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High-mobility group AT-hook 2 (HMGA2) is rearranged in various types of mesenchymal tumors, particularly lipomas. HMGA2 is also co-amplified with mouse double minute 2 (MDM2) in well-differentiated liposarcoma/dedifferentiated liposarcoma (WDLPS/DDLPS). We report a case of relapsed DDLPS with a novel in-frame fusion between HMGA2 and KITLG, which encodes the ligand for KIT kinase, a critical protein involved in gametogenesis, hematopoiesis, and melanogenesis. The HMGA2 breakpoint is in intron 3, a commonly observed location for HMGA2 rearrangements, while the KITLG breakpoint is in intron 2, leading to a fusion protein that contains almost the entire coding sequence of KITLG. By immunohistochemical staining, tumor cells expressed KIT and showed phosphorylated MAPK, a major KIT downstream target. We suggest an oncogenic mechanism that involves the overexpression of KITLG caused by its rearrangement with HMGA2, leading to the constitutive activation of KIT kinase. While MDM2 amplification was observed in both the primary tumor and the relapsed tumor, the HMGA2::KITLG was only present in the relapsed tumor, indicating the role of HMGA2::KITLG in disease progression.
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Lipoma , Lipossarcoma , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Humanos , Animais , Camundongos , Lipossarcoma/genética , Lipossarcoma/patologia , Lipoma/genética , Lipoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Amplificação de GenesRESUMO
Developing efficient water-splitting electrocatalysts to accelerate the slow oxygen evolution reaction (OER) kinetics is urgently desired for hydrogen production. Herein, ultralow phosphorus (P)-doped NiFe LDH (NiFePx LDH) with mild compressive strain is synthesized as an efficient OER electrocatalyst. Remarkably, NiFePx LDH with the phosphorus mass ratio of 0.32 wt.% and compressive strain ratio of 2.53% (denoted as NiFeP0.32 LDH) exhibits extraordinary OER activity with an overpotential as low as 210 mV, which is superior to that of commercial IrO2 and other reported P-based OER electrocatalysts. Both experimental performance and density function theory (DFT) calculation demonstrate that the doping of P atoms can generate covalent FeâP coordination bonds and lattice distortion, thus resulting in the consequent depletion of electrons around the Fe active center and the downward shift of the d-band center, which can lead to a weaker adsorption ability of *O intermediate to improve the catalytic performance of NiFeP0.32 LDH for OER. This work provides novel insights into the distinctive coordinated configuration of P in NiFePx LDH, which can result in superior catalytic performance for OER.
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BACKGROUND: Chronic inflammation and fibrosis are characteristics of silicosis, and the inflammatory mediators involved in silicosis have not been fully elucidated. Recently, macrophage-derived exosomes have been reported to be inflammatory modulators, but their role in silicosis has not been explored. The purpose of the present study was to investigate the role of macrophage-derived exosomal high mobility group box 3 (HMGB3) in silica-induced pulmonary inflammation. METHODS: The induction of the inflammatory response and the recruitment of monocytes/macrophages were evaluated by immunofluorescence, flow cytometry and transwell assays. The expression of inflammatory cytokines was examined by RT-PCR and ELISA, and the signalling pathways involved were examined by western blot analysis. RESULTS: HMGB3 expression was increased in exosomes derived from silica-exposed macrophages. Exosomal HMGB3 significantly upregulated the expression of inflammatory cytokines, activated the STAT3/MAPK (ERK1/2 and p38)/NF-κB pathways in monocytes/macrophages, and promoted the migration of these cells by CCR2. CONCLUSIONS: Exosomal HMGB3 is a proinflammatory modulator of silica-induced inflammation that promotes the inflammatory response and recruitment of monocytes/macrophages by regulating the activation of the STAT3/MAPK/NF-κB/CCR2 pathways.
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Pneumonia , Silicose , Humanos , Dióxido de Silício/toxicidade , Dióxido de Silício/metabolismo , NF-kappa B/metabolismo , Macrófagos/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Citocinas/genética , Citocinas/metabolismoRESUMO
BACKGROUND: Many medical graduate students lack a thorough understanding of decision curve analysis (DCA), a valuable tool in clinical research for evaluating diagnostic models. METHODS: This article elucidates the concept and process of DCA through the lens of clinical research practices, exemplified by its application in diagnosing liver cancer using serum alpha-fetoprotein levels and radiomics indices. It covers the calculation of probability thresholds, computation of net benefits for each threshold, construction of decision curves, and comparison of decision curves from different models to identify the one offering the highest net benefit. RESULTS: The paper provides a detailed explanation of DCA, including the creation and comparison of decision curves, and discusses the relationship and differences between decision curves and receiver operating characteristic curves. It highlights the superiority of decision curves in supporting clinical decision-making processes. CONCLUSION: By clarifying the concept of DCA and highlighting its benefits in clinical decisionmaking, this article has improved researchers' comprehension of how DCA is applied and interpreted, thereby enhancing the quality of research in the medical field.
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Técnicas de Apoio para a Decisão , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/diagnóstico , Tomada de Decisão Clínica , Curva ROC , alfa-Fetoproteínas/análise , alfa-Fetoproteínas/metabolismo , Pesquisa BiomédicaRESUMO
Pseudomyogenic hemangioendothelioma (PHE) is a rare angiogenic tumor. Histologically, the morphological characteristics of neoplastic vessels and endothelial differentiation are not obvious, and it is easy to be confused with epithelioid sarcoma, epithelioid hemangioendothelioma and myogenic tumor. PHE usually occurs in arms and legs in young people and has a significant male predominance. The tumor has a predilection for the distal extremities and its typical manifestation is multiple center invasion of a single limb, which can involve all layers of skin and subcutaneous tissues,and is often accompanied by abvious pain. Histologically, PHE is characterized by infiltrative growth of tumor. Most tumor lesions are composed of sheets and loose fascicles of plump spindle or epithelioid cells within a background of variably prominent inflammatory infiltration, which was commonly composed of neutrophils. Some cells may resemble rhabdomyoblasts, and nuclear atypia and mitosis were rare. The tumor cells generally expressed positive cytokeratin (CK), ETS-related gene (ERG), Friend leukemia virus integration 1 (FLI1) and integrase interactor 1(INI1). In some cases, the tumor cells expressed CD31. A case of a young woman was reported in this paper, who presented with a subcutaneous mass with severe pain and was chronologically misdiagnosed with herpes zoster, low-grade malignant fibrous histiocytoma and epithelioid hemangioendothelioma. In this study, the clinical and pathological features, differential diagnosis and the latest progress in therapy of PHE were analyzed based on relevant literature.
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Hemangioendotelioma Epitelioide , Hemangioma , Histiocitoma Fibroso Maligno , Lesões Pré-Cancerosas , Adolescente , Adulto , Biomarcadores Tumorais , Criança , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/patologia , Histiocitoma Fibroso Maligno/diagnóstico , Humanos , Masculino , Dor , Lesões Pré-Cancerosas/diagnósticoRESUMO
Macrophages play a key role in silicosis, and exosomes are potent mediators of intercellular communication. This suggests that macrophage-derived exosomes have a potential contribution to the pathogenesis of silicosis. To investigate whether macrophage-derived exosomes promote or inhibit lung fibrosis, in vitro, silica-exposed macrophage-derived exosomes (SiO2 -Exos) were collected and cocultured with fibroblasts. The expression of collagen I and α-SMA was evaluated. Furthermore, the endoplasmic reticulum (ER) stress markers BIP, XBP1s and P-eIF2α were assessed after treatment with or without the ER stress inhibitor 4-PBA. In vivo, mice were pre-treated with the exosome secretion inhibitor GW4869 prior to silica exposure. After sacrifice, lung tissues were histologically examined, and the expression of proinflammatory cytokines (TNF-α, IL-1ß and IL-6) in bronchoalveolar lavage fluid (BALF) was measured. The results showed that the expression of collagen I and α-SMA was up-regulated after treatment with SiO2 -Exos, accompanied by increased expression of BIP, XBP1s and P-eIF2α. Pre-treatment with 4-PBA reversed this effect. More importantly, an in vivo study demonstrated that pre-treatment with GW4869 decreased lung fibrosis and the expression of TNF-α, IL-1ß and IL-6 in BALF. These results suggested that SiO2 -Exos are profibrogenic and that the facilitating effect is dependent on ER stress.
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Estresse do Retículo Endoplasmático , Exossomos/fisiologia , Fibroblastos/patologia , Macrófagos/fisiologia , Fibrose Pulmonar/patologia , Dióxido de Silício/toxicidade , Silicose/patologia , Animais , Comunicação Celular , Citocinas , Fibroblastos/metabolismo , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Transdução de Sinais , Silicose/etiologia , Silicose/metabolismoRESUMO
Atrial fibrillation (AF), a common arrhythmia that usually occurs in patients with heart disease, is one of the leading causes for mortality and disability worldwide. Current drug therapy for AF patients lacks sufficient efficacy and has side effects. Radiofrequency ablation is more effective than traditional drug therapy, but this invasive procedure is associated with potential risks and postoperative recurrence, limiting the clinical benefits for AF patients. Therefore, it is necessary to expand our understanding about the underlying molecular mechanism of AF and to explore the new therapeutic strategies. Long noncoding RNA (lncRNA) is a set of noncoding RNA longer than 200 nucleotides. Growing evidence indicates that lncRNA is involved in numerous pathophysiological processes of AF, such as structural remodeling, electrical remodeling, renin-angiotensin system, abnormal calcium regulation, etc. In addition, lncRNA involved in structural remodeling and electrical remodeling has the potential to be a novel target for the diagnosis and treatment of AF, and lncRNA involved in autonomic nerve remodeling may bring new enlightenment for the prognosis and recurrence of AF.
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Fibrilação Atrial , Remodelamento Atrial , RNA Longo não Codificante , Fibrilação Atrial/genética , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Recidiva , Sistema Renina-AngiotensinaAssuntos
Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Humanos , Proteínas de Ligação ao Cálcio , Família de Proteínas EGF , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/genética , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de TranscriçãoRESUMO
OBJECTIVE: To analyze the differential expression of RAW264.7 macrophage-derived exosomes miRNA stimulated by free silicon dioxide (SiO2).â© Methods: RAW264.7 was stimulated with SiO2 (200 mg/L) for 48 h (exo_48 h group), and the supernatant was collected. The exosomes in the supernatant were extracted by ultracentrifugation. Transmission microscopy, nanoparticle tracking analysis (NTA) and Western blotting were used to identify exosomes. High-throughput sequencing was performed to compare the differential expression of exosome miRNAs between the exo_control group (RAW264.7 cultured for 48 h without SiO2) and the exo_48 h group; miRanda, TargetScan and starBase were used to predict target genes of differential miRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on target genes to further analyze the biological functions of genes.â© Results: The transmission microscopy showed that the exosomes were lipid membrane coated vesicles, which were heterogeneously distributed, with a diameter ranging from 30 to 100 nm, and the shape was round or elliptical. The volume kurtosis was concentrated between 40 and 100 nm and the exosome marker protein TSG101 was positive. High-throughput sequencing screened 148 differentially expressed exosomal miRNAs. MiR-219c-3p, let-7d-3p, let-7a-1-3p, miR-328-3p, miR-365-3p, and miR-7219-3p were significantly up-regulated, and miR-378d and miR-5106 were significantly down-regulated compared with the control group. Target genes were mainly enriched in mTOR signaling pathway, Wnt signaling pathway, TGF-ß signaling pathway, and so on.â© Conclusion: The exosomes secreted by SiO2-induced macrophages contain abundant miRNAs, and their expressions are significantly different. These differential miRNAs may be involved in the activation of lung fibroblasts and epithelial-mesenchymal transition.
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Exossomos , Macrófagos , Animais , Linhagem Celular , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos , MicroRNAs , Dióxido de SilícioRESUMO
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. Although molecular diagnostic tools and targeted therapies have been developed over the past few decades, the survival rate is still rather low. Numerous researches suggest that some microRNAs (miRNAs) are key regulators of tumor progression. Among those miRNAs that has attracted much attention for their multiple roles in human cancers, the function of miR-221-3p in EOC has not been elucidated. Herein, we examined the expression of miR-221-3p in EOC patients and cell lines. Our data revealed that higher expression of miR-221-3p was linked to better overall survival in EOC patients. In-vitro experiments indicated that miR-221-3p inhibited EOC cell proliferation and migration. By performing subsequent systematic molecular biological and bioinformatic analyses, we found ADP-ribosylation factor (ARF) 4 is one of the putative target genes, the direct binding relationship was further confirmed by dual-luciferase reporter assay. Finally, a distinct gene expression between miR-221-3p and ARF4 in EOC group and normal group was identified, and the negative correlation between their expression levels in EOC specimens was further confirmed. Taken together, our research uncovered the tumor suppressive role of miR-221-3p in EOC and directly targeted ARF4, suggesting that miR-221-3p might be a novel potential candidate for clinical prognosis and therapeutics of EOC.
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Fatores de Ribosilação do ADP/antagonistas & inibidores , MicroRNAs/fisiologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Fatores de Ribosilação do ADP/genética , Adulto , Carcinoma Epitelial do Ovário , Linhagem Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Taxa de SobrevidaRESUMO
The objective of this study was to investigate the expression, proliferation, and apoptosis function of long-chain non-coding RNA maternally expressed gene 3 (MEG3) and antisense non-coding RNA at the INK4 locus (ANRIL) in gallbladder cancer (GBC) tissues. GBC tissues and adjacent normal samples were collected from 84 patients from January 2008 to June 2010. Empty vector, pcDNA-MEG3, and pcDNA-ANRIL vectors were transfected into GBC-SD and QBC939 cells. An MTT assay, real-time quantitative polymerase chain reaction (RT-qPCR), flow cytometry, Western blotting, and immunohistochemistry were applied. The effects of MEG3 and ANRIL were also verified in mice. Compared with normal tissues, the expression of MEG3 was significantly lower in GBC tissues, whereas the expression of ANRIL was significantly higher (both P < 0.05). The overexpression of MEG3 and underexpression of ANRIL were significantly associated with GBC prognosis (both P < 0.05). The expressions of MEG3 and ANRIL were higher in pcDNA-MEG3 and pcDNA-ANRIL-transfected cells than in empty vector-transfected cells in vitro (both P < 0.05). Most of the pcDNA-MEG3-transfected cells were in the G0-G1 phase, which showed reduced cell activity and clone counts and increased p53 and decreased cyclin D1, whereas the pcDNA-ANRIL-transfected cells were mostly in the S phase and showed contrasting behavior. Mice injected with pcDNA-MEG3-transfected cells had smaller and lighter tumors, decreased ki-67 levels, and increased caspase 3 levels, whereas those injected with pcDNA-ANRIL showed contrasting results (all P < 0.05). MEG3 can inhibit the proliferation of GBC cells and promote apoptosis, whereas ANRIL can improve the proliferation of gallbladder cells and inhibit apoptosis. Collectively, our results suggest that therapeutic strategies directed toward upregulating MEG3 and downregulating ANRIL may be clinically relevant for the inhibition of GBC deterioration.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias da Vesícula Biliar/genética , RNA Longo não Codificante/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To establish 2-dimensional gel electrophoresis (2-DE) image for the early lung injury rats induced by silica dioxide and to identify differentially expressed protein biomarkers during the early stage of silicosis.â© METHODS: The animal models of silicosis were established and morphology changes were observed by HE staining, and then the key protein biomarkers in silicosis were identified by 2-DE and matrix-assisted laser desorption/ionization time of flight tandem mass spectrometry (MALDI-TOF-MS) and verified by Western blot.â© RESULTS: The well qualified 2-DE gel images for experimental and control lung tissues were successfully established, and 40 different protein spots was observed when comparing the gel images between the experimental and control groups. Twenty of them were analyzed by MALDI-TOF-MS. A total of 13 altered proteins were identified, including alpha B-crystallin, mast cell protease 6, annexin 1, etc. The expression of alpha B-crystallin in lung was further verified by Western blot.â© CONCLUSION: The protein expression of alpha B-crystallin was increased significantly, suggesting that it might play an important role in the progress of silicosis.
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Proteômica , Silicose/diagnóstico , Cadeia B de alfa-Cristalina/metabolismo , Animais , Biomarcadores/metabolismo , Western Blotting , Modelos Animais de Doenças , Eletroforese em Gel Bidimensional , Pulmão/metabolismo , Pulmão/patologia , Ratos , Dióxido de Silício/efeitos adversos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Water splitting is a promising technique for clean hydrogen production. To improve the sluggish hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), the development of efficient bifunctional electrocatalysts for both HER and OER is urgent to approach the scale-up applications of water splitting. Nowadays transition metal oxides (TMOs) are considered as the promising electrocatalysts due to their low cost, structural flexibility and stability, however, their electrocatalytic activities are eager to be improved. Here, we synthesized waxberry-like hydrophilic Co-doped ZnFe2O4 electrocatalysts as bifunctional electrocatalysts for water splitting. Due to the enhanced active sites by electronic structure tuning and modified super-hydrophilic characteristics, the spinel ZFO-Co0.5 electrocatalyst exhibits excellent catalytic activities for both OER and HER. It exhibits a remarkable low OER overpotential of 220 mV at a current density of 10 mA cm-2 and a Tafel slope of 28.2 mV dec-1. Meanwhile, it achieves a low overpotential of 73 mV at a current density of 10 mA cm-2 with the Tafel slope of 87 mV dec-1 for HER. In addition, for water electrolysis device, the electrocatalytic performance of ZFO-Co0.5||ZFO-Co0.5 surpasses that of commercial IrO2||Pt/C. Our work reveals that the hydrophilic morphology regulation combined with metallic doping strategy is a facile and effective approach to synthesize spinel TMOs as excellent bifunctional electrocatalyst for water splitting.
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OBJECTIVE: To evaluate the role of transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF) in the pathogenesis of pulmonary artery hypertension, we observed the dynamic expression of TGF-ß1 and CTGF in rats with high blood flow. METHODS: Fifty adult male SD rats were randomly divided into 5 groups: a sham group (group S) and groups with right pneumonectomy for 1, 2, 4 and 6 weeks (PE1, PE2, PE4 and PE6 group), 10 rats per group. The mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index (RVHI) were measured. TGF-ß1 and CTGF protein expression in the lung tissues were determined with immunohistochemistry and Western blot. The expression of TGF-ß1 mRNA and CTGF mRNA in the lung tissues was evaluated by RT-PCR. RESULTS: Compared with group S, the mPAP and RVHI in the rats were significantly increased in group PE1, PE2, PE4, and PE6 (P<0.05); the indicators of vascular remodeling [(MA+PMA)%, RMT, and RMA] were markedly elevated in group PE4 and PE6 (P<0.05), but not in group PE1 and PE2. Immunohistochemical staining of TGF-ß1 and CTGF were more prominent in all of the right pneumonectomy groups than in the sham group. Western blot showed that the level of TGF-ß1 protein was significantly increased in all of the right pneumonectomy groups (P<0.01), and the peak was observed in group PE2, whereas the level of CTGF protein was markedly elevated in group PE4 and PE6 (P<0.05), but no change was noticed in group PE1 and PE2. Compare to group S, the mRNA level of TGF-ß1 was dramatically increased in all right pneumonectomy groups (P<0.01), peaked at group PE2, and remained high in group PE4 and PE6. In contrast, the elevation of mRNA level of CTGF was not significant in group PE1, but group PE2, PE4 and PE6 demonstrated significant mRNA level of CTGF (P<0.01). Correlation analysis showed that the protein and mRNA levels of CTGF were positively correlated with RMT and RMA ( r=0.743, r=0.906; P<0.05), while no correlation between the protein and mRNA level of TGF-ß1 with RMT or RMA. There was no correlation between the mRNA level of TGF-ß1 and CTGF. CONCLUSION: TGF-ß1 and CTGF play a role in the pathogenesis of increased pulmonary blood flow-induced pulmonary hypertension.
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Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Masculino , Artéria Pulmonar , RNA Mensageiro , Ratos , Ratos Sprague-DawleyRESUMO
The polymeric immunoglobulin receptor (PIGR), an exosome-associated glycoprotein, plays an important role in the occurrence and development of different tumors. This study aimed to investigate whether PIGR is essential for colorectal cancer (CRC). Comprehensive bioinformatics analysis and immunohistochemistry (IHC) revealed that expression of PIGR was significantly decreased in CRC patients. Upregulated PIGR displayed favorable prognostic values in CRC patients. Several algorithms, such as TISIDB and TIMER, were used to evaluate the roles of PIGR expression in the regulation of immune response in CRC. Moreover, GSEA enrichment analysis indicated the underlying role of PIGR in the regulation of fatty acid metabolism in CRC. Taken together, our findings might provide a new potential prognostic and immune-associated biomarker for CRC and supply a new destination for PIGR-related immunotherapy in clinical treatment.
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Silicosis is one of the most serious occupational diseases with the main feature of inflammatory cell infiltration, fibroblasts activation, and large deposition of extracellular matrix in the lung. Increasing evidence indicates that macrophage-derived exosomes may play an important role in the development of silicosis by transferring their loaded microRNAs (miRNAs). Hence we carried out high-throughput sequencing to identify the expression of exosomal miRNA from macrophages exposed to silica or not in the previous study. Then we verified that miR-7219-3p was significantly up-regulated in macrophages and their exosomes after silica-exposure, as well as in the silicotic mice model by qRT-PCR, subsequent experiments confirmed that the increase of miR-7219-3p facilitated fibroblast to myofibroblast trans-differentiation (FMT), as well as cell proliferation and migration. Spouty1 (SPRY1), which served as a negative modulator of the Ras/ERK/MAPK signaling pathway, was verified as the target gene of miR-7219-3p, the knockdown or over-expression of SPRY1 apparently promoted or inhibited FMT via the Ras/ERK/MAPK signaling pathway. Furthermore, the inhibition of exosomal miR-7219-3p partially suppressed FMT and silica-induced pulmonary fibrosis in vitro and in vivo. In brief, our results demonstrated that exosomal miR-7219-3p played an important role in FMT and might be a novel therapeutic target of silicosis.
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Exossomos , MicroRNAs , Silicose , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Transdiferenciação Celular , Exossomos/genética , Fibroblastos/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Dióxido de Silício/metabolismo , Dióxido de Silício/toxicidade , Silicose/genéticaRESUMO
Nano-hydroxylapatite (nano-HAP)/polycaprolactone (PCL) composite scaffold is proved to possess great potential for bone tissue engineering application since the biocompatibility of PCL and the osteoinduction ability of nano-HAP. However, the interfacial bonding between nano-HAP and PCL is weak by reason of the difference in thermodynamic properties. Herein, nano-HAP was modified by polydopamine (PDA) and then added to the PCL matrix to enhance their interface bonding in bone scaffold manufactured by selective laser sintering (SLS). The results indicated that PDA acted as an interfacial molecular bridge between PCL and nano-HAP. On one hand, the amino groups of PDA formed hydrogen bonding with the hydroxyl groups of nano-HAP, and on the other hand, the catechol groups of PDA formed hydrogen bonding with the ester groups of PCL. Compared with the HAP/PCL scaffolds, the tensile and compressive strength of the P-HAP/PCL scaffolds loading 12â¯wt% P-HAP were increased by 10% and 16%, respectively. Meanwhile, the scaffold possessed great bioactivity and cytocompatibility that could accelerate the formation of apatite layers and promote the cell adhesion, proliferation and differentiation.
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Durapatita , Alicerces Teciduais , Durapatita/farmacologia , Indóis , Poliésteres/farmacologia , Polímeros , Engenharia Tecidual/métodosRESUMO
Fibrosis is a persistent inflammatory response that causes scarring and tissue sclerosis by stimulating myofibroblasts to create significant quantities of extracellular matrix protein deposits in the tissue. Oxidative stress has also been linked to the development of fibrosis in several studies. The nuclear erythroid 2-related factor 2 (NRF2) transcription factor controls the expression of several detoxification and antioxidant genes. By binding to antioxidant response elements, NRF2 is activated by oxidative or electrophilic stress and promotes its target genes, resulting in a protective effect on cells. NRF2 is essential for cell survival under oxidative stress conditions. This review describes Kelch-like epichlorohydrin-associated protein 1 (KEAP1)/NRF2 signaling mechanisms and presents recent research advances regarding NRF2 and its involvement in primary fibrotic lesions such as pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, and renal fibrosis. The related antioxidant substances and drugs are described, along with the mechanisms by which KEAP1/NRF2 regulation positively affects the therapeutic response. Finally, the therapeutic prospects and potential value of NRF2 in fibrosis are summarized. Further studies on NRF2 may provide novel therapeutic approaches for fibrosis.
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OBJECTIVE: To determine the role of extracellular signal regulated kinase (ERK) signaling pathway in SiO2 induced epithelial-mesenchymal transition (EMT) in human bronchial epithelial cells (HBEC) in vitro. METHODS: HBEC were treated with SiO2 (0-300 µg/mL) for 72 h or pretreated with U0126 (0-30 µmol/L) for 1 h and then treated with 200 µg/mL SiO2 for 72 h. Western blot was used to detect the protein expression of E-cadherin and α-smooth muscle actin (α-SMA). The activity of ERK was examined by mitogen-activated protein kinase (MAPK) activity assay kit in HBEC exposing to SiO2 (200 µg/mL) for 0-8 h. RESULTS: The expression of E-cadherin decreased gradually in SiO2 -stimulated HBEC, and the effect was most significant at 300 µg/mL (P<0.01). The expression of α-SMA increased and the effect was most evident at 200 µg/mL (P<0.01). With SiO2 treatment, the activity of ERK was upregulated significantly. The phosphorylation of ERK increased at 30 min and decreased after 1 h. U0126 significantly inhibited SiO2 -induced expression changes in E-cadherin and α-SMA. At 30 µmol/L, the effect was most evident(P<0.01). CONCLUSION: ERK signaling pathway mediated EMT induced by SiO2 in HBEC.
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Transdiferenciação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Transição Epitelial-Mesenquimal , Sistema de Sinalização das MAP Quinases/fisiologia , Dióxido de Silício/farmacologia , Actinas/metabolismo , Brônquios/citologia , Caderinas/metabolismo , Células Cultivadas , Células Epiteliais/fisiologia , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismoRESUMO
OBJECTIVE: To investigate SiO2-induced EMT in human bronchial epithelial cells HBE in vitro. METHODS: HBE cells were cultured and then stimulated with indicated doses of SiO2 (0, 50, 100, 200, 300 µg/ml). The morphological changes were observed by microscope. In addition, Western blot was per-formed to detect the expression of E-cad, α-SMA and Vim. The changes of migration ability were examined by wound-healing assay in vitro. RESULTS: (1) After exposure to SiO2, HBE cells lost contact with their neighbor and displayed a spindle-shape, fibroblast-like morphology. (2) Compared with the control, the E-cad (300 µg/ml group) expression downregulated 2.98 fold (P < 0.05), and the Vim (300 µg/ml group) and α-SMA (200 µg/ml group) expression upregulated 4.46 fold and 3.55 fold (P < 0.05). There were significant differences between 100, 200, 300 µg/ml groups and the control group (P < 0.05). (3) In the test group, the percentage of wound-healing areas/wound areas were larger than those in control group (P < 0.05). CONCLUSIONS: SiO2 could induce EMT in human bronchial epithelial cells.