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The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.
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Morte Celular , Inflamação , Fator Regulador 1 de Interferon , Processamento de Proteína Pós-Traducional , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Humanos , Morte Celular/efeitos da radiação , Inflamação/patologia , Animais , Camundongos , SARS-CoV-2 , COVID-19/imunologia , Fosforilação , Radiação Ionizante , Células HEK293 , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Sinais de Localização Nuclear , Ativação TranscricionalRESUMO
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.
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Infected diabetic wound (DW) presents a prolonged and challenging healing process within the field of regenerative medicine. The effectiveness of conventional drug therapies is hindered by their limited ability to reach deep tissues and promote adequate wound healing rates. Therefore, there is an imperative to develop drug delivery systems that can penetrate deep tissues while exhibiting multifunctional properties to expedite wound healing. In this study, w e devised a soluble microneedle (MN) patch made of γ-PGA, featuring multiple arrays, which w as loaded with core-shell structured nanoparticles (NPs) known as Ag@MSN@CeO2, to enhance the healing of infected DWs. The NP comprises a cerium dioxide (CeO2) core with anti-inflammatory and antioxidant properties, a mesoporous silica NP (MSN) shell with angiogenic characteristics, and an outermost layer doped with Ag to combat bacterial infections. W e demonstrated that the MN platform loaded with Ag@MSN@CeO2 successfully penetrated deep tissues for effective drug delivery. These MN tips induced the formation of multiple regenerative sites at various points, leading to antibacterial, reactive oxygen species-lowering, macrophage ecological niche-regulating, vascular regeneration-promoting, and collagen deposition-promoting effects, thus significantly expediting the healing process of infected DWs. Considering these findings, the multifunctional MN@Ag@MSN@CeO2 patch exhibits substantial potential for clinical applications in the treatment of infected DW.
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Cério , Nanocompostos , Cicatrização , Cicatrização/efeitos dos fármacos , Nanocompostos/química , Animais , Cério/química , Cério/farmacologia , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Agulhas , Prata/química , Prata/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Dióxido de Silício/química , Espécies Reativas de Oxigênio/metabolismo , HumanosRESUMO
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.
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Inflamação , Pele , Animais , Pele/metabolismo , Pele/efeitos da radiação , Pele/efeitos dos fármacos , Ratos , Inflamação/metabolismo , Protetores contra Radiação/farmacologia , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genética , Peptídeos/farmacologia , Peptídeos/metabolismo , Ranidae/metabolismo , Modelos Animais de Doenças , Cicatrização/efeitos dos fármacos , Anuros/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genéticaRESUMO
Ultraviolet (UV) radiation is ubiquitous in the environment, which has been classified as an established human carcinogen. As the largest and outermost organ of the body, direct exposure of skin to sunlight or UV radiation can result in sunburn, inflammation, photo-immunosuppression, photoaging and even skin cancers. To date, there are tactics to protect the skin by preventing UV radiation and reducing the amount of UV radiation to the skin. Nevertheless, deciphering the essential regulatory mechanisms may pave the way for therapeutic interventions against UV-induced skin disorders. Additionally, UV light is considered beneficial for specific skin-related conditions in medical UV therapy. Recent evidence indicates that the biological effects of UV exposure extend beyond the skin and include the treatment of inflammatory diseases, solid tumors and certain abnormal behaviors. This review mainly focuses on the effects of UV on the skin. Moreover, novel findings of the biological effects of UV in other organs and systems are also summarized. Nevertheless, the mechanisms through which UV affects the human organism remain to be fully elucidated to achieve a more comprehensive understanding of its biological effects.
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Dermatopatias , Neoplasias Cutâneas , Humanos , Raios Ultravioleta/efeitos adversos , Pele , Luz Solar , Neoplasias Cutâneas/prevenção & controle , Dermatopatias/etiologiaRESUMO
The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.
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Células-Tronco Mesenquimais , Superóxido Dismutase , Camundongos , Humanos , Animais , Diferenciação Celular , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Adipócitos , Células-Tronco Mesenquimais/metabolismoRESUMO
OBJECTIVE: 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. METHODS: 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. RESULTS: 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-ß-muricholic acid (Tß-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. CONCLUSIONS: Ionizing radiation modulates the metabolism of BAs. DCA is a prospective therapeutic agent for the treatment of RSI.
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Ácidos e Sais Biliares , Metabolismo dos Lipídeos , Humanos , Ratos , Animais , Ratos Sprague-Dawley , Ácido Desoxicólico/farmacologia , Radiação IonizanteRESUMO
Human skin is daily exposed to oxidative stresses in the environment such as physical stimulation, chemical pollutants and pathogenic microorganisms, which are likely to cause skin diseases. As important post-translational modifications, protein ubiquitination and deubiquitination play crucial roles in maintaining cellular homeostasis by the proteolytic removal of oxidized proteins. We have previously reported that the expression of ubiquitin-specific protease 47 (USP47), a kind of deubiquitinating enzymes (DUBs), was significantly elevated in response to oxidative stress. However, the role of USP47 in cutaneous oxidative injury remains unclear. Usp47 wild-type (Usp47+/+) mice and Usp47 knockout (Usp47-/-) mice were used to establish two animal models of oxidative skin damage: (1) radiation- and (2) imiquimod (IMQ)-induced skin injury. Loss of Usp47 consistently aggravated mouse skin damage in vivo. Subsequently, we screened 63 upregulated and 170 downregulated proteins between the skin tissues of wild-type and Usp47-/- mice after 35 Gy electron beam radiation using proteomic analysis. Among the dysregulated proteins, nicotinamide nucleotide transhydrogenase (NNT), which has been reported as a significant regulator of oxidative stress and redox homeostasis, was further investigated in detail. Results showed that NNT was regulated by USP47 through direct ubiquitination mediated degradation and involved in the pathogenesis of cutaneous oxidative injury. Knockdown of NNT expression dramatically limited the energy production ability, with elevated mitochondrial reactive oxygen species (ROS) accumulation and increased mitochondrial membrane potential in irradiated HaCaT cells. Taken together, our present findings illustrate the critical role of USP47 in oxidative skin damage by modulating NNT degradation and mitochondrial homeostasis.
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NADP Trans-Hidrogenases , Animais , Humanos , Camundongos , Mitocôndrias/metabolismo , NADP Trans-Hidrogenases/metabolismo , Estresse Oxidativo/fisiologia , Proteômica , Proteases Específicas de Ubiquitina/metabolismoRESUMO
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.
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Queimaduras , Sepse , Humanos , Sepse/genética , Ativação Transcricional , Coagulação Sanguínea , Queimaduras/genética , Progressão da Doença , Biologia ComputacionalRESUMO
Binary metallic nanocrystals are attractive as they offer an extra degree of freedom for structure and phase modulation to generate synergistic effects and extraordinary properties. However, whether the binary structures and phases at the nanoscale still follow the rules established on the bulk counterparts remains unclear. In this work, AuAg nanorods were used as a sample to probe into this issue. An in situ heating method by combining aberration-corrected transmission electron microscopes with a chip-based heating holder was employed to perform the heating experiments. It was found that the AuAg nanorods, which initially possessed heterostructures, can be designed and engineered to be gradient phase alloys with thermal pulses over 350 °C. Atomic diffusion inside the rod structures did not alter the shape of the rods but provided a route to fine-tune their properties. At higher temperatures, the discrepant sublimation behaviours between Au and Ag lead to dealloying of the nanorods. Durative sublimation of the Ag element can continuously tailor the lengths of the nanorods while concentrating the Au composition simultaneously. Especially, nearly pure Au nanocrystals can be obtained with the depletion of Ag by sublimation. These findings give insights into the nanoscale structure and phase behaviours in binary alloys and provide an alternative way to fine-tune their structure, phase, and properties.
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PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Queloide , Humanos , Queloide/radioterapia , Queloide/genética , Queloide/metabolismo , Apoptose , RNA Mensageiro/metabolismo , Senescência Celular , Radiação Ionizante , Fibroblastos/efeitos da radiação , Células Cultivadas , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismoRESUMO
Background: Radiation-induced skin injury (RISI) is still the most common and severe side effect of radiotherapy. The role of the skin's microbial barrier in the pathogenesis and progression of RISI needs to be fully investigated. Methods: This study aimed to explore the alterations in and functions of the skin microbiota in RISI. We applied the unculturable approach to characterize the cutaneous microbiomes of a radiation-induced animal model by sequencing the V1-V3 regions of the 16S ribosomal RNA (rRNA) gene. Combined with the downloaded clinical data of patients, a comprehensive analysis was performed to identify potential radioprotective species and metabolic pathways. Results: There were no significant differences in the alpha diversity indices (Sobs, Shannon, Simpson, Ace, and Chao) between the acute radiation injury and control groups. Phylum-level analysis of the RISI microbiomes exhibited significant predominance of Firmicutes (mean abundance = 67%, corrected p = 0.0035). The high abundance of Firmicutes was significantly associated with rapid healing of RISI (average relative abundance = 52%; Kruskal-Wallis: p = 5.7E-4). Among its members, Streptococcus, Staphylococcus, Acetivibrio ethanolgignens group, Peptostreptococcus, Anaerofilum, and UCG-002 [linear discriminant analysis (LDA) > 3, p < 0.05] were identified as the core genera of Firmicutes. In addition, Lachnosiraceae and Lactobacillus occupied an important position in the interaction network (r > 0.6, p < 0.05). The differential metabolic pathways of RISI were mainly associated with carbohydrate metabolism (butanoate and propanoate metabolism), amino acid metabolism (tryptophan and histidine metabolism), energy metabolism, and lipid metabolism (fatty acid degradation and biosynthesis). Conclusion: This study provides new insights into the potential mechanism and skin microbial changes in the progression of RISI. The overwhelming predominance of members of Firmicutes, including Streptococcaceae, Staphylococcaceae, Lachnospiraceae, and Lactobacillus, is potentially related to rapid healing of RISI. The microbiota-metabolite axis plays a critical role in RISI and provides promising therapeutic targets for the treatment of adverse side effects.
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Microbiota , Lesões por Radiação , Animais , Pele , Radiação Ionizante , Cicatrização , Firmicutes , LactobacillusRESUMO
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.
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Fosfatidilinositol 3-Quinases , Úlcera Cutânea , Humanos , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Simulação de Acoplamento Molecular , Reprodutibilidade dos Testes , Úlcera , Transdução de SinaisRESUMO
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.
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Background: Infantile hemangiomas (IH) and venous malformations (VM) are the most common types of vascular abnormalities that seriously affect the health of children. Although there is evidence that these two diseases share some common genetic changes, the underlying mechanisms need to be further studied. Methods: The microarray datasets of IH (GSE127487) and VM (GSE7190) were downloaded from GEO database. Extensive bioinformatics methods were used to investigate the common differentially expressed genes (DEGs) of IH and VM, and to estimate their Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Trough the constructing of protein-protein interaction (PPI) network, gene models and hub genes were obtained by using Cytoscape and STRING. Finally, we analyzed the co-expression and the TF-mRNA-microRNA regulatory network of hub genes. Results: A total of 144 common DEGs were identified between IH and VM. Functional analysis indicated their important role in cell growth, regulation of vasculature development and regulation of angiogenesis. Five hub genes (CTNNB1, IL6, CD34, IGF2, MAPK11) and two microRNA (has-miR-141-3p, has-miR-150-5p) were significantly differentially expressed between IH and normal control (p < 0.05). Conclusion: In conclusion, our study investigated the common DEGs and molecular mechanism in IH and VM. Identified hub genes and signaling pathways can regulate both diseases simultaneously. This study provides insight into the crosstalk of IH and VM and obtains several biomarkers relevant to the diagnosis and pathophysiology of vascular abnormalities.
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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.
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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.
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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.
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Carcinoma de Células Escamosas , Ferroptose , MicroRNAs , Neoplasias Cutâneas , Trifosfato de Adenosina , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Ferroptose/genética , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro , Neoplasias Cutâneas/genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
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.
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Diabetes Mellitus , Pé Diabético , Doença Arterial Periférica , Biologia Computacional , Mineração de Dados , Pé Diabético/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Doença Arterial Periférica/genética , Qualidade de VidaRESUMO
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.