RESUMEN

Purpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.

Asunto(s)

Antineoplásicos , Carcinoma Hepatocelular , Liberación de Fármacos , Ferroptosis , Estructuras Metalorgánicas , Piridinas , Estructuras Metalorgánicas/química , Animales , Humanos , Piridinas/química , Piridinas/administración & dosificación , Piridinas/farmacocinética , Piridinas/farmacología , Ratones , Células Hep G2 , Concentración de Iones de Hidrógeno , Ferroptosis/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Tamaño de la Partícula , Nanopartículas/química

RESUMEN

Triple negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSCs), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets including NQO1. Here, we identified the antioxidant enzymes NQO1 and SOD1 as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by utilizing IB-DNQ, a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species (ROS) including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacological inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resided in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase 3-mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial-mesenchymal continuum, could be a promising therapeutic approach for treating TNBC patients.

RESUMEN

To create a healthier indoor environment via sustainable technologies, there is a growing demand for constructing high-performance air filters from natural materials. Addressing this need, we have fabricated high-performance protein air filters with a tailored frame-channel structure via electrospinning. The innovative feature of the protein air filter is generated by adding a small amount of an organic salt, tetrabutylammonium chloride (TBAC), to modulate the denaturation of zein for tuning electrical charge distribution and hydrophilicity of the protein solutions. The results highlight that the optimized filter with 1.0 wt% TBAC exhibits a denser nanofiber assembly on the frame and a sparser arrangement on the channel. Functionally, the filter demonstrates ultralow pressure drop (ca. 9.04 Pa) that is only a third of that observed in unmodified formulation and commercial air filters, while it maintains high filtration efficiency in capturing PM2.5 (99.42% ± 0.30%) and PM0.3 (98.25 ± 0.39%). More importantly, the filter indicates multifunctional perspectives, e.g., high removal efficiency for formaldehyde (HCHO) and PM2.5 under high airflow rates (up to 8 L/min) or after prolonged testing period (120 min). Our design of the frame-channel structure for the protein air filter marks a leap forward in developing biomass-based structural materials.

Asunto(s)

Filtros de Aire , Tamaño de la Partícula , Ensayo de Materiales , Materiales Biocompatibles/química , Proteínas/química , Material Particulado/química , Nanofibras/química

RESUMEN

Integrating biomechanical and biomolecular sensing mechanisms into wearable devices is a formidable challenge and key to acquiring personalized health management. To address this, we have developed an innovative multifunctional sensor enabled by plasma functionalized silk fabric, which possesses multimodal sensing capabilities for biomechanics and biomolecules. A seed-mediated in situ growth method was employed to coat silver nanoparticles (AgNPs) onto silk fibers, resulting in silk fibers functionalized with AgNPs (SFs@Ag) that exhibit both piezoresistive response and localized surface plasmon resonance effects. The SFs@Ag membrane enables accurate detection of mechanical pressure and specific biomolecules during wearable sensing, offering a versatile solution for comprehensive personalized health monitoring. Additionally, a machine learning algorithm has been established to specifically recognize muscle strain signals, potentially extending to the diagnosis and monitoring of neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). Unlike electromyography, which detects large muscles in clinical medicine, sensing data for tiny muscles enhance our understanding of muscle coordination using the SFs@Ag sensor. This detection model provides feasibility for the early detection and prevention of neuromuscular diseases. Beyond muscle stress and strain sensing, biomolecular detection is a critical addition to achieving effective health management. In this study, we developed highly sensitive surface-enhanced Raman scattering (SERS) detection for wearable health monitoring. Finite-difference time-domain numerical simulations ware utilized to analyze the efficacy of the SFs@Ag sensor for wearable SERS sensing of biomolecules. Based on the specific SERS spectra, automatic extraction of signals of sweat molecules was also achieved. In summary, the SFs@Ag sensor bridges the gap between biomechanical and biomolecular sensing in wearable applications, providing significant value for personalized health management.

RESUMEN

BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular emergency that is often misdiagnosed as other chest pain conditions. Physiologically, AD may cause abnormalities in peripheral blood flow, which can be detected using pulse oximetry waveforms. PURPOSE: This study aimed to assess the feasibility of identifying AD based on pulse oximetry waveforms and to highlight the key waveform features that play a crucial role in this diagnostic method. METHODS: This prospective study employed high-risk chest pain cohorts from two emergency departments. The initial cohort was enriched with AD patients (n = 258, 47% AD) for model development, while the second cohort consisted of chest pain patients awaiting angiography (n = 71, 25% AD) and was used for external validation. Pulse oximetry waveforms from the four extremities were collected for each patient. After data preprocessing, a recognition model based on the random forest algorithm was trained using patients' gender, age, and waveform difference features extracted from the pulse oximetry waveforms. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). The importance of features was also assessed using Shapley Value and Gini importance. RESULTS: The model demonstrated strong performance in identifying AD in both the training and external validation sets. In the training set, the model achieved an area under the ROC curve of 0.979 (95% CI: 0.961-0.990), sensitivity of 0.918 (95% CI: 0.873-0.955), specificity of 0.949 (95% CI: 0.912-0.985), and accuracy of 0.933 (95% CI: 0.904-0.959). In the external validation set, the model attained an area under the ROC curve of 0.855 (95% CI: 0.720-0.965), sensitivity of 0.889 (95% CI: 0.722-1.000), specificity of 0.698 (95% CI: 0.566-0.812), and accuracy of 0.794 (95% CI: 0.672-0.878). Decision curve analysis (DCA) further showed that the model provided a substantial net benefit for identifying AD. The median mean and median variance of the four limbs' signals were the most influential features in the recognition model. CONCLUSIONS: This study demonstrated the feasibility and strong performance of identifying AD based on peripheral pulse oximetry waveforms in high-risk chest pain populations in the emergency setting. The findings also provided valuable insights for future human fluid dynamics simulations to elucidate the impact of AD on blood flow in greater detail.

RESUMEN

Time and frequency division multiplexing (TFDM) coherent passive optical networks (PONs) are considered as a promising candidate for future optical access networks due to the advantage of high sensitivity, high spectral efficiency, and flexibility. We propose a novel, to our knowledge, bidirectional TFDM 200-Gb/s coherent PON architecture based on the digital subcarrier multiplexing (DSCM) technology. A polarization-insensitive simplified coherent receiver is achieved at the ONU side by Alamouti coding and heterodyne detection. We experimentally demonstrate this bidirectional coherent PON with a 50-Gbaud Alamouti 16 quadrature amplitude modulation (QAM) signal transmitted downstream and a 25-Gbaud dual polarization (DP)-16QAM signal transmitted upstream. By using a single sideband modulated transmitter, only one laser source is required at the optical network unit (ONU) side. The power budgets can reach 30 and 33 dB for the downstream and upstream, respectively, after the 20-km transmission over a standard single-mode fiber (SSMF).

RESUMEN

Pectobacterium carotovorum and Pectobacterium aroidearum represent the primary pathogens causing variable soft rot disease. However, the fundamental defense responses of Pinellia ternata to pathogens remain unclear. Our investigation demonstrated that the disease produced by P. carotovorum is more serious than P. aroidearum. RNA-seq analysis indicated that many cell wall-related genes, receptor-like kinase genes, and resistance-related genes were induced by P. aroidearum and P. carotovorum similarly. But many different regulatory pathways exert a crucial function in plant immunity against P. aroidearum and P. carotovorum, including hormone signaling, whereas more auxin-responsive genes were responsive to P. carotovorum, while more ethylene and gibberellin-responsive genes were responsive to P. aroidearum. 12 GDSL esterase/lipase genes and 3 fasciclin-like arabinogalactan protein genes were specifically upregulated by P. carotovorum, whereas 11 receptor-like kinase genes and 8 disease resistance genes were up-regulated only by P. aroidearum. Among them, a lectin gene (part1transcript/39001) was induced by P. carotovorum and P. aroidearum simultaneously. Transient expression in N. benthamiana demonstrated that the lectin gene improves plant resistance to P. carotovorum. This study offers a comprehensive perspective on P. ternata immunity produced by different soft rot pathogens and reveals the importance of lectin in anti-soft rot of P. ternata for the first time.

Asunto(s)

Resistencia a la Enfermedad , Perfilación de la Expresión Génica , Pectobacterium carotovorum , Pinellia , Enfermedades de las Plantas , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Pinellia/genética , Pinellia/microbiología , Pectobacterium carotovorum/fisiología , Resistencia a la Enfermedad/genética , Pectobacterium/genética , Regulación de la Expresión Génica de las Plantas , Transcriptoma

RESUMEN

Detect the expression of Farnesoid X Receptor(FXR), Multiple Drug Resistance Associated Protein-1(MRP-1) and Solute Carrier Family 7, Member 5 (SLC7A5) in hepatocellular carcinoma(HCC) of rat model, so as to provide new therapeutic targets for gene therapy of HCC. Sixty male Wistar rats were randomly divided into three groups. The rats in experimental group were given 0.2% diethylnitrosamine (DEN) by gavage with a dose of 10 mg/kg, 3 times a week, and it stopped at 12 weeks. The control group rats were given physiological saline by gavage, while the sham operation group did not receive anything by gavage. At 10 weeks, one rat in the experimental group was euthanized, and the changes of livers were recorded. The procedure was repeated at 12 weeks. After 12 weeks, HCC only occurred in the experimental group. After confirming the formation of the tumor through pathological examination, liver tissues and tumor tissues were taken from the three groups. FXR, MRP-1 and SLC7A5 expression in liver tissues and tumor tissues was detected. After 7 weeks the rats in experimental group ate less, and their weight was significantly reduced. Three months later, HCC was detected in 15 rats in the experimental group. The ratio of FXR/GAPDH mRNA, MRP-1/GAPDH mRNA, SLC7A5/GAPDH mRNA were significantly different among the three groups. Under the light microscope the FXR protein, MRP-1 protein, and SLC7A5 protein react with their respective antibodies, and they showed granular expression. Every pathological section included different numbers of positive cells in each group. FXR expression in HCC of rats was significantly lower than that in normal liver tissues, but MRP-1 and SLC7A5 expression in HCC were significantly higher than that in normal liver tissues, suggesting that drugs targeting FXR, MRP-1 and SLC7A5 may be new strategies for the treatment of HCC.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Receptores Citoplasmáticos y Nucleares , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Modelos Animales de Enfermedad , Dietilnitrosamina , Hígado/metabolismo , Hígado/patología , Ratas Wistar

RESUMEN

Epigallocatechin gallate (EGCG) is a prominent catechin found in green tea polyphenols and has shown promising anti-tumor properties. However, the exact regulatory mechanism of EGCG on liver cancer is not fully revealed. In this study, we conducted integrative analyses using the SwissTargetPrediction and GeneCards repositories, which identified 98 targets. These targets were used to construct a protein-protein interaction network using STRING and visualised with Cytoscape. Central to this network are hub proteins, notably TNF and PIK3CA, suggesting pivotal roles in the therapeutic landscape. Gene Ontology (GO) enrichment analysis unveiled 1,570 biological terms with a notable preponderance within oxidative stress response processes. Complementary pathway enrichment via the Kyoto Encyclopaedia of Genes and Genomes (KEGG) highlighted 134 pathways, with the PI3K-Akt pathway emerging as prominent. In silico molecular docking supported these findings, revealing binding energies of EGCG-target complexes below -7.0 kcal/mol, indicative of robust interactions. Moreover, cellular assays including CCK-8, wound-healing, and Transwell modalities, established EGCG's inhibitory concentration-dependent effects on HepG2 cell proliferation, migration, and invasion. Apoptotic assays affirmed by FACS, evidenced enhanced apoptosis with escalating EGCG concentrations, underpinned by modulations in caspase activity and apoptotic protein levels. Notably, Western blot analysis demonstrated the attenuation of the PI3K/AKT signalling cascade by EGCG, paralleling the inhibitory profile of LY294002. These multifaceted inhibitory effects underscore EGCG's potential as an anti-tumor agent, deploying a strategic blockade of oncogenic pathways and augmenting apoptotic mechanisms, which provide a strong rationale for its application in liver cancer therapeutics.

RESUMEN

N6-methyladenosine (m6A) modification plays an important role in RNA molecular functions, therefore affecting the initiation and development of hepatocellular carcinoma (HCC). Herein, multiple datasets were applied to conduct a comprehensive analysis of DEGs within HCC and the analysis revealed significant dysregulation of numerous genes. Functional and signaling pathway enrichment analyses were performed. Further, TP53RK binding protein (TPRKB) emerged as a significant factor, exhibiting high expression level within HCC tissue samples and cells which could predict HCC patients' poor OS. Knockdown investigations of TPRKB in vitro demonstrated the effect of TPRKB knockdown on attenuating the aggressiveness of HCC cells by suppressing the viability, colony formation, invasive ability, and migratory ability, inducing cell cycle arrest, and facilitating the apoptosis of HCC cells. Investigations in vivo revealed that TPRKB knockdown significantly suppressed tumor growth in mice model. Additionally, the study identified methyltransferase 5, N6-adenosine (METTL5) as a potential regulator of TPRKB expression via m6A modification, positively regulating TPRKB expression by enhancing TPRKB mRNA stability. The dynamic effects of METTL5 and TPRKB upon the phenotypes of HCC cells further confirmed that TPRKB overexpression partially abolished the anti-cancer effects of METTL5 knockdown upon the aggressiveness of HCC cells. Conclusively, our findings uncover that TPRKB, significantly overexpressed in HCC, exerts a critical effect on promoting tumor aggressiveness, and its expression shows to be positively regulated by METTL5 via m6A methylation. These insights deepen the understanding of HCC pathogenesis and open new avenues for targeted therapies, highlighting that METTL5-TPRKB axis is an underlying new therapeutic target in HCC management.

Asunto(s)

Adenosina , Carcinoma Hepatocelular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Metiltransferasas , Estabilidad del ARN , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Humanos , Metiltransferasas/genética , Metiltransferasas/metabolismo , Animales , Ratones , Regulación Neoplásica de la Expresión Génica/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Estabilidad del ARN/genética , Proliferación Celular/genética , Apoptosis/genética , Ratones Desnudos , Línea Celular Tumoral , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Movimiento Celular/genética , Ratones Endogámicos BALB C , Proteínas de Unión al ARN

RESUMEN

The emergence of generative artificial intelligence (AI) has revolutionized various fields. In ophthalmology, generative AI has the potential to enhance efficiency, accuracy, personalization and innovation in clinical practice and medical research, through processing data, streamlining medical documentation, facilitating patient-doctor communication, aiding in clinical decision-making, and simulating clinical trials. This review focuses on the development and integration of generative AI models into clinical workflows and scientific research of ophthalmology. It outlines the need for development of a standard framework for comprehensive assessments, robust evidence, and exploration of the potential of multimodal capabilities and intelligent agents. Additionally, the review addresses the risks in AI model development and application in clinical service and research of ophthalmology, including data privacy, data bias, adaptation friction, over interdependence, and job replacement, based on which we summarized a risk management framework to mitigate these concerns. This review highlights the transformative potential of generative AI in enhancing patient care, improving operational efficiency in the clinical service and research in ophthalmology. It also advocates for a balanced approach to its adoption.

Asunto(s)

Inteligencia Artificial , Oftalmología , Inteligencia Artificial/tendencias , Humanos , Oftalmología/tendencias , Oftalmología/métodos

RESUMEN

BACKGROUND: The role of selinexor, a targeted inhibitor of exportin 1 (XPO1), in the treatment of cholangiocarcinoma is not yet fully understood. This study conducted comprehensive in vitro and in vivo investigations to elucidate the effects of selinexor on cholangiocarcinoma, with a focus on its mechanistic relationship with the cellular localization of Paternally Expressed Gene 3 (PEG3). METHODS: A patient-derived xenograft (PDX) model was established using samples from a cholangiocarcinoma patient in immunodeficient mice to assess the in vivo effects of selinexor. Additionally, cholangiocarcinoma cell lines HuCC-T1 and BRE were cultured to evaluate selinexor's impact on cell proliferation, invasion, migration, cell cycle, and apoptosis. HuCC-T1 cells were also implanted in immunodeficient mice for further investigation. Immunofluorescence and Western blotting were employed to observe the expression and localization of the PEG3 protein. RESULTS: The results demonstrated that selinexor significantly inhibited tumor growth in the cholangiocarcinoma PDX model and promoted the accumulation of PEG3 protein within the nuclei of tumor cells. In vitro experiments showed that selinexor effectively suppressed cholangiocarcinoma cell proliferation, invasion, and migration, while also impeding the cell cycle and inducing apoptosis. Notably, selinexor markedly facilitated the nuclear accumulation of PEG3 protein in cholangiocarcinoma cells. However, when PEG3 expression was knocked down, the effects of selinexor on cholangiocarcinoma were significantly reversed. CONCLUSION: These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.

RESUMEN

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

Asunto(s)

Adenocarcinoma del Pulmón , Resistencia a Antineoplásicos , Receptores ErbB , Glutatión Transferasa , Neoplasias Pulmonares , Proteínas Nucleares , Nucleofosmina , Inhibidores de Proteínas Quinasas , Humanos , Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Ratones , Línea Celular Tumoral , Metástasis de la Neoplasia , Transducción de Señal , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , FN-kappa B/metabolismo

RESUMEN

Sphingolipids play an important role in cotton fiber development, but the regulatory mechanism is largely unclear. We found that serine palmitoyltransferase (SPT) enzyme inhibitors, myriocin and sphingosine (dihydrosphingosine (DHS) and phytosphingosine (PHS)), affected early fiber elongation in cotton, and we performed a sphingolipidomic and transcriptomic analysis of control and PHS-treated fibers. Myriocin inhibited fiber elongation, while DHS and PHS promoted it in a dose-effect manner. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that contents of 22 sphingolipids in the PHS-treated fibers for 10 days were changed, of which the contents of 4 sphingolipids increased and 18 sphingolipids decreased. The transcriptome analysis identified 432 differentially expressed genes (238 up-regulated and 194 down-regulated) in the PHS-treated fibers. Among them, the phenylpropanoid biosynthesis pathway is the most significant enrichment. The expression levels of transcription factors such as MYB, ERF, LBD, and bHLH in the fibers also changed, and most of MYB and ERF were up-regulated. Auxin-related genes IAA, GH3 and BIG GRAIN 1 were up-regulated, while ABPs were down-regulated, and the contents of 3 auxin metabolites were decreased. Our results provide important sphingolipid metabolites and regulatory pathways that influence fiber elongation.

RESUMEN

In brief: Genes expressed in cumulus cells might be used as markers for competent oocytes/embryos. This study identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos. Abstract: Studies on the mechanisms behind cumulus expansion and cumulus cell (CC) apoptosis are essential for understanding the mechanisms for oocyte maturation. Genes expressed in CCs might be used as markers for competent oocytes and/or embryos. In this study, both in vitro (IVT) and in vivo (IVO) mouse oocyte models with significant difference in cumulus expansion and CC apoptosis were used to identify and validate new genes regulating cumulus expansion and CC apoptosis of mouse oocytes. We first performed mRNA sequencing and bioinformatic analysis using the IVT oocyte model to identify candidate genes. We then analyzed functions of the candidate genes by RNAi or gene overexpression to select the candidate cumulus expansion and CC apoptosis-regulating genes. Finally, we validated the cumulus expansion and CC apoptosis-regulating genes using the IVO oocyte model. The results showed that while Spp1, Sdc1, Ldlr, Ezr and Mmp2 promoted, Bmp2, Angpt2, Edn1, Itgb8, Cxcl10 and Agt inhibited cumulus expansion. Furthermore, Spp1, Sdc1 and Ldlr inhibited CC apoptosis. In conclusion, by using both IVT and IVO oocyte models, we have identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos and for elucidating the molecular mechanisms behind oocyte maturation.

Asunto(s)

Apoptosis , Células del Cúmulo , Perfilación de la Expresión Génica , Oocitos , Animales , Células del Cúmulo/metabolismo , Oocitos/metabolismo , Oocitos/fisiología , Ratones , Femenino , Técnicas de Maduración In Vitro de los Oocitos , Sindecano-1/metabolismo , Sindecano-1/genética , Oogénesis/genética , Osteopontina

RESUMEN

BACKGROUND: Ubiquilin-4 (UBQLN4), a member of the ubiquilin family, has received limited attention in cancer research to date. Here, we investigated for the first time the functional role and mechanism of UBQLN4 in non-small cell lung cancer (NSCLC). METHODS: The Cancer Genome Atlas (TCGA) database was employed to validate UBQLN4 as a differentially expressed gene. Expression differences of UBQLN4 in NSCLC cells and tissues were assessed using immunohistochemistry (IHC) experiment and western blotting (WB) experiment. Kaplan-Meier analysis was conducted to examine the association between UBQLN4 expression and NSCLC prognosis. Functional analyses of UBQLN4 were performed through cell counting kit-8 (CCK-8), colony formation, and transwell invasion assays. The impact of UBQLN4 on tumor-associated signaling pathways was assessed using the path scan intracellular signaling array. In vivo tumorigenesis experiments were conducted to further investigate the influence of UBQLN4 on tumor formation. RESULTS: UBQLN4 exhibited up-regulation in both NSCLC tissues and cells. Additionally, over-expression of UBQLN4 was associated with an unfavorable prognosis in NSCLC patients. Functional loss analyses demonstrated that inhibiting UBQLN4 could suppress the proliferation and invasion of NSCLC cells in both in vitro and in vivo settings. Conversely, functional gain experiments yielded opposite results. Path scan intracellular signaling array results suggested that the role of UBQLN4 is associated with the PI3K/AKT pathway, a correlation substantiated by in vitro and in vivo tumorigenesis experiments. CONCLUSION: We validated that UBQLN4 promotes proliferation and invasion of NSCLC cells by activating the PI3K/AKT pathway, thereby facilitating the progression of NSCLC. These findings underscore the potential of targeting UBQLN4 as a therapeutic strategy for NSCLC.

Asunto(s)

Proteínas Relacionadas con la Autofagia , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Neoplasias Pulmonares , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Animales , Ratones , Femenino , Masculino , Pronóstico , Línea Celular Tumoral , Ratones Desnudos , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Portadoras , Proteínas Nucleares

RESUMEN

Importance: Although augmenting large language models (LLMs) with knowledge bases may improve medical domain-specific performance, practical methods are needed for local implementation of LLMs that address privacy concerns and enhance accessibility for health care professionals. Objective: To develop an accurate, cost-effective local implementation of an LLM to mitigate privacy concerns and support their practical deployment in health care settings. Design, Setting, and Participants: ChatZOC (Sun Yat-Sen University Zhongshan Ophthalmology Center), a retrieval-augmented LLM framework, was developed by enhancing a baseline LLM with a comprehensive ophthalmic dataset and evaluation framework (CODE), which includes over 30 000 pieces of ophthalmic knowledge. This LLM was benchmarked against 10 representative LLMs, including GPT-4 and GPT-3.5 Turbo (OpenAI), across 300 clinical questions in ophthalmology. The evaluation, involving a panel of medical experts and biomedical researchers, focused on accuracy, utility, and safety. A double-masked approach was used to try to minimize bias assessment across all models. The study used a comprehensive knowledge base derived from ophthalmic clinical practice, without directly involving clinical patients. Exposures: LLM response to clinical questions. Main Outcomes and Measures: Accuracy, utility, and safety of LLMs in responding to clinical questions. Results: The baseline model achieved a human ranking score of 0.48. The retrieval-augmented LLM had a score of 0.60, a difference of 0.12 (95% CI, 0.02-0.22; P = .02) from baseline and not different from GPT-4 with a score of 0.61 (difference = 0.01; 95% CI, -0.11 to 0.13; P = .89). For scientific consensus, the retrieval-augmented LLM was 84.0% compared with the baseline model of 46.5% (difference = 37.5%; 95% CI, 29.0%-46.0%; P < .001) and not different from GPT-4 with a value of 79.2% (difference = 4.8%; 95% CI, -0.3% to 10.0%; P = .06). Conclusions and Relevance: Results of this quality improvement study suggest that the integration of high-quality knowledge bases improved the LLM's performance in medical domains. This study highlights the transformative potential of augmented LLMs in clinical practice by providing reliable, safe, and practical clinical information. Further research is needed to explore the broader application of such frameworks in the real world.

Asunto(s)

Oftalmología , Humanos , Bases del Conocimiento

RESUMEN

Although the cell membrane and cytoskeleton play essential roles in cellular morphogenesis, the interaction between the membrane and cytoskeleton is poorly understood. Cotton fibers are extremely elongated single cells, which makes them an ideal model for studying cell development. Here, we used the sphingolipid biosynthesis inhibitor, fumonisin B1 (FB1), and found that it effectively suppressed the myeloblastosis (MYB) transcription factor GhMYB86, thereby negatively affecting fiber elongation. A direct target of GhMYB86 is GhTUB7, which encodes the tubulin protein, the major component of the microtubule cytoskeleton. Interestingly, both the overexpression of GhMYB86 and GhTUB7 caused an ectopic microtubule arrangement at the fiber tips, and then leading to shortened fibers. Moreover, we found that GhMBE2 interacted with GhMYB86 and that FB1 and reactive oxygen species induced its transport into the nucleus, thereby enhancing the promotion of GhTUB7 by GhMYB86. Overall, we established a GhMBE2-GhMYB86-GhTUB7 regulation module for fiber elongation and revealed that membrane sphingolipids affect fiber elongation by altering microtubule arrangement.

RESUMEN

In mammals, specificity protein 1 (SP1) was the first Cys2-His2 zinc finger transcription factor to be isolated within the specificity protein and Krüppel-like factor (Sp/KLF) gene family. SP1 regulates gene expression by binding to Guanine-Cytosine (GC)-rich sequences on promoter regions of target genes, affecting various cellular processes. Additionally, the activity of SP1 is markedly influenced by posttranslational modifications, such as phosphorylation, acetylation, glycosylation, and proteolysis. SP1 is implicated in the regulation of apoptosis, cell hypertrophy, inflammation, oxidative stress, lipid metabolism, plaque stabilization, endothelial dysfunction, fibrosis, calcification, and other pathological processes. These processes impact the onset and progression of numerous cardiovascular disorders, including coronary heart disease, ischemia-reperfusion injury, cardiomyopathy, arrhythmia, and vascular disease. SP1 emerges as a potential target for the prevention and therapeutic intervention of cardiac ailments. In this review, we delve into the biological functions, pathophysiological mechanisms, and potential clinical implications of SP1 in cardiac pathology to offer valuable insights into the regulatory functions of SP1 in heart diseases and unveil novel avenues for the prevention and treatment of cardiovascular conditions.

Asunto(s)

Enfermedades Cardiovasculares , Factor de Transcripción Sp1 , Humanos , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/terapia , Animales , Regulación de la Expresión Génica

RESUMEN

Quantum networks promise unprecedented advantages in information processing and open up intriguing new opportunities in fundamental research, where network topology and network nonlocality fundamentally underlie these applications. Hence, the detections of network topology and nonlocality are crucial, which, however, remain an open problem. Here, we conceive and experimentally demonstrate to determine the network topology and network nonlocality hosted by a triangle quantum network comprising three parties, within and beyond Bell theorem, with a general witness operator for the first time. We anticipate that this unique approach may stimulate further studies toward the efficient characterization of large complex quantum networks so as to better harness the advantage of quantum networks for quantum information applications.