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PU.1 (SPI1) is pivotal in hematopoiesis, yet its role in human endothelial-to-hematopoietic transition (EHT) remains unclear. Comparing human in vivo and in vitro EHT transcriptomes revealed SPI1's regulatory role. Knocking down SPI1 during in vitro EHT led to a decrease in the generation of hematopoietic progenitor cells (HPCs) and their differentiation potential. Through multi-omic analysis, we identified KLF1 and LYL1 - transcription factors specific to erythroid/myeloid and lymphoid cells, respectively - as downstream targets of SPI1. Overexpressing KLF1 or LYL1 partially rescues the SPI1 knockdown-induced reduction in HPC formation. Specifically, KLF1 overexpression restores myeloid lineage potential, while LYL1 overexpression re-establishes lymphoid lineage potential. We also observed a SPI1-LYL1 axis in the regulatory network in in vivo EHT. Taken together, our findings shed new light on the role of SPI1 in regulating lineage commitment during EHT, potentially contributing to the heterogeneity of hematopoietic stem cells (HSCs).
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Asymmetric micro-supercapacitors (MSCs) exhibit higher energy density while face significant challenges in power density as well as cycling life and large dimensions. The key factors contributing to these dilemmas include the match of electrode materials and electrolytes, poor uniformity of device, and complicated while low-precise fabrication processes. Herein we develop a laser scribing-engraving (LSE) strategy to fabricate MSCs with monolithic high-voltage output and scalable array integration. Utilizing this strategy, we induce the conversion of the majority of Ti3C2Tx-MXene into TiO2 and graphene oxide into laser-scribed graphene (LSG), yielding asymmetric MSCs with laser-induced MXene/graphene oxide as the negative electrode and MXene/graphene oxide as the positive electrode. A single asymmetric micro-supercapacitor exhibits a high voltage window of 1.8 V, delivering an outstanding energy density (240 mWh cm-3) and power density (9503 mW cm-3), coupled with excellent cycling stability. Moreover, the LSE strategy enables monolithically integrated 64 devices to achieve a high-voltage output of 115.2 V. Our approach showcases the potential for integrating micro-energy storage devices into various microsystems, increasing the practicality of asymmetric micro-supercapacitors.
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BACKGROUND: Pulmonary embolism is a common disease associated with high mortality and morbidity. Diagnosing pulmonary embolism is challenging due to diverse clinical presentations and the lack of specific biomarkers. The study aimed to investigate the diagnostic value on pulmonary embolism for postpartum women by D-dimer to fibrinogen ratio, and it combined with neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio. METHODS: A total of 537 women with suspected pulmonary embolism were selected as the research subjects from the Shanghai First Maternity and Infant Hospital between 1 January 2019 and 31 October 2022. The D-dimer to fibrinogen ratio and it combined with neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio were applied to evaluate the clinical probability of pulmonary embolism, and the positive predictive value of both scores were calculated using computed tomography pulmonary arteriography as a gold standard. The diagnostic value of D-dimer to fibrinogen ratio, combined with neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio was evaluated by the area under the curve, sensitivity, specificity, and other indicators in the receiver operator characteristic curve. RESULTS: Among the 502 women included for analysis, 194 (38.65%) were definitely diagnosed as pulmonary embolism. The positive predictive values of D-dimer to fibrinogen ratio and it combined with platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio were 70.1%, 50.5%, and 56.5%, respectively in the postpartum women, the area under the curve for the D-dimer to fibrinogen ratio and it combined with platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio were 0.606 (95%CI: 0.562-0.650), 0.624 (95%CI: 0.575-0.673), and 0.639 (95%CI: 0.592-0.686), respectively. The negative predictive values of D-dimer to fibrinogen ratio, it combined with platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio were 50.5%, 70.1%, and 69.8%, respectively. CONCLUSION: The diagnostic value of the D-dimer to fibrinogen ratio was higher than the D-dimer for the postpartum women with suspected pulmonary embolism. The combination of either the neutrophil-to-lymphocyte ratio or the platelet-to-lymphocyte ratio with D-dimer to fibrinogen ratio is an appropriate strategy to rule out pulmonary embolism.
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Biomarcadores , Produtos de Degradação da Fibrina e do Fibrinogênio , Fibrinogênio , Período Pós-Parto , Valor Preditivo dos Testes , Embolia Pulmonar , Humanos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/sangue , Fibrinogênio/análise , Fibrinogênio/metabolismo , Adulto , Biomarcadores/sangue , Neutrófilos , Sensibilidade e Especificidade , Gravidez , China , Curva ROC , LinfócitosRESUMO
The development of oxygen evolution reaction (OER) electrocatalysts is essential for the production of green hydrogen from water electrolysis, but it is challenging. Herein, ruthenium (Ru) single-atom-modified Co-HHTP (HHTP = 2,3,6,7,10,11-hexahydroxytriphenylene) (Ru@Co-HHTP) was prepared via a solvothermal and ion exchange method. Systematic experiments highlight that the atomically dispersed Ru can optimize the electronic structure and electronic conductivity of Co-HHTP. As a result, the obtained Ru@Co-HHTP shows a low overpotential of 247 mV at 100 mA cm-2, a small Tafel slope of 38.14 mV dec-1, and good stability, which are superior to those of Co-HHTP, commercial IrO2, and most previously reported catalysts. This work provides a new avenue for designing highly efficient elongated OER electrocatalysts.
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The oncogenic role of KRAS in colorectal cancer (CRC) progression is well-established. Despite this, identifying effective therapeutic targets for KRAS-mutated CRC remains a significant challenge. This study identifies pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) as a previously unrecognized yet crucial regulator in the progression of KRAS mutant CRC. A substantial upregulation of PDP1 expression is observed in KRAS mutant CRC cells and tissues compared to wild-type KRAS samples, which correlates with poorer prognosis. Functional experiments elucidate that PDP1 accelerates the malignance of KRAS mutant CRC cells, both in vitro and in vivo. Mechanistically, PDP1 acts as a scaffold, enhancing BRAF and MEK1 interaction and activating the MAPK signaling, thereby promoting CRC progression. Additionally, transcription factor KLF5 is identified as the key regulator for PDP1 upregulation in KRAS mutant CRC. Crucially, targeting PDP1 combined with MAPK inhibitors exhibits an obvious inhibitory effect on KRAS mutant CRC. Overall, PDP1 is underscored as a vital oncogenic driver and promising therapeutic target for KRAS mutant CRC.
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Neoplasias Colorretais , Progressão da Doença , MAP Quinase Quinase 1 , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Animais , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , Camundongos , Linhagem Celular Tumoral , Mutação , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Feminino , Proliferação de Células , Camundongos Nus , Masculino , Regulação para CimaRESUMO
Objectives: The lymphotactin receptor X-C motif chemokine receptor 1 (XCR1) is an essential member of the chemokine receptor family and is related to tumor development and progression. Nevertheless, further investigation is required to explore its expression patterns, prognostic values, and functions related to target or immune therapies in patients with hepatocellular carcinoma (HCC). Materials and methods: The differential expression patterns of XCR1 and its prognostic influences were performed through The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Subsequently, immunohistochemistry (IHC) staining and univariate and multivariate Cox regressions were performed to validate the prognostic values in different subgroups. Furthermore, the potential roles of XCR1 in predicting target and immune therapeutic responses were also investigated. Results: Increased expression level of XCR1 was associated with favorable overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis revealed that a high expression level of XCR1 or positive immune cell proportion score (iCPS) were associated with favorable OS in the HCC patients with favorable tumor characteristics. In addition, the enhanced XCR1 expression was associated with the tumor environment scores, immune cell infiltration levels, and the expression levels of immune checkpoint genes. Further analysis revealed that improved expression of XCR1 was linked to better OS and RFS in HCC patients who received sorafenib. Conclusion: This study identified that XCR1 is a valuable prognostic biomarker in the HCC population, especially in those with favorable tumor characteristics. The combination of iCPS status and BCLC status has a synergistic effect on stratifying patients' OS and RFS. Further analyses showed that XCR1 has the potential ability to predict treatment responses to sorafenib and immune-based therapies.
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Background: H. pylori (Helicobacter pylori) infections typically occur in early childhood. Although the prevalence of H. pylori in children is lower than that in adults, the eradication rate of this infection in children is relatively low because of resistance. In this study, we analyzed personalized treatment strategies to achieve treatment goals based on H. pylori resistance characteristics. This retrospective single-center study was conducted between January 2019 and December 2022 and enrolled 1,587 children who presented with upper gastrointestinal symptoms and underwent endoscopy. H. pylori culturing and antimicrobial susceptibility testing were performed. Results: Culture-positive results for H. pylori were obtained in 535 children. The resistance rates to clarithromycin (CLA), metronidazole (MET), and levofloxacin (LEV) were 39.8%, 78.1%, and 20.2%, respectively. None of the isolates were resistant to tetracycline (TET), amoxicillin (AMO), or furazolidone (FZD). Double resistance rates to CLA + MET, CLA + LEV, and MET + LEV were 19.1%, 3.0%, and 5.8%, respectively. Notably, triple-resistant to CLA + MET + LEV was 9.7%. Based on susceptibility tests, individualized triple therapy [proton pump inhibitor (PPI) +AMO + CLA/MET] was selected for 380 children with H. pylori sensitive to MET and/or CLA. In 155 children resistant to CLA and MET, bismuth-based quadruple therapy was recommended; for unable to receive bismuth, concomitant therapy was recommended for 14 children (<8 years of age); triple therapy with TET was recommended for 141 children (>8 years of age), with 43 children (>14 years of age) requiring FZD rather than TET. Conclusion: Resistance to H. pylori in Chinese children was relatively poor. Personalized therapy regimens should be based on susceptibility tests and avoided factors associated with treatment failure.
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O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA's noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA's stalk domain in protein substrate recognition and functional modulation during malignant cell progression.
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Citoesqueleto , Proteínas com Domínio LIM , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Proteínas com Domínio LIM/metabolismo , Proteínas com Domínio LIM/genética , Citoesqueleto/metabolismo , Acetilglucosamina/metabolismo , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Linhagem Celular Tumoral , Glicosilação , Hidrólise , Mutação , Movimento Celular , Antígenos de Neoplasias , Hialuronoglucosaminidase , Histona AcetiltransferasesRESUMO
The dried pseudobulbs of Bletilla striata, an important traditional Chinese medicine named BaiJi, have an extraordinary polysaccharide content and excellent prospects for medicinal effects. However, the distribution and molecular mechanism underlying biosynthesis are poorly understood. In this study, chemical and immunologic analyses were performed in representative tissues of B. striata, and the results showed that what are conventionally termed Bletilla striata polysaccharides (BSPs) are water-soluble polysaccharides deposited only in pseudobulbs. The structural component of BSPs is glucomannan, with a mannose:glucose mass ratio of ~3:2. BSPs are present in the parenchyma of the pseudobulbs in cells known as glucomannan idioblasts and distributed in the cytoplasm within cellular membranes, but are not contained in the vacuole. Comparative transcriptomics and bioinformatics analyses mapped the pathway from sucrose to BSP and identified BsGPI, BsmanA, and BsCSLAs as the key genes of BSP biosynthesis, suggesting that the functional differentiation of the cellulose synthase-like family A (CSLA) may be critical for the flow of glucomannan to the BSP or cell wall. Subsequently, virus-mediated gene silencing showed that silencing of two CSLAs (Bs03G11846 and Bs03G11849) led to a decrease in BSP content, and yeast two-hybrid and luciferase complementation experiments confirmed that four CSLAs (Bs03G11846, Bs03G11847, Bs03G11848, and Bs03G11849) can form homo- or heterodimers, suggesting that multiple CSLAs may form a large complex that functions in BSP synthesis. Our results provide cytological evidence of BSP and describe the isolation and characterization of candidate genes involved in BSP synthesis, laying a solid foundation for further research on its regulation mechanisms and the genetic engineering breeding of B. striata.
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The Electrochemical reduction of nitrate to ammonia (NH3) is a process of great significance to energy utilization and environmental protection. However, it suffers from sluggish multielectron/proton-involved steps involving coupling reactions between different reaction intermediates and active hydrogen species (Hads) produced by water decomposition. In this study, a Ru-doped NiFe-MIL-53 (NiFeRu-MIL-53) supported on Ni foam (NF) has been designed for the nitrate reduction reaction (NO3RR). The NiFeRu-MIL-53 exhibits excellent NO3RR activity with a maximum Faradaic efficiency (FE) of 100% at -0.4 V vs. RHE for NH3 and a maximum NH3 yield of 62.39 mg h-1 cm-2 at -0.7 V vs. RHE in alkaline media. This excellent performance for the NO3RR is attributed to a strong synergistic effect between Ru and reconstructed NiFe(OH)2. Additionally, the doped Ru facilitates water dissociation, leading to an appropriate supply of Hads required for N species hydrogenation during NO3RR, thereby further enhancing its performance. Furthermore, in situ Raman analysis reveals that incorporating Ru facilitates the reconstruction of MOFs and promotes the formation of hydroxide active species during the NO3RR process. This work provides a valuable strategy for designing electrocatalysts to improve the efficiency of the reduction of electrochemical nitrate to ammonia.
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Osteosarcoma (OS) is an aggressive bone tumor with strong invasiveness, rapid metastasis, and dreadful mortality. Chemotherapy is a commonly used approach for OS treatment but is limited by the development of drug resistance and long-term adverse effects. To date, OS still lacks the curative treatment. Herein, we fabricated pyrite-based nanoparticles (FeS2@CP NPs) as synergetic therapeutic platform by integrating photothermal therapy (PTT) and chemo-dynamic therapy (CDT) into one system. The synthetic FeS2@CP NPs showed superior Fenton reaction catalytic activity. FeS2@CP NPs-based CDT efficaciously eradicated the tumor cells by initiating dual-effect of killing of apoptosis and ferroptosis. Furthermore, the generated heat from FeS2@CP under near-infrared region II (NIR-II) laser irradiation could not only inhibit tumor's growth, but also promote tumor cell apoptosis and ferroptosis by accelerating â¢OH production and GSH depletion. Finally, the photothermal/NIR II-enhanced CDT synergistic therapy showed excellent osteosarcoma treatment effects both in vitro and in vivo with negligible side effects. Overall, this work provided a high-performance and multifunctional Fenton catalyst for osteosarcoma synergistic therapy, which provided a pathway for the clinical application of PTT augmented CDT.
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Neoplasias Ósseas , Nanopartículas , Neoplasias , Osteossarcoma , Sulfetos , Humanos , Terapia Fototérmica , Osteossarcoma/tratamento farmacológico , Ferro , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Peróxido de HidrogênioRESUMO
Unraveling the mechanism of chirality transfer across length scales is crucial to the rational development of functional materials with hierarchical chirality. The key obstacle is the lack of structural information, especially at the mesoscopic level. We report herein the structural identification of helical covalent organic frameworks (heliCOFs) with hierarchical chirality, which integrate molecular chirality, channel chirality, and morphology chirality into one crystalline entity. Specifically, benefiting from the highly ordered structure of heliCOFs, the existence of chiral channels at the mesoscopic level has been confirmed by electron crystallography, and the handedness of these chiral channels has been directly determined through the stereopair imaging technique. Accordingly, the chirality transfer in heliCOFs from microscopic to macroscopic levels could be rationalized with a layer-rotating model that has been supported by both crystal structure analysis and theoretical calculations. Observation of chiral channels in heliCOFs not only provides unprecedented data for the understanding of the chirality transfer process but also sheds new light on the rational construction of highly ordered polymeric materials with hierarchical chirality.
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Background: Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumour, and its early diagnosis remains challenging. This study aims to comprehensively analyse the imaging features of PEH and develop a model for predicting PEH. Methods: Retrospective and pooled analyses of imaging findings were performed in PEH patients at our center (n=25) and in published cases (n=71), respectively. Relevant computed tomography (CT) images were extracted and used to build a deep learning model for PEH identification and differentiation from other diseases. Results: In this study, bilateral multiple nodules/masses (n=19) appeared to be more common with most nodules less than 2 cm. In addition to the common types and features, the pattern of mixed type (n=4) and isolated nodules (n=4), punctate calcifications (5/25) and lymph node enlargement were also observed (10/25). The presence of pleural effusion is associated with a poor prognosis in PEH. The deep learning model, with an area under the receiver operating characteristic curve (AUC) of 0.71 [95% confidence interval (CI): 0.69-0.72], has a differentiation accuracy of 100% and 74% for the training and test sets respectively. Conclusions: This study confirmed the heterogeneity of the imaging findings in PEH and showed several previously undescribed types and features. The current deep learning model based on CT has potential for clinical application and needs to be further explored in the future.
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The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.
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Colesterol , Hormônios , Proteínas de Ligação a RNA , Animais , Humanos , Camundongos , Colesterol/metabolismo , Hormônios/genética , Hormônios/metabolismo , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Transdução de Sinais , Proteínas de Ligação a RNA/metabolismoRESUMO
Gut microbiota can regulate host brain functions and influence various physiological and pathological processes through the brain-gut axis. To systematically elucidate the intervention of different gut environments on different brain regions, we implemented an integrated approach that combines 11-plex DiLeu isobaric tags with a "BRIDGE" normalization strategy to comparatively analyze the proteome of six brain regions in germ-free (GF)- and conventionally raised (ConvR)-mice. A total of 5945 proteins were identified and 5656 were quantifiable, while 1906 of them were significantly changed between GF- and ConvR-mice; 281 proteins were filtered with FC greater than 1.2 in at least one brain region, of which heatmap analysis showed clear protein profile disparities, both between brain regions and gut microbiome conditions. Gut microbiome impact is most overt in the hypothalamus and the least in the thalamus region. Collectively, this approach allows an in-depth investigation of the induced protein changes by multiple gut microbiome environments in a brain region-specific manner. This comprehensive proteomic work improves the understanding of the brain region protein association networks impacted by the gut microbiome and highlights the critical roles of the brain-gut axis.
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Microbioma Gastrointestinal , Camundongos , Animais , Proteômica , Encéfalo , ProteomaRESUMO
BACKGROUND & AIMS: As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn's disease (CD) patients, CD4+ tissue-resident memory T (TRM) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4+ TRM cells. METHODS: CD4+ TRM cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4+ TRM cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4+ TRM cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4+ TRM cells on the migration of normal intestinal epithelial cells. RESULTS: Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4+ TRM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4+ TRM cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4+ TRM cells from CD patients. Targeting FAO of CD4+ TRM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients. CONCLUSIONS: CD4+ TRM cells process an accelerated FAO mediated by activated nuclear factor kappa B signaling in CD patients; targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.
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Apoptose , Linfócitos T CD4-Positivos , Doença de Crohn , Ácidos Graxos , Células T de Memória , Oxirredução , Fenótipo , Humanos , Doença de Crohn/imunologia , Doença de Crohn/patologia , Doença de Crohn/metabolismo , Ácidos Graxos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células T de Memória/imunologia , Células T de Memória/metabolismo , Adulto , Masculino , Feminino , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , NF-kappa B/metabolismo , Estudos de Casos e Controles , Memória Imunológica , Inflamação/patologia , Inflamação/imunologia , Inflamação/metabolismo , Transdução de SinaisRESUMO
Breast cancer is often treated with chemotherapy. However, the development of chemoresistance results in treatment failure. Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to contribute to chemoresistance in breast cancer cells. In studying the transcriptional regulation of NEAT1 using multi-omics approaches, we showed that NEAT1 is up-regulated by 5-fluorouracil in breast cancer cells with wild-type cellular tumor antigen p53 but not in mutant-p53-expressing breast cancer cells. The regulation of NEAT1 involves mediator complex subunit 12 (MED12)-mediated repression of histone acetylation marks at the promoter region of NEAT1. Knockdown of MED12 but not coactivator-associated arginine methyltransferase 1 (CARM1) induced histone acetylation at the NEAT1 promoter, leading to elevated NEAT1 mRNAs, resulting in a chemoresistant phenotype. The MED12-dependent regulation of NEAT1 differs between wild-type and mutant p53-expressing cells. MED12 depletion led to increased expression of NEAT1 in a wild-type p53 cell line, but decreased expression in a mutant p53 cell line. Chemoresistance caused by MED12 depletion can be partially rescued by NEAT1 knockdown in p53 wild-type cells. Collectively, our study reveals a novel mechanism of chemoresistance dependent on MED12 transcriptional regulation of NEAT1 in p53 wild-type breast cancer cells.
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Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Complexo Mediador , RNA Longo não Codificante , Proteína Supressora de Tumor p53 , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Complexo Mediador/genética , Complexo Mediador/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fluoruracila/farmacologia , Linhagem Celular Tumoral , Regiões Promotoras Genéticas , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Acetilação/efeitos dos fármacos , Histonas/metabolismo , Histonas/genéticaRESUMO
Photocatalytic nitrogen fixation using solar illumination under ambient conditions is a promising strategy for production of the indispensable chemical NH3 . However, due to the catalyst's limitations in solar energy utilization, loss of hot electrons during transfer, and low nitrogen adsorption and activation capacity, the unsatisfactory solar-to-chemical conversion (SCC) efficiencies of most photocatalysts limit their practical applications. Herein, cerium oxide nanosheets with abundant strain-VO defects were anchored on Au hollow nanomushroom through atomically sharp interfaces to construct a novel semiconductor/plasmonic metal hollow nanomushroom-like heterostructure (denoted cerium oxide-AD/Au). Plasmonic Au extended the absorption of light from the visible to the second near-infrared region. The superior interface greatly enhanced the transfer efficiency of hot electrons. Abundant strain-VO defects induced by interfacial compressive strain promoted adsorption and in situ activation of nitrogen, and such synergistic promotion of strain and VO defects was further confirmed by density functional theory calculations. The judicious structural and defect engineering co-promoted the efficient nitrogen photofixation of the cerium oxide-AD/Au heterostructures with a SCC efficiency of 0.1 % under simulated AM 1.5G solar illumination, which is comparable to the average solar-to-biomass conversion efficiency of natural photosynthesis by typical plants, thus exhibiting significant potential as a new candidate for artificial photosynthesis.