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Currently, the improvement in the processing capacity of traditional processors considerably lags behind the demands of real-time image processing caused by the advancement of photodetectors and the widespread deployment of high-definition image sensors. Therefore, achieving real-time image processing at the sensor level has become a prominent research domain in the field of photodetector technology. This goal underscores the need for photodetectors with enhanced multifunctional integration capabilities than can perform real-time computations using optical or electrical signals. In this study, we employ an innovative p-type semiconductor GaTe0.5Se0.5 to construct a polarization-sensitive wide-spectral photodetector. Leveraging the wide-spectral photoresponse, we realize three-band imaging within a wavelength range of 390-810 nm. Furthermore, real-time image convolutional processing is enabled by configuring appropriate convolution kernels based on the polarization-sensitive photocurrents. The innovative design of the polarization-sensitive wide-spectral GaTe0.5Se0.5-based photodetector represents a notable contribution to the domain of real-time image perception and processing.
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BACKGROUND: Ubiquitin-specific proteases family is crucial to host immunity against pathogens. However, the correlations between USP21 and immunosurveillance and immunotherapy for colorectal cancer (CRC) have not been reported. METHODS: The differential expression of USP21 between CRC tissues and normal tissues was analyzed using multiple public databases. Validation was carried out in clinical samples through qRT-PCR and IHC. The correlation between USP21 and the prognosis, as well as clinical pathological characteristics of CRC patients, was investigated. Moreover, cell models were established to assess the influence of USP21 on CRC growth and progression, employing CCK-8 assays, colony formation assays, and wound-healing assays. Subsequently, gene set variation analysis (GSVA) was used to explore the potential biological functions of USP21 in CRC. The study also examined the impact of USP21 on cytokine levels and immune cell infiltration in the tumor microenvironment (TME). Finally, the effect of USP21 on the response to immunotherapy and chemotherapy in CRC was analyzed. RESULTS: The expression of USP21 was significantly upregulated in CRC. High USP21 is correlated with poor prognosis in CRC patients and facilitates the proliferation and migration capacities of CRC cells. GSVA indicated an association between low USP21 and immune activation. Moreover, low USP21 was linked to an immune-activated TME, characterized by high immune cell infiltration. Importantly, CRC with low USP21 exhibited higher tumor mutational burden, high PD-L1 expression, and better responsiveness to immunotherapy and chemotherapeutic drugs. CONCLUSION: This study revealed the role of USP21 in TME, response to therapy, and clinical prognosis in CRC, which provided novel insights for the therapeutic application in CRC.
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Neoplasias Colorrectales , Microambiente Tumoral , Ubiquitina Tiolesterasa , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Microambiente Tumoral/inmunología , Pronóstico , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Masculino , Femenino , Proliferación Celular , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Inmunoterapia/métodosRESUMEN
INTRODUCTION: As the primary members of the deubiquitinase family, ubiquitin-specific proteases can regulate the efficacy of immunotherapy and mediate immune evasion. However, further research is needed to explore the influence of USP52 on the prognosis of colorectal cancer (CRC), the tumor immune microenvironment, and therapeutic response. METHODS: The differential expression of USP52 between CRC and normal tissues was analyzed using multiple public databases. The relationship between USP52 with the prognosis and clinicopathological characteristics of CRC patients was evaluated, and a nomogram was constructed to predict patient survival based on USP52 expression. Subsequently, gene set variation analysis (GSVA) was used to explore the potential biological functions of USP52 in CRC. The impact of USP52 on the tumor microenvironment (TME) was estimated. Moreover, the effect of USP52 on the response to immunotherapy and chemotherapeutic drugs in CRC was investigated. Finally, the correlation between tumor mutation burden (TMB)/microsatellite instability (MSI) status and USP52 was explored. RESULTS: The expression of USP52 was markedly upregulated in CRC, correlating with a poor prognosis in patients. GSVA uncovered a strong association between high USP52 and immune suppression. Furthermore, high USP52 was found to be correlated with a non-inflamed TME, resulting in reduced immune cell infiltration levels. Additionally, it was observed that patients with high USP52 exhibited low sensitivity to both immunotherapy and chemotherapeutic drugs. Lastly, high USP52 was negatively associated with high TMB and MSI. CONCLUSION: This study revealed the significance of USP52 in TME, efficacy of therapy, and clinical prognosis in CRC, offering novel insights for the therapeutic advancements in CRC.
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BACKGROUND: The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel 2-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions. METHODS: Primary microvessels were cultured in the TGM2D medium (tubular microvascular growth medium on 2-dimensional substrates). Stiff ECM was prepared by incubating ECM solution in regular culture dishes for 1 hour followed by PBS wash. Soft ECM with Young modulus of ≈6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, RT-qPCR (real-time quantitative polymerase chain reaction), Western blotting, and knockdown experiments were performed on the cells. RESULTS: Primary microvascular pericytes differentiated into myofibroblasts (NG2+αSMA+) on stiff ECM, even with the TGFß (transforming growth factor beta) signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2+αSMA-/low). We thus defined 2 pericyte subpopulations: primary (NG2+αSMA-/low) and activated (NG2+αSMA+) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As integrins are the major mechanosensor, we performed RT-qPCR screening of integrin family members and found Itgb1 (integrin ß1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down Itgb1 suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF (connective tissue growth factor), to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation. CONCLUSIONS: ECM stiffness and TGFß signaling cooperatively regulate microvascular stability and pericyte-myofibroblast differentiation. Stiff ECM promotes EC ITGB1 phosphorylation (Y783) and CTGF secretion, which induces pericyte-myofibroblast differentiation.
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Comunicación Paracrina , Pericitos , Ratas , Animales , Pericitos/metabolismo , Células Endoteliales/metabolismo , Células Cultivadas , Factor de Crecimiento Transformador beta/metabolismo , Fibrosis , Matriz Extracelular/metabolismo , Miofibroblastos/metabolismoRESUMEN
Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Moléculas de Adhesión Celular , Progresión de la Enfermedad , Línea Celular TumoralRESUMEN
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 µg/g body weight) in 100 µL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 µg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.
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Red swamp crayfish, Procambarus clarkii (P. clarkii), is an important model crustacean organism used in many types of research. However, the effects of different doses of aminomethylphosphonic acid (AMAP) on the transcriptome and metabolites of P. clarkii have not been explored. Thus, this study investigated the molecular and metabolic mechanisms activated at the different exposure dosages of AMAP in P. clarkii to provide new insights into the strategies of P. clarkii in response to the high concentrations of AMAP in the environment. In the present study, the P. clarkii were divided into three groups (control group; low-dosage AMAP exposure; high-dosage AMAP exposure), and hepatopancreatic tissue samples were dependently taken from the three groups. The response mechanisms at the different dosages of AMAP were investigated based on the transcriptome and metabolome data of P. clarkii. Differentially expressed genes and differentially abundant metabolites were identified in the distinct AMAP dosage exposure groups. The genes related to ribosome cell components were significantly up-regulated, suggesting that ribosomes play an essential role in responding to AMAP stress. The metabolite taurine, involved in the taurine and hypotaurine metabolism pathway, was significantly down-regulated. P. clarkii may provide feedback to counteract different dosages of AMAP via the upregulation of ribosome-related genes and multiple metabolic pathways. These key genes and metabolites play an important role in the response to AMAP stress to better prepare for survival in high AMAP concentrations.
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Astacoidea , Organofosfonatos , Transcriptoma , Animales , Astacoidea/genética , Metaboloma , TaurinaRESUMEN
BACKGROUND: Cuproptosis, a novel form of cell death regulated by protein lipoylation and implicated in mitochondrial metabolism. However, the impact of the cuproptosis-related gene γ-glutamylcysteine synthetase (GCSH) on endometrial cancer (EC) prognosis, tumor immune microenvironment, and therapeutic response remains to be further researched. METHODS: The differential expression of GCSH between endometrial cancer and normal tissues was analyzed using multiple public databases. Additionally, cancer and adjacent tissues were prospectively collected from 17 EC patients, and immunohistochemical analysis was performed to further investigate GCSH expression differences. The relationship between GCSH and the prognosis and clinicopathological characteristics of EC patients was evaluated, and a nomogram was constructed to predict patient survival based on GCSH expression. Then, Gene set variation analysis (GSVA) was utilized to explore the potential biological functions of GCSH in EC. The impact of GCSH on the tumor microenvironment (TME) was estimated. Finally, the effect of GCSH on the response to immunotherapy and chemotherapeutic drugs in EC was investigated. RESULTS: The expression of GCSH was significantly upregulated in EC. High GCSH expression was associated with poor prognosis in EC patients. Enrichment analysis showed that high GCSH was associated with immune suppression. Furthermore, high GCSH was found to be associated with a non-inflamed TME, leading to decreased infiltration levels of immune cells. Finally, it was observed that patients with high GCSH were insensitive to both immunotherapy and chemotherapeutic drugs. CONCLUSION: This study revealed the role of GCSH in TME, response to therapy, and clinical prognosis in EC, which provided novel insights for the therapeutic application in EC.
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This study aims to evaluate the effects of different storage conditions (temperature and relative humidity) on the physicochemical and functional properties of egg white peptide powders (EWPPs). The samples (EWPPs) were stored for 28 d under four conditions (4 °C, 50% RH; 4 °C, 75% RH; 25 °C, 50% RH; 25 °C, 75% RH). Results showed that storage temperature and relative humidity had a significant effect on the physicochemical and functional properties of EWPPs. The contents of antioxidant amino acids such as histidine, tyrosine, tryptophan, and lysine were reduced significantly under different storage conditions, which resulted in the decrease of the antioxidant activity of EWPPs. Circular dichroism spectroscopy analysis indicated that the secondary structure of EWPPs changed from the regular structure to the irregular coiled structure during the storage. Additionally, the hydrophobic groups of the EWPPs originally embedded inside the molecules were exposed to the surface of the molecules during the storage, which led to an aggregation of EWPPs molecule and a decrease in solubility of EWPPs. The aggregation of EWPPs molecules resulted in a decrease in emulsification, emulsification stability, foaming ability and foaming stability of the EWPPs. Therefore, different storage conditions do have an impact on the physicochemical and functional properties of EWPPs. Lower temperature and humidity storing conditions were beneficial to retain the functional property of the EWPPs.
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BACKGROUND: The accuracy of CT and tumour markers in screening lung cancer needs to be improved. Computer-aided diagnosis has been reported to effectively improve the diagnostic accuracy of imaging data, and recent studies have shown that circulating genetically abnormal cell (CAC) has the potential to become a novel marker of lung cancer. The purpose of this research is explore new ways of lung cancer screening. METHODS: From May 2020 to April 2021, patients with pulmonary nodules who had received CAC examination within one week before surgery or biopsy at First Affiliated Hospital of Zhengzhou University were enrolled. CAC counts, CT scan images, serum tumour marker (CEA, CYFRA21-1, NSE) levels and demographic characteristics of the patients were collected for analysis. CT were uploaded to the Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) to assess the malignancy probability of nodules. We compared diagnosis based on PNAIDS, CAC, Mayo Clinic Model, tumour markers alone and their combination. The combination models were built through logistic regression, and was compared through the area under (AUC) the ROC curve. RESULTS: A total of 93 of 111 patients were included. The AUC of PNAIDS was 0.696, which increased to 0.847 when combined with CAC. The sensitivity (SE), specificity (SP), and positive (PPV) and negative (NPV) predictive values of the combined model were 61.0%, 94.1%, 94.7% and 58.2%, respectively. In addition, we evaluated the diagnostic value of CAC, which showed an AUC of 0.779, an SE of 76.3%, an SP of 64.7%, a PPV of 78.9%, and an NPV of 61.1%, higher than those of any single serum tumour marker and Mayo Clinic Model. The combination of PNAIDS and CAC exhibited significantly higher AUC values than the PNAIDS (P = 0.009) or the CAC (P = 0.047) indicator alone. However, including additional tumour markers did not significantly alter the performance of CAC and PNAIDS. CONCLUSIONS: CAC had a higher diagnostic value than traditional tumour markers in early-stage lung cancer and a supportive value for PNAIDS in the diagnosis of cancer based on lung nodules. The results of this study offer a new mode of screening for early-stage lung cancer using lung nodules.
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Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Nódulo Pulmonar Solitario , Antígenos de Neoplasias , Inteligencia Artificial , Biomarcadores de Tumor , Detección Precoz del Cáncer/métodos , Humanos , Queratina-19 , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulo Pulmonar Solitario/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodosRESUMEN
Bromoalkynes play important roles in coupling reactions because they can show obvious stereoselectivity to form E- and Z-isomers when substituents are different. However, the origin of the stereoselectivity in the bromoalkynes reaction is still unclear. Density functional theory (DFT) calculations were performed to provide an in-depth study of the reaction mechanism, clarifying the mechanistic details of the main reaction and the origin of the stereoselectivity. By comparing the syn-insertion mechanism of alkynes and the radical pathway, it is indicated that the electrostatic effect caused by the different charge distributions of the reactants is the main reason that Ni(I) species are more prone to syn-insertion of alkynes than Ni(II) species. In addition, the lower reaction energy barrier in the radical pathway suggests that it is more advantageous in terms of kinetics. The bond between Ni(I) species and alkenylation products has two directions to generate products of different configurations, which are the direct stereoselectivity-determining stages. The distortion/interaction analysis shows that the distortion energy mainly affects the product configuration, and the steric hindrance is the main factor controlling the stereoselectivity.
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Alquinos , Dióxido de Carbono , Alquinos/química , Catálisis , Ciclización , EstereoisomerismoRESUMEN
Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is one of the most commonly detected pharmaceuticals in wastewater treatment plants. However, the fate of DCF in waste activated sludge (WAS) anaerobic fermentation has not been well-understood so far. This work therefore aims to comprehensively reveal whether and how DCF is transformed in WAS mesophilic anaerobic fermentation through both experimental investigation and density functional theory (DFT) calculation. Experimental results showed that â¼28.8% and 45.8% of DCF were respectively degraded during the batch and long-term fermentation processes. Based on the detected intermediates and DFT-predicted active sites, three metabolic pathways, i.e., chlorination, hydroxylation, and dichlorination, responsible for DCF transformation were proposed. DFT calculation also showed that the Gibbs free energy (ΔG) of the three transformation pathways was respectively 19.0, -4.3, and -19.3 kcal/mol, suggesting that the latter two reactions (i.e., hydroxylation and dichlorination) were thermodynamically favorable. Illumina MiSeq sequencing analyses revealed that DCF improved the populations of complex organic degradation microbes such as Proteiniclasticum and Tissierellales, which was in accord with the chemical analyses above. This work updates the fundamental understanding of the degradation of DCF in WAS anaerobic fermentation process and enlightens engineers to apply theoretical calculation to the field of sludge treatment or other complex microbial ecosystems.
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Aguas del Alcantarillado , Contaminantes Químicos del Agua , Anaerobiosis , Antiinflamatorios no Esteroideos , Diclofenaco/química , Ecosistema , Fermentación , Preparaciones Farmacéuticas , Aguas del Alcantarillado/química , Aguas Residuales/análisis , Contaminantes Químicos del Agua/químicaRESUMEN
Glochidiol has been shown to have potentially antiproliferative activity in vitro, however its anticancer mechanisms specifically against lung cancer remain unknown. This study aimed to investigate the anti-lung cancer effects of glochidiol in HCC-44 cells in vitro and in vivo. In the present study, glochidiol was found to have potent antiproliferative activity against lung cancer cell lines NCI-H2087, HOP-62, NCI-H520, HCC-44, HARA, EPLC-272H, NCI-H3122, COR-L105 and Calu-6 with IC50 values of 4.12 µM, 2.01 µM, 7.53 µM, 1.62 µM, 4.79 µM, 7.69 µM, 2.36 µM, 6.07 µM and 2.10 µM, respectively. In vivo, glochidiol was found to effectively inhibit lung cancer HCC-44 xenograft tumor growth in nude mice. Docking analysis found that glochidiol forms hydrogen bonds with residues of tubulin. Glochidiol was also found to inhibit tubulin polymerization in vitro with an IC50 value of 2.76 µM. Immunofluorescence staining and EBI competition assay suggest that glochidiol may interact with tubulin by targeting the colchicine binding site. Thus, glochidiol might be a novel colchicine binding site inhibitor with the potential to treat lung cancer.
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Triterpenos/farmacología , Tubulina (Proteína)/efectos de los fármacos , Animales , Línea Celular Tumoral , Colchicina/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Distribución Aleatoria , Tubulina (Proteína)/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Chronic mucocutaneous candidiasis (CMC) is the most common clinical symptom of singer transducer and signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations. Bronchiectasis is a chronic lung disease that is characterized by permanent bronchiectasis, causing cough, expectoration, and even haemoptysis. The underlying pathogeny is not yet clear. Immunoglobulin (Ig) A is derived from memory B cells and correlates with immune-related diseases. STAT1 is closely associated with signal transmission and immune regulation. CASE PRESENTATION: We report a 17-year-old male patient carrying a GOF mutation in STAT1. The variant led to CMC, bronchiectasis, and elevated serum IgA levels, as well as stunting. Whole-exome sequencing (WES) revealed a c.986C>G (p.P329R) heterozygous mutation in the STAT1 gene. CONCLUSION: Further Sanger sequencing analysis of STAT1 in the patient and his parents showed that the patient harboured a de novo mutation.
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Bronquiectasia/genética , Candidiasis Mucocutánea Crónica/genética , Trastornos del Crecimiento/genética , Factor de Transcripción STAT1/genética , Adolescente , Linfocitos B/inmunología , Bronquiectasia/inmunología , Candidiasis Mucocutánea Crónica/diagnóstico , Candidiasis Mucocutánea Crónica/inmunología , Mutación con Ganancia de Función , Heterocigoto , Humanos , Inmunoglobulina A/sangre , Inmunoglobulinas/sangre , Inmunoglobulinas/genética , Masculino , Secuenciación del ExomaRESUMEN
BACKGROUND AND AIM: Epigenetic modification is an important part of the pathogenesis of inflammatory bowel disease (IBD). Some studies proved that p62 was involved in inflammatory response and upregulated in IBD patients, and histone modification plays an important role in regulating p62 expression. SETD8, a histone H4K20 methyltransferase, has been reported downregulated in some inflammatory diseases. Here, we investigated the role of SETD8 in the development of IBD and its underlying mechanisms. METHODS: An inflammatory cell model was established to elucidate whether SETD8 involved in inflammatory response in macrophages. Three percent dextran sodium sulfate-induced colitis murine model injection with SETD8 inhibitor was used in our study to investigate whether SETD8 inhibition can affect the progress of IBD. The expression of SETD8 and p62 was measured by qRT-PCR and western blot. The mRNA level of inflammatory cytokines was analyzed by qRT-PCR. In addition, chromatin immunoprecipitation-PCR was performed to identify the mechanism by which SETD8 regulates p62. RESULTS: SETD8 expression obviously decreased in vitro, in vivo models and in IBD patients. In lipopolysaccharide-activated RAW264.7 cells, knockdown of SETD8 significantly increased the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, IL-6, IL-1ß, and MCP-1. Based on the dataset, we verified that p62 was a target gene of SETD8 and chromatin immunoprecipitation-PCR assay identified that silence of SETD8 distinctly decreases the H4K20me1 enrichment in the promoter of p62. Moreover, silencing of p62 partly reverses the SETD8 inhibition-mediated pro-inflammatory effect in vitro. Finally, SETD8 pharmacological inhibitor (UNC0379) aggravated the disease progression in dextran sodium sulfate-induced murine colitis. CONCLUSION: Our findings elucidate an epigenetic mechanism by which SETD8 regulates the p62 expression and restrains the inflammatory response in colitis. Our result suggests that targeting SETD8 may be a promising therapy for IBD.
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Colitis , N-Metiltransferasa de Histona-Lisina/metabolismo , Enfermedades Inflamatorias del Intestino , Animales , Colitis/inducido químicamente , Colitis/genética , Citocinas , Sulfato de Dextran , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Lipopolisacáridos , Ratones , ARN MensajeroRESUMEN
BACKGROUND: This study was performed to evaluate the diagnostic and prognostic value, as well as the role of long-chain noncoding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) in osteosarcoma (OS). MATERIALS AND METHODS: A quantitative real-time polymerase chain reaction assay was to determine lncRNA CRNDE and microRNA-335-3p (miR-335-3p) expressions. The Kaplan-Meier analysis was to analyze the relationship between lncRNA CRNDE expression and survival in patients with OS. Receiver operating characteristic curves were to evaluate the diagnostic value of lncRNA CRNDE in OS. Bioinformatics analysis and luciferase reporter assays were used to predict and confirm the relationship between lncRNA CRNDE and miR-335-3p. Cell counting Kit-8 and transwell migration assays assessed the role of lncRNA CRNDE and miR-335-3p in OS cells. RESULTS: lncRNA CRNDE expression was upregulated and miR-355-3p expression was downregulated in OS. In patients with OS, low lncRNA CRNDE expression demonstrated higher overall survival, whereas high lncRNA CRNDE expression was an independent poor prognostic factor. Furthermore, increased lncRNA CRNDE expression was associated with distant metastasis and the tumor-node-metastasis stage in patients with OS, which can be considered as an independent diagnostic biomarker in OS. We revealed that miR-335-3p was the target of lncRNA CRNDE. It also demonstrated that knockdown of lncRNA CRNDE inhibited OS cell proliferation, migration, and invasion, and inhibition of miR-355-3p promoted this effect. Finally, miR-335-3p partially mediated the stimulatory effects of lncRNA CRNDE in OS. CONCLUSION: We demonstrated that lncRNA CRNDE is a potential diagnostic and prognostic biomarker for OS, and the lncRNA CRNDE/miR-335-3p axis participates in OS progression.
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Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/metabolismo , MicroARNs/metabolismo , Osteosarcoma/metabolismo , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Línea Celular Tumoral , Humanos , MicroARNs/genética , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Pronóstico , ARN Largo no Codificante/genética , ARN Neoplásico/genéticaRESUMEN
Grass carp is one of the most common farmed fish and its growth rate has been the focus of various studies. However, the impact of long-term exercise on growth rate of juvenile grass carp has not been clearly established. In this study, a four-month exercise trial and liver transcriptome analysis were performed to investigate changes in growth, liver molecular regulatory network and key genes in grass carp. When compared to the non-exercised grass carp (N-EXF), the exercised grass carp (EXF) showed a significant improvement in growth. Liver transcriptome analysis revealed 1714 significantly up-regulated and 1672 significantly down-regulated genes. These genes were enriched in various signaling pathways. These pathways included: those associated with growth, such as the PI3K-Akt and mTOR signaling pathways; those associated with glucose metabolism, such as glycolysis/gluconeogenesis, insulin and AMPK signaling pathways as well as those associated with oxygen transport, such as HIF-1, PI3K-Akt, PPAR and MAPK signaling pathways. In addition, growth-associated genes, such as ghr, igf1 and igf1r; glucose metabolism-associated genes, such as ins and insr as well as oxygen transport-associated genes, such as vhl, pdha and epo were identified. In conclusion, long-term moderate exercise improved the growth rate of grass carp. Our findings elucidate on changes in the liver molecular regulatory network and functional genes that occur during moderate exercise in fish.
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Carpas/genética , Metabolismo Energético/genética , Perfilación de la Expresión Génica , Glucosa/metabolismo , Hígado/metabolismo , Oxígeno/metabolismo , Condicionamiento Físico Animal , Transducción de Señal/genética , Transcriptoma , Animales , Carpas/crecimiento & desarrollo , Carpas/metabolismo , Regulación de la Expresión Génica , Esfuerzo Físico , RNA-Seq , Factores de TiempoRESUMEN
Depurination occurs via hydrolysis of the purine-deoxyribose glycosyl bond and causes nucleic acid damage. In particular, the DNA sequences that can undergo a self-catalyzed depurination (SCD) will cause a great uncertainty in duplicating, separating, purifying, and storing the DNA samples. Therefore, there is a great demand to develop a rapid detection method for SCD events. Herein, the use of a convenient fluorescence method to follow the site-specific SCD was demonstrated. We found that the resultant apurine site (AP site) from depurination can be selectively recognized by a fluorescent probe of palmatine (PAL) with a turn-on fluorescence response. The dependence of SCD on the bases of the depurination site, pH, metal ions, and time shows that our method can be used to rapidly evaluate the depurination process. Furthermore, the depurination process can be photo-switched using a photoacid as an external initiator. Our work will find wide applications in preliminarily identifying the DNA depurination.
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Alcaloides de Berberina/química , ADN Glicosilasas/química , ADN Catalítico/química , Colorantes Fluorescentes/química , Catálisis , Estructura MolecularRESUMEN
Relative to the individual intensity-dependent strategy, the multicolor fluorescence sensor has promise to achieve a high signaling contrast. In this work, we develop a cucurbituril-based supramolecular and multicolor DNA recognition rationale via indicator competition assay (ICA). Alkaloids of coptisine (COP) and palmatine (PAL) are identified as the proof-of-principle indicators with a lighting-up fluorescence upon supramolecular complexation to cucurbit[7]uril (CB[7]). With an introduced abasic site (AP site) as the contestant, DNAs having pyrimidines opposite this site can compete for COP with CB[7] to bring an emission color change from green to yellow brown, while those having purines opposite the AP site do not compete for COP and still have the green emission, indicative of a high selectivity for the multicolor nucleotide transversion recognition. However, because of the relatively weaker binding of PAL with CB[7], the AP site-containing DNA can take away PAL from its CB[7] complex and resultantly bring a blue-to-green emission color change independent of the AP site-opposite nucleotide identity, dissimilar to the remaining blue color for the fully matched DNA without the AP site, suggesting a preferable strategy for the AP site biomarker detection. Our method demonstrates a new way to develop an ICA-based multicolor DNA sensor with the supramolecular cucurbituril complexation to ensure a highly selective performance.
Asunto(s)
Alcaloides de Berberina/química , Bioensayo/métodos , Hidrocarburos Aromáticos con Puentes/química , ADN/química , Indicadores y Reactivos/química , Espectrometría de Fluorescencia/métodos , Sitios de Unión , Color , FluorescenciaRESUMEN
Molecularly imprinted polymers (MIPs) provide versatile sensor platforms to recognize targets by shape complementarity. However, the rigid structure of the classic MIPs compromises the signal transduction with necessary polymer and target modifications. Herein, we tried to use a flexible DNA that has a perfectly structured folding as the soft molecularly imprinted polymer (SMIP) for a straightforward sensor. As a proof of concept, the guanosine SMIP recognition was achieved by removal of a guanosine from a G-quadruplex-forming sequence (G4). The G4 folding structure with such an apurinic site (AP site) provides a well-defined MIP binding accommodation for guanosine according to the shape complementarity. The guanosine binding at the AP site subsequently leads to a conformation change suitable for remote readout using a G4-specific fluorescent ligand. The G4 sequence and AP site position were optimized for this SMIP behavior. Due to the G4 compact structure and the remaining hydrogen bonding pattern, nucleosides other than guanosine and negatively charged nucleotides exhibit no binding with the AP site, suggesting a high selectivity in the SMIP recognition. The proposed rationale was then convinced by the alkaline phosphatase-catalyzed GMP hydrolysis. Our work will inspire more interest in exploring nucleic acids as the SMIP frameworks due to their variant conformations and well-established molecular engineering.