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Pneumoconiosis is one of the most serious occupational diseases worldwide. Silicosis due to prolonged inhalation of free silica dust during occupational activities is one of the main types. Cuproptosis is a newly discovered mode of programmed cell death characterized by the accumulation of free copper in the cell, which ultimately leads to cell death. Increased copper in the serum of silicosis patients, suggests that the development of silicosis is accompanied by changes in copper metabolism, but whether cuproptosis is involved in the progression of silicosis is actually to be determined. To test this hypothesis, we screened the genetic changes in patients with idiopathic fibrosis by bioinformatics methods and predicted and functionally annotated the cuproptosis-related genes among them. Subsequently, we established a mouse silicosis model and detected the concentration of copper ions and the activity of ceruloplasmin (CP) in serum, as well as changes of the concentration of copper and cuproptosis related genes in mouse lung tissues. We identified 9 cuproptosis-related genes among the differential genes in patients with IPF at different times and the tissue-specific expression levels of ferredoxin 1 (FDX1) and Lipoyl synthase (LIAS) proteins. Furthermore, serum CP activity and copper ion levels in silicosis mice were elevated on days 7th and 56th after silica exposure. The expression of CP in mouse lung tissue elevated at all stages after silica exposure. The mRNA level of FDX1 decreased on days 7th and 56th, and the protein level remained in accordance with the mRNA level on day 56th. LIAS and Dihydrolipoamide dehydrogenase (DLD) levels were downregulated at all times after silica exposure. In addition, Heatshockprotein70 (HSP70) expression was increased on day 56. In brief, our results demonstrate that there may be cellular cuproptosis during the development of experimental silicosis in mice and show synchronization with enhanced copper loading in mice.
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Cobre , Silicose , Humanos , Animais , Camundongos , Cobre/toxicidade , Silicose/genética , Apoptose , Biologia Computacional , Modelos Animais de Doenças , RNA Mensageiro , Dióxido de Silício/toxicidadeRESUMO
We have previously found that a mixture exposure of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand-receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 µM) or Cd (5 µM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.
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Cádmio , Receptores de Hidrocarboneto Arílico , Receptores de Hidrocarboneto Arílico/metabolismo , Cádmio/toxicidade , Caspase 3/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Piroptose , Éter , Células Epiteliais/metabolismoRESUMO
Regulating the chemical/thermal stability and catalytic activity of coordination polymers (CPs) to achieve high catalytic performance is topical and challenging. The CPs are competent in promoting oxidative cross-coupling, yet they have not received substantial attention. Here, the ligand effect of the secondary ligand of CPs for oxidative cross-coupling reactions was investigated. Specifically, four new isostructural CPs [Co(Fbtx)1.5(4-R-1,2-BDC)]n (denoted as Co-CP-R, Fbtx = 1,4-bis(1,2,4-triazole-1-ylmethyl)-2,3,5,6-tetrafluorobenzene, 4-R-1,2-BDC = 4-R-1,2-benzenedicarboxylate, R = F, Cl, Br, CF3) were prepared. It was found that in the reactions of oxidative amination of benzoxazoles with secondary amines and the oxidative coupling of styrenes with benzaldehydes, both the chemical and thermal stabilities of the four Co-CPs with the R group followed the trend of -CF3 > -Br > -Cl > -F. Density functional theory (DFT) calculations suggested that the difference in reactivity may be ascribed to the effect of substituent groups on the electron transition energy of the cobalt(II) center of these Co-CPs. These findings highlight the secondary ligand effect in regulating the stability and catalytic performance of coordination networks.
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Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising candidates for cell-free therapy in various diseases, including chronic cutaneous wounds. However, the lack of standardized protocols for EVs' preparation and identification poses a significant challenge to their clinical application. Thus, the objective was to develop a safe and efficient method for the large-scale production of hUCMSC-derived EVs while establishing a comprehensive identification protocol encompassing morphology, particle size distribution, protein expression, and purity. This study observed that most of the EVs acquired through the protocol exhibited either a cup-shaped or round-shaped structure, with a median diameter of ~73.25 nm. The proportions of EVs positive for CD9, CD63, and CD81 were 37.5%, 38.6%, and 19.8%, respectively. To enhance their therapeutic potential in wound treatment, EVs were incorporated into chitosan hydrogel, forming chitosan hydrogel-EVs (CS-EVs). Furthermore, it was demonstrated that CS-EVs exhibited continuous release of EVs into the surrounding environment and, importantly, that the released EVs were internalized by human umbilical vein endothelial cells (HUVECs), resulting in significant enhancement of cell migration and angiogenesis. Additionally, in a rat model of diabetic foot ulcers, CS-EVs demonstrated a robust therapeutic effect in promoting wound healing. Following a 15-day treatment period, the group treated with CS-EVs demonstrated an impressive 93.3% wound closure ability, accompanied by a high degree of re-epithelialization. In contrast, the control group exhibited only a 71.5% reduction in wound size. In summary, this study offers solutions for the purification, characterization, and application of EVs in clinical wound treatment. These results not only offer fresh perspectives on the involvement of hUCMSC-derived EVs in wound healing but also introduce a non-invasive approach for applying EVs that holds practical significance in skin repair.
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Quitosana , Diabetes Mellitus , Pé Diabético , Vesículas Extracelulares , Células-Tronco Mesenquimais , Humanos , Animais , Ratos , Pé Diabético/terapia , Hidrogéis , Células Endoteliais da Veia Umbilical HumanaRESUMO
Silicosis caused by long-term inhalation of crystalline silica during occupational activities seriously threatens the health of occupational populations. Imbalances in T helper 1(Th1), Th2, Th17, and regulatory T cells (Tregs) promote the development of pulmonary silicosis. Exosomes and their contents, especially microRNAs (miRNAs), represent a new type of intercellular signal transmission mediator related to various diseases including pulmonary fibrosis. However, whether exosomal miRNAs can affect the progression of silicosis by regulating T cell differentiation remains to be determined. To test this hypothesis, we established a miR-125a-5p antagomir mouse model and examined changes in miR-125a-5p levels and T cell subtypes. We found that miR-125a-5p levels were increased in lung tissues and serum exosomes in the silica group at 7 days and 28 days. Downregulation of miR-125a-5p attenuated α-smooth muscle actin (α-SMA), collagen I, fibronectin, p-p65, and p-inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK) protein expression, while tumor necrosis factor receptor-associated factor 6 (TRAF6) and p-inhibitor of κBα (IKBα) expression were increased. MiR-125a-5p anta-miR treatment contributes to the maintenance of Th1/Th2 balance during the progression of pulmonary fibrosis. Our findings indicated that knockdown miR-125a-5p could regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6.
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Exossomos , MicroRNAs , Fibrose Pulmonar , Dióxido de Silício , Silicose , Animais , Camundongos , Proliferação de Células , MicroRNAs/genética , MicroRNAs/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Dióxido de Silício/toxicidade , Silicose/genética , Silicose/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Exossomos/genética , Exossomos/metabolismoRESUMO
Until now, the specific pathogenesis of silicosis is not clear. Exosomal miRNAs, as a newly discovered intercellular communication medium, play an important role in many diseases. Our previous research found that serum exosomal miR125a-5p was increased in silicosis patients by miRNAs high-throughput sequencing. TRAF6, is a target gene of miR125a-5p, which is involved in T-cell differentiation. Furthermore, results from animal study indicate that knockdown of miR-125a-5p can regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6. However, the level of serum exosomal miR125a-5p in silicosis patients has not been reported, the role of macrophages-secreted exosomal miR-125a-5p in regulating T cell differentiation to promote fibroblast transdifferentiation (FMT) remains unknown. In this study, the levels of serum exosomal miR125a-5p and serum TGF-ß1, IL-17A, IL-4 cytokines in silicosis patients were elevated, with the progression of silicosis, the level of serum exosomal miR125a-5p and serum IL-4 were increased; thus, the serum level of IFN-γ was negatively correlated with the progression of silicosis. In vitro, the levels of miR125a-5p in macrophages, exosomes, and T cells stimulated by silica were significantly increased. When the mimic was transfected into T cells, which directly suppressed TRAF6 and caused the imbalance of T cells differentiation, induced FMT. To sum up, these results indicate that exosomal miR-125a-5p may by targeting TRAF6 of T cells, induces the activation and apoptosis of T cells and the remodeling of Th1/Th2 and Th17/Tregs distribution, ultimately promotes FMT. Suggesting that exosomal miR-125a-5p may be a potential therapeutic target for silicosis.
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MicroRNAs , Silicose , Animais , Humanos , Linfócitos T Reguladores , Dióxido de Silício/toxicidade , Transdiferenciação Celular , Interleucina-4 , Fator 6 Associado a Receptor de TNF , Células Th17 , Silicose/genética , MicroRNAs/genética , FibroblastosRESUMO
OBJECTIVES: Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share many clinical manifestations and serological features. The aim of this study was to identify the common transcriptional profiling and composition of immune cells in peripheral blood in these autoimmune diseases (ADs). METHODS: We analysed bulk RNA-seq data for enrichment of biological processes, transcription factors (TFs) and deconvolution-based immune cell types from peripheral blood mononuclear cells (PBMCs) in 119 treatment-naive patients (41 RA, 38 pSS, 28 SLE and 12 polyautoimmunity) and 20 healthy controls. The single-cell RNA-seq (scRNA-seq) and flow cytometry had been performed to further define the immune cell subsets on PBMCs. RESULTS: Similar transcriptional profiles and common gene expression signatures associated with nucleosome assembly and haemostasis were identified across RA, SLE, pSS and polyautoimmunity. Distinct TF ensembles and gene regulatory network were mainly enriched in haematopoiesis. The upregulated cell-lineage-specific TFs PBX1, GATA1, TAL1 and GFI1B demonstrated a strong gene expression signature of megakaryocyte (MK) expansion. Gene expression-based cell type enrichment revealed elevated MK composition, specifically, CD41b+CD42b+ and CD41b+CD61+ MKs were expanded, further confirmed by flow cytometry in these ADs. In scRNA-seq data, MKs were defined by TFs PBX1/GATA1/TAL1 and pre-T-cell antigen receptor gene, PTCRA. Cellular heterogeneity and a distinct immune subpopulation with functional enrichment of antigen presentation were observed in MKs. CONCLUSIONS: The identification of MK expansion provided new insights into the peripheral immune cell atlas across RA, SLE, pSS and polyautoimmunity. Aberrant regulation of the MK expansion might contribute to the pathogenesis of these ADs.
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Artrite Reumatoide/sangue , Autoimunidade/genética , Lúpus Eritematoso Sistêmico/sangue , Megacariócitos/imunologia , Síndrome de Sjogren/sangue , Adulto , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Leucócitos Mononucleares , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , Síndrome de Sjogren/imunologia , Transcriptoma/imunologiaRESUMO
AIM OF THE STUDY: The aim of the study was to fabricate collagen-based composite dressings, evaluate the efficiency for wound healing and reveal the mechanism of promoting wound healing. MATERIALS AND METHODS: An innovative bi-layered composite wound dressing was developed using two marine biomacromolecules (collagen and chitosan). Full-thickness skin defect model was performed to evaluate the wound healing activity in vivo. The levels of inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL-1, IL-6, IL-8) and growth factors like transforming growth factor beta (TGF-ß), vascular epidermal growth factor (VEGF) and basic fibroblast growth factor (bFGF) were quantified by ELISA assays. The total amount of collagen was quantified by hydroxyproline content. The proliferation and viability of fibroblast cells cultured on collagen sponges were determined by CCK-8 assay. RESULTS: The results of wound closure and histopathological analysis indicated that non-crosslinked collagen-based bi-layered composite dressing stimulated wound healing, accelerated re-epithelialization and accomplished wound healing within a time span of 28 days. The results of levels of inflammatory cytokines and growth factors showed that collagen-based composite dressings could reduce the inflammatory response and upregulate growth factors levels to accelerate the wound healing. The results of hydroxyproline content and CCK-8 assay indicated that collagen-based composite dressings could also promote collagen synthesis and fibroblasts viability and proliferation. CONCLUSION: The non-crosslinked collagen-based bi-layered composite dressing could be applied for an efficient and ideal wound dressing. Therefore, the findings provided the essential theoretical basis for the potential of collagen-based composite dressing applied in wound healing fields.
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Bandagens , Cicatrização , Colágeno , Reepitelização , PeleRESUMO
OBJECTIVES: Familial aggregation of primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and co-aggregation of these autoimmune diseases (ADs) (also called familial autoimmunity) is well recognised. However, the genetic predisposition variants that explain this clustering remains poorly defined. METHODS: We used whole-exome sequencing on 31 families (9 pSS, 11 SLE, 6 RA and 5 mixed autoimmunity), followed by heterozygous filtering and cosegregation analysis of a family-focused approach to document rare variants predicted to be pathogenic by in silico analysis. Potential importance in immune-related processes, gene ontology, pathway enrichment and overlap analyses were performed to prioritise gene sets. RESULTS: A range from 1 to 50 rare possible pathogenic variants, including 39 variants in immune-related genes across SLE, RA and pSS families, were identified. Among this gene set, regulation of T cell activation (p=4.06×10-7) and T cell receptor (TCR) signalling pathway (p=1.73×10-6) were particularly concentrated, including PTPRC (CD45), LCK, LAT-SLP76 complex genes (THEMIS, LAT, ITK, TEC, TESPA1, PLCL1), DGKD, PRKD1, PAK2 and NFAT5, shared across 14 SLE, RA and pSS families. TCR-interactive genes P2RX7, LAG3, PTPN3 and LAX1 were also detected. Overlap analysis demonstrated that the antiviral immunity gene DUS2 variant cosegregated with SLE, RA and pSS phenotypes in an extended family, that variants in the TCR-pathway genes CD45, LCK and PRKD1 occurred independently in three mixed autoimmunity families, and that variants in CD36 and VWA8 occurred in both RA-pSS and SLE-pSS families. CONCLUSIONS: Our preliminary results define common genetic characteristics linked to familial pSS, SLE and RA and highlight rare genetic variations in TCR signalling pathway genes which might provide innovative molecular targets for therapeutic interventions for those three ADs.
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Artrite Reumatoide/genética , Autoimunidade/genética , Mutação em Linhagem Germinativa/imunologia , Lúpus Eritematoso Sistêmico/genética , Síndrome de Sjogren/genética , Linfócitos T/imunologia , Artrite Reumatoide/imunologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Síndrome de Sjogren/imunologiaRESUMO
Reflection loss can cause harmful effects on the performance of optoelectronic devices, such as cell phones, notebooks, displays, solar cells, and light-emitting diode (LED) devices. In order to obtain broadband antireflection (AR) properties, many researchers have utilized surface texture techniques to produce AR subwavelength structures on the interfaces. Among the AR subwavelength structures, the moth-eye nanostructure is one of the most promising structures, with the potential for commercialization in the near future. In this research, to obtain broadband AR performance, the optimization of moth-eye nanostructures was first carried out using the finite difference time domain method within the spectral ranges of 400-800 nm, including the optimization of shape, height, pitch, and residual layer thickness. In addition, the continuous production of moth-eye nanostructure array upon a flexible polyethylene terephthalate substrate was demonstrated by using the roll-to-roll ultraviolet nanoimprint lithography (R2R UV-NIL) process and anodic aluminum oxide mold, which provided a solution for the cost-effective fabrication of moth-eye nanostructure array. The AR performance of moth-eye nanostructure array obtained by the R2R UV-NIL process was also investigated experimentally, and good consistence was shown with the simulated results. This research can provide a beneficial direction for the optimization and cost-effective production of the moth-eye nanostructure array.
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Materiais Biomiméticos , Olho/ultraestrutura , Luz , Mariposas/anatomia & histologia , Nanoestruturas/ultraestrutura , Polietilenotereftalatos , Espalhamento de Radiação , Animais , Análise Custo-Benefício , Desenho de Equipamento , Microscopia de Força Atômica , Dispositivos Ópticos , Refração Ocular , Propriedades de SuperfícieRESUMO
Base editors, developed from the CRISPR/Cas system, consist of components such as deaminase and Cas variants. Since their emergence in 2016, the precision, efficiency, and safety of base editors have been gradually optimized. The feasibility of using base editors in gene therapy has been demonstrated in several disease models. Compared with the CRISPR/Cas system, base editors have shown great potential in hematopoietic stem cells (HSCs) and HSC-based gene therapy, because they do not generate double-stranded breaks (DSBs) while achieving the precise realization of single-base substitutions. This precise editing mechanism allows for the permanent correction of genetic defects directly at their source within HSCs, thus promising a lasting therapeutic effect. Recent advances in base editors are expected to significantly increase the number of clinical trials for HSC-based gene therapies. In this review, we summarize the development and recent progress of DNA base editors, discuss their applications in HSC gene therapy, and highlight the prospects and challenges of future clinical stem cell therapies.
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Sistemas CRISPR-Cas , Edição de Genes , Terapia Genética , Doenças Hematológicas , Células-Tronco Hematopoéticas , Humanos , Terapia Genética/métodos , Edição de Genes/métodos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Doenças Hematológicas/terapia , Doenças Hematológicas/genética , Sistemas CRISPR-Cas/genética , Animais , Transplante de Células-Tronco HematopoéticasRESUMO
Flexible strain sensors have been widely researched in fields such as smart wearables, human health monitoring, and biomedical applications. However, achieving a wide sensing range and high sensitivity of flexible strain sensors simultaneously remains a challenge, limiting their further applications. To address these issues, a cross-scale combinatorial bionic hierarchical design featuring microscale morphology combined with a macroscale base to balance the sensing range and sensitivity is presented. Inspired by the combination of serpentine and butterfly wing structures, this study employs three-dimensional printing, prestretching, and mold transfer processes to construct a combinatorial bionic hierarchical flexible strain sensor (CBH-sensor) with serpentine-shaped inverted-V-groove/wrinkling-cracking structures. The CBH-sensor has a high wide sensing range of 150% and high sensitivity with a gauge factor of up to 2416.67. In addition, it demonstrates the application of the CBH-sensor array in sign language gesture recognition, successfully identifying nine different sign language gestures with an impressive accuracy of 100% with the assistance of machine learning. The CBH-sensor exhibits considerable promise for use in enabling unobstructed communication between individuals who use sign language and those who do not. Furthermore, it has wide-ranging possibilities for use in the field of gesture-driven interactions in human-computer interfaces.
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Aprendizado de Máquina , Língua de Sinais , Humanos , Biônica , Dispositivos Eletrônicos Vestíveis , Gestos , Impressão TridimensionalRESUMO
Flexible strain sensors have been continuously optimized and widely used in various fields such as health monitoring, motion detection, and human-machine interfaces. There is a higher demand for sensors that can sensitively identify both the strain amplitude and direction in real-time to adapt to complex human movements. This study proposes a flexible strain sensor construction strategy based on V-groove/wrinkle hierarchical structures via a facile and scalable prestretching approach. A gold film is sputtered on a V-groove structure soft substrate under a vertical biaxial prestrain. When the strain is released, a variety of wondrous V-groove/wrinkle hierarchical structures are formed. The microstructure and the properties of the resulting sensor can be controlled by adjusting the prestrain, which has obvious anisotropic response characteristics and exhibits high sensitivity (maximum gauge factor up to 20,727.46) and a wide sensing range (up to 51%). In addition, the resulting multidirectional sensor based on double-sided microstructures has an exceptional directional selectivity of 67.39, at an advanced level among all stretchable multidirectional strain sensors reported so far. The sensor can detect human motion signals and distinguish motion patterns, proving its great potential in the field of human motion detection and laying a foundation for high-performance wearable devices.
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Chemical molecular structures are a direct and convenient means of expressing chemical knowledge, playing a vital role in academic communication. In chemistry, hand drawing is a common task for students and researchers. If we can convert hand-drawn chemical molecular structures into machine-readable formats, like SMILES encoding, computers can efficiently process and analyze these structures, significantly enhancing the efficiency of chemical research. Furthermore, with the progress of educational technology, automated grading is gaining popularity. When machines automatically recognize chemical molecular structures and assess the correctness of the drawings, it offers great convenience to teachers. We created ChemReco, a tool designed to identify chemical molecular structures involving three atoms: C, H, and O, providing convenience for chemical researchers. Currently, there are limited studies on hand-drawn chemical molecular structures. Therefore, the primary focus of this paper is constructing datasets. We propose a synthetic image method to rapidly generate images resembling hand-drawn chemical molecular structures, enhancing dataset acquisition efficiency. Regarding model selection, the hand-drawn chemical molecule structural recognition model developed in this article achieves a final recognition accuracy of 96.90%. This model employs the encoder-decoder architecture of EfficientNet + Transformer, demonstrating superior performance compared to other encoder-decoder combinations.
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Polymer modification using silicone rubber represents a promising avenue for enhancing physico-mechanical properties. However, achieving optimal performance through direct blending is hindered by the poor interface compatibility between silicone rubber and the matrix. In this study, we prepared super-tough thermoplastic vulcanizates (TPVs) of polylactic acid/silicone rubber through dynamic vulcanization with PLA, methyl vinyl silicone rubber (MVQ), glycidyl methacrylate grafted MVQ (MVQ-g-GMA), and fumed silica nanoparticles (SiO2). The impact of the SiO2 addition in MVQ on the morphology, mechanical properties, crystallization, and thermal properties of the TPVs was investigated. The results showed that MVQ-g-GMA and SiO2 exhibited a synergistic compatibilization effect significantly improving the interfacial adhesion between PLA and MVQ. Therefore, the impact and tensile strength of the TPVs increased from 8.0 kJ/m2 and 22.2 MPa to 62.6 kJ/m2 and 36.7 MPa, respectively. Moreover, the TPVs also presented good low-temperature toughness with a maximum impact strength of 40.4 kJ/m2 at -20 °C. Additionally, improvements in thermal stability and crystallization rate were also observed. Overall, combining organic and inorganic synergistic compatibilization is a feasible and effective method to fabricate outstanding low-temperature toughness to PLA.
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Dióxido de Silício , Elastômeros de Silicone , Poliésteres , PolímerosRESUMO
Silicosis is one of the most common and severe types of pneumoconiosis and is characterized by lung dysfunction, persistent lung inflammation, pulmonary nodule formation, and irreversible pulmonary fibrosis. The transdifferentiation of fibroblasts into myofibroblasts is one of the main reasons for the exacerbation of silicosis. However, the underlying mechanism of transcription factors regulating silicosis fibrosis has not been clarified. The aim of this study was to investigate the potential mechanism of transcription factor FOXF1 in fibroblast transdifferentiation in silica-induced pulmonary fibrosis. Therefore, a silicosis mouse model was established, and we found that FOXF1 expression level was significantly down-regulated in the silicosis group, and after overexpression of FOXF1 by adeno-associated virus (AAV), FOXF1 expression level was up-regulated, and silicosis fibrosis was alleviated. In order to further explore the specific regulatory mechanism of FOXF1 in silicosis, we established a fibroblasts transdifferentiation model induced by TGF-ß in vitro. In the model, the expression levels of SMAD2/3 and P-SMAD2/3 were up-regulated, but the expression levels of SMAD2/3 and P-SMAD2/3 were down-regulated, inhibiting transdifferentiation and accumulation of extracellular matrix after the overexpressed FOXF1 plasmid was constructed. However, after silencing FOXF1, the expression levels of SMAD2/3 and P-SMAD2/3 were further up-regulated, aggravating transdifferentiation and accumulation of extracellular matrix. These results indicate that the activation of FOXF1 in fibroblasts can slow down the progression of silicosis fibrosis by inhibiting TGF-ß/SMAD2/3 classical pathway, which provides a new idea for further exploration of silicosis treatment.
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Transdiferenciação Celular , Fibroblastos , Fibrose Pulmonar , Transdução de Sinais , Silicose , Fator de Crescimento Transformador beta , Animais , Humanos , Masculino , Camundongos , Transdiferenciação Celular/genética , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/citologia , Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Pulmão/patologia , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Dióxido de Silício , Silicose/complicações , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Gastric cancer (GC) is one of the main causes of cancer-related death. Lysine acetyltransferases 2 A (KAT2A) is a succinyltransferase that plays an essential role in cancer development. The pyruvate kinase M2 (PKM2) is a glycolysis rate-limiting enzyme that mediates the glycolysis of cancers. This study aimed to explore the effects and mechanism of KAT2A in GC progression. The effects of biological behaviors of GC cells were evaluated by MTT, colony formation and seahorse assays. The succinylation modification was assessed by immunoprecipitation (IP). The interaction between proteins were detected by Co-IP and immunofluorescence. A pyruvate kinase activity detection kit was used to evaluate the activity of PKM2. Western blot was performed to detect the expression and oligomerization of protein. Herein, we confirmed that KAT2A was highly expressed in GC tissues and was associated with a poor prognosis. Function studies showed that knockdown of KAT2A inhibited cell proliferation and glycolytic metabolism of GC. Mechanistically, KAT2A could directly interacted with PKM2 and KAT2A silencing inhibited the succinylation of PKM2 at K475 site. In addition, the succinylation of PKM2 altered its activity rather than its protein levels. Rescue experiments showed that KAT2A promoted GC cell growth, glycolysis, and tumor growth by promoting PKM2 K475 succinylation. Taken together, KAT2A promotes the succinylation of PKM2 at K475 to inhibit PKM2 activity, thus promotes the progression of GC. Therefore, targeting KATA2 and PKM2 may provide novel strategies for the treatment of GC.
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ABSTRACT: Blast lung injuries (BLIs) are frequent because of industrial accidents and terrorist groups. Bone marrow mesenchymal stem cells (BMSCs) and exosomes derived from BMSCs (BMSCs-Exo) have become a hot topic in modern biology because of their significance in damage healing, immune regulation, and gene therapy. The aim of this study is to investigate the effect of BMSCs and BMSCs-Exo on BLI in rats caused by gas explosion. Here, BMSCs and BMSCs-Exo were transplanted into BLI rats via tail vein and then evaluated pathological alterations, oxidative stress, apoptosis, autophagy, and pyroptosis in the lung tissue. Through histopathology and changes in malondialdehyde (MDA) and superoxide dismutase (SOD) contents, we discovered that oxidative stress and inflammatory infiltration in the lungs were significantly reduced by BMSCs and BMSCs-Exo. After treatment with BMSCs and BMSCs-Exo, apoptosis-related proteins, such as cleaved caspase-3 and Bax, were significantly decreased, and the ratio of Bcl-2/Bax was significantly increased; the level of pyroptosis-associated proteins, including NLRP3, GSDMD-N, cleaved caspase-1, IL-1ß, and IL-18, were decreased; autophagy-related proteins, beclin-1 and LC3, were downregulated while P62 was upregulated; the number of autophagosomes was decreased. In summary, BMSCs and BMSCs-Exo attenuate BLI caused by gas explosion, which may be associated with apoptosis, aberrant autophagy, and pyroptosis.
Assuntos
Exossomos , Lesão Pulmonar , Células-Tronco Mesenquimais , Humanos , Lesão Pulmonar/metabolismo , Proteína X Associada a bcl-2/metabolismo , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , ApoptoseRESUMO
BACKGROUND: We performed a bioinformatics analysis to screen for cell cycle-related differentially expressed genes (DEGs) and constructed a model for the prognostic prediction of patients with early-stage lung squamous cell carcinoma (LSCC). METHODS: From a gene expression omnibus (GEO) database, the GSE157011 dataset was randomly divided into an internal training group and an internal testing group at a 1:1 ratio, and the GSE30219, GSE37745, GSE42127, and GSE73403 datasets were merged as the external validation group. We performed single-sample gene set enrichment analysis (ssGSEA), univariate Cox analysis, and difference analysis, and identified 372 cell cycle-related genes. Additionally, we combined LASSO/Cox regression analysis to construct a prognostic model. Then, patients were divided into high-risk and low-risk groups according to risk scores. The internal testing group, discovery set, and external verification set were used to assess model reliability. We used a nomogram to predict patient prognoses based on clinical features and risk values. Clinical relevance analysis and the Human Protein Atlas (HPA) database were used to verify signature gene expression. RESULTS: Ten cell cycle-related DEGs (EIF2B1, FSD1L, FSTL3, ORC3, HMMR, SETD6, PRELP, PIGW, HSD17B6, and GNG7) were identified and a model based on the internal training group constructed. From this, patients in the low-risk group had a higher survival rate when compared with the high-risk group. Time-dependent receiver operating characteristic (tROC) and Cox regression analyses showed the model was efficient and accurate. Clinical relevance analysis and the HPA database showed that DEGs were significantly dysregulated in LSCC tissue. CONCLUSION: Our model predicted the prognosis of early-stage LSCC patients and demonstrated potential applications for clinical decision-making and individualized therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Proteínas Relacionadas à Folistatina , Neoplasias Pulmonares , Humanos , Prognóstico , Reprodutibilidade dos Testes , Carcinoma de Células Escamosas/genética , Ciclo Celular , Neoplasias Pulmonares/genética , Pulmão , Proteínas MetiltransferasesRESUMO
Society and consumers are increasingly concerned about food safety and the sustainability of food production systems. A significant amount of by-products and discards are generated during the processing of aquatic animals, which still needs to be fully utilized by the food industry. The management and sustainable use of these resources are essential to avoiding environmental pollution and resource waste. These by-products are rich in biologically active proteins, which can be converted into peptides by enzymatic hydrolysis or fermentation treatment. Therefore, exploring the extraction of collagen peptides from these by-products using an enzymatic hydrolysis technology has attracted a wide range of attention from numerous researchers. Collagen peptides have been found to possess multiple biological activities, including antioxidant, anticancer, antitumor, hypotensive, hypoglycemic, and anti-inflammatory properties. These properties can enhance the physiological functions of organisms and make collagen peptides useful as ingredients in food, pharmaceuticals, or cosmetics. This paper reviews the general methods for extracting collagen peptides from various processing by-products of aquatic animals, including fish skin, scales, bones, and offal. It also summarizes the functional activities of collagen peptides as well as their applications.