 hours (mean, 8 hours). The size of soft tissue defect ranged from 3 cm×2 cm to 12 cm×8 cm after debridement. Nine propeller flaps, 6 rotating flaps, and 2 V-Y advanced flaps were used; and 9 cases were repaired by single flap and 4 cases were repaired by combined flaps. The size of flap ranged from 7.5 cm×2.5 cm to 20.0 cm×6.0 cm. The donor sites were sutured directly., Results: The flaps survived smoothly and incisions healed by first intention in 12 cases. The congestion occurred in 1 case, which obtained delayed healing after symptomatic treatment. All incisions at donor sites healed by first intention. All patients were followed up 3-24 months with an average of 6 months. The shape and motions of knee were satisfactory., Conclusion: The free-style perforator flap can maximize the utilization of the donor area around the knee wound, with reliable blood supply, small trauma, and easy operation. It is an ideal flap for the soft tissue defect of knee.

The present study determined the expression of microRNA (miR)-663 in hypertrophic scar (HS) tissues and investigate the regulatory mechanisms of miR-663 in HS. A total of 51 patients diagnosed with HS between December 2013 and February 2016 were included in the present study. HS tissues (experimental group) and HS-adjacent tissues (control group) were collected. Primary fibroblasts were obtained from HS tissue and transfected with small-interfering RNA against transforming growth factor (TGF)-β1 or miR-663 mimics. Reverse-transcription quantitative PCR was used to determine the levels of TGF-β1 mRNA and miR-663. Western blot analysis was performed to determine TGF-β1 protein expression. An MTT assay was employed to detect the proliferation of fibroblasts, and a dual luciferase reporter assay was performed to identify the binding of miR-663 with TGF-β1 mRNA. TGF-β1 was found to have a regulatory role in HS at the transcriptional level. The expression of TGF-β1 was upregulated in HS tissues, and knockdown of TGF-β1 in cultured fibroblasts led to inhibition of proliferation. The expression of miR-663 was downregulated in HS. miR-663 was revealed to regulate the expression of TGF-β1 by binding with the 3'-untranslated region of TGF-β1 mRNA. Elevated expression of miR-663 inhibited the proliferation of fibroblasts by regulating TGF-β1 expression. The present study demonstrated that upregulation of TGF-β1 in HS tissues is associated with the downregulation of miR-663 expression. miR-663 may regulate the proliferation of fibroblasts in HS and the expression of associated proteins.

Radiation-induced skin injury, which remains a serious concern in radiation therapy, is currently believed to be the result of vascular endothelial cell injury and apoptosis. Here, we established a model of acute radiation-induced skin injury and compared the effect of different vascular growth factors on skin healing by observing the changes of microcirculation and cell apoptosis. Vascular endothelial growth factor (VEGF) was more effective at inhibiting apoptosis and preventing injury progression than other factors. A new strategy for improving the bioavailability of vascular growth factors was developed by loading VEGF with chitosan nanoparticles. The VEGF-chitosan nanoparticles showed a protective effect on vascular endothelial cells, improved the local microcirculation, and delayed the development of radioactive skin damage., Competing Interests: The authors declare no conflict of interest.

Objective: To evaluate the effectiveness of double pedicled flap and technique of geometric broken line (GBL) for primary repair of serious dog bite wound., Methods: Between October 2006 and December 2014, 9 patients with serious dog bite wound were treated. There were 3 males and 6 females with an average age of 34.5 years (range, 8-68 years), and with a mean disease duration of 4 hours (range, 30 minutes to 24 hours). The defect ranged from 1.7 cm×0.5 cm to 15.0 cm×8.0 cm, with the mean depth of 0.5 cm (range, 0.3-0.8 cm). Deep tissue exposure was observed. After routine debridement, a vacuum sealing drainage (VSD) was equipped to suck and irrigate for 1 day, then wound was repaired. The superomedial edge of defect was trimmed, then a GBL shape mainly with square and rectangular was designed. According to defect size, a double pedicled flap was designed at the lateroinferior edge of defect, which size ranged from 1.7 cm×1.5 cm to 18.0 cm×15.0 cm. The donor site was sutured directly. VSD was used for 3 days after operation., Results: All flaps survived and wound healed, and donor site incision healed well, with invisible scar. All patients were followed up 6 months to 8 years (mean, 4 years). The wounds were repaired well, and the patients had good facial appearance. No rabies attack was observed during follow-up., Conclusions: It is an ideal repair method to chose double pedicled flap and technique of GBL for primary repair of dog bite wounds. Satisfactory cosmetic appearance can be obtained.

Objective: To investigate the clinical application of the modified keystone perforator island flap for reconstruction of skin defects at head and face., Methods: From January 2013 to September 2014,13 cases with skin defects at head and face were repaired by modified keystone perforator island flap. The skin defects ranged from 0.8 cm× 1.0 cm to 20.0 cm × 10.0 cm. And the flap size ranged from 1.5 cm × 1.0 cm to 22.0 cm × 12.0 cm. The flap was designed along the edge of the defect, the vascular supply was supported by muscular perforators. In order to relieve suture tension and have a good cosmetic effect, auxiliary incisions should be as less as possible. Flap should be designed to hide parts of facial incision or surgical margins within the natural borders of each facial unit, or along the direction of striae. Incision within the hairline should be taken to minimize damage to the hair follicles. The direction of hair growth shouldn't be changed after the flap transfer., Results: All cases had 1-12 months' follow-up period.12 flaps survived completely, with one partial flap necrosis. The flaps had good appearance with high aesthetic satisfactory., Conclusions: The modified keystone perforator island flap produces excellent aesthetic results. It can be a very useful flap for the individual reconstruction of skin defects at head and face.