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Serine/threonine kinase receptor-associated protein (STRAP) serves as a scaffold protein and is engaged in a variety of cellular activities, although its importance in antiviral innate immunity is unknown. We discovered that STRAP works as an interferon (IFN)-inducible positive regulator, facilitating type I IFN signaling during pseudorabies virus infection. Mechanistically, STRAP interacts with TBK1 to activate type I IFN signaling. Both the CT and WD40 7 - 6 domains contribute to the function of STRAP. Furthermore, TBK1 competes with PRV-UL50 for binding to STRAP, and STRAP impedes the degradation of TBK1 mediated by PRV-UL50, thereby increasing the interaction between STRAP and TBK1. Overall, these findings reveal a previously unrecognized role for STRAP in innate antiviral immune responses during PRV infection. STRAP could be a potential therapeutic target for viral infectious diseases.
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Herpesvirus Suido 1 , Inmunidad Innata , Interferón Tipo I , Proteínas Serina-Treonina Quinasas , Animales , Línea Celular , Herpesvirus Suido 1/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Seudorrabia/inmunología , Seudorrabia/virología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Regulación hacia ArribaRESUMEN
BACKGROUND: Although cumulative studies have demonstrated a beneficial effect of high-flow nasal cannula oxygen (HFNC) in acute hypercapnic respiratory failure, randomized trials to compare HFNC with non-invasive ventilation (NIV) as initial treatment in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients with acute-moderate hypercapnic respiratory failure are limited. The aim of this randomized, open label, non-inferiority trial was to compare treatment failure rates between HFNC and NIV in such patients. METHODS: Patients diagnosed with AECOPD with a baseline arterial blood gas pH between 7.25 and 7.35 and PaCO2 ≥ 50 mmHg admitted to two intensive care units (ICUs) at a large tertiary academic teaching hospital between March 2018 and December 2022 were randomly assigned to HFNC or NIV. The primary endpoint was the rate of treatment failure, defined as endotracheal intubation or a switch to the other study treatment modality. Secondary endpoints were rates of intubation or treatment change, blood gas values, vital signs at one, 12, and 48 h, 28-day mortality, as well as ICU and hospital lengths of stay. RESULTS: 225 total patients (113 in the HFNC group and 112 in the NIV group) were included in the intention-to-treat analysis. The failure rate of the HFNC group was 25.7%, while the NIV group was 14.3%. The failure rate risk difference between the two groups was 11.38% (95% CI 0.25-21.20, P = 0.033), which was higher than the non-inferiority cut-off of 9%. In the per-protocol analysis, treatment failure occurred in 28 of 110 patients (25.5%) in the HFNC group and 15 of 109 patients (13.8%) in the NIV group (risk difference, 11.69%; 95% CI 0.48-22.60). The intubation rate in the HFNC group was higher than in the NIV group (14.2% vs 5.4%, P = 0.026). The treatment switch rate, ICU and hospital length of stay or 28-day mortality in the HFNC group were not statistically different from the NIV group (all P > 0.05). CONCLUSION: HFNC was not shown to be non-inferior to NIV and resulted in a higher incidence of treatment failure than NIV when used as the initial respiratory support for AECOPD patients with acute-moderate hypercapnic respiratory failure. TRIAL REGISTRATION: chictr.org (ChiCTR1800014553). Registered 21 January 2018, http://www.chictr.org.cn.
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Cánula , Hipercapnia , Ventilación no Invasiva , Terapia por Inhalación de Oxígeno , Enfermedad Pulmonar Obstructiva Crónica , Insuficiencia Respiratoria , Humanos , Enfermedad Pulmonar Obstructiva Crónica/terapia , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Masculino , Ventilación no Invasiva/métodos , Ventilación no Invasiva/estadística & datos numéricos , Femenino , Anciano , Terapia por Inhalación de Oxígeno/métodos , Terapia por Inhalación de Oxígeno/estadística & datos numéricos , Terapia por Inhalación de Oxígeno/normas , Persona de Mediana Edad , Insuficiencia Respiratoria/terapia , Hipercapnia/terapia , Hipercapnia/etiología , Anciano de 80 o más Años , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricosRESUMEN
Aflatoxin B1 (AFB1) is known to inhibit growth, and inflict hepatic damage by interfering with protein synthesis. Allicin, has been acknowledged as an efficacious antioxidant capable of shielding the liver from oxidative harm. This study aimed to examine the damage caused by AFB1 on bovine hepatic cells and the protective role of allicin against AFB1-induced cytotoxicity. In this study, cells were pretreated with allicin before the addition of AFB1 for co-cultivation. Our findings indicate that AFB1 compromises cellular integrity, suppresses the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, allicin attenuates oxidative damage to bovine hepatic cells caused by AFB1 by promoting the expression of the Nrf2 pathway and reducing cell apoptosis. In conclusion, the results of this study will help advance clinical research and applications, providing new options and directions for the prevention and treatment of liver diseases.
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Aflatoxina B1 , Antioxidantes , Apoptosis , Disulfuros , Hepatocitos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Transducción de Señal , Ácidos Sulfínicos , Animales , Ácidos Sulfínicos/farmacología , Aflatoxina B1/toxicidad , Bovinos , Disulfuros/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antioxidantes/farmacología , FemeninoRESUMEN
BACKGROUND: Empirical research has consistently documented the concurrent manifestation of frailty and chronic kidney disease (CKD). However, the existence of a reverse causal association or the influence of confounding variables on these correlations remains ambiguous. METHODS: Our analysis of 7,078 participants from National Health and Nutrition Examination Survey(NHANES) (1999-2018) applied weighted logistic regression and Mendelian Randomization (MR) to investigate the correlation between the frailty index (FI) and renal function. The multivariate MR analysis was specifically adjusted for type 2 diabetes and hypertension. Further analysis explored 3282 plasma proteins to link FI to CKD. A two-step network MR highlighted immune cells' mediating roles in the FI-CKD relationship. RESULT: Genetically inferred FI and various renal function markers are significantly correlated, as supported by NHANES analyses. Multivariate MR analysis revealed a direct causal association between the FI and CKD. Additionally, our investigation into plasma proteins identified Tmprss11D and MICB correlated with FI and CKD, respectively. A two-step network MR to reveal 15 immune cell types, notably Central Memory CD4+ T cells and Lymphocytes, as crucial mediators between FI and CKD. CONCLUSION: Our work establishes a causal connection between frailty and CKD, mediated by specific immune cell profiles. These findings highlight the importance of immune mechanisms in the frailty-CKD interplay and suggest that targeting shared risk factors and immune pathways could improve management strategies for these conditions. Our research contributes to a more nuanced understanding of frailty and CKD, offering new avenues for intervention and patient care in an aging population.
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Fragilidad , Análisis de la Aleatorización Mendeliana , Encuestas Nutricionales , Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/inmunología , Fragilidad/inmunología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Factores de Riesgo , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/complicaciones , Modelos Logísticos , MultiómicaRESUMEN
The built environment's impact on human activities has been a hot issue in urban research. Compared to motorized spaces, the built environment of pedestrian and cycling street spaces dramatically influences people's travel experience and travel mode choice. The streets' built environment data play a vital role in urban design and management. However, the multi-source, heterogeneous, and massive data acquisition methods and tools for the built environment have become obstacles for urban design and management. To better realize the data acquisition and for deeper understanding of the urban built environment, this study develops a new portable, low-cost Arduino-based multi-sensor array integrated into a single portable unit for built environment measurements of street cycling spaces. The system consists of five sensors and an Arduino Mega board, aimed at measuring the characteristics of the street cycling space. It takes air quality, human sensation, road quality, and greenery as the detection objects. An integrated particulate matter laser sensor, a light intensity sensor, a temperature and humidity sensor, noise sensors, and an 8K panoramic camera are used for multi-source data acquisition in the street. The device has a mobile power supply display and a secure digital card to improve its portability. The study took Beijing as a sample case. A total of 127.97 G of video data and 4794 Kb of txt records were acquired in 36 working hours using the street built environment data acquisition device. The efficiency rose to 8474.21% compared to last year. As an alternative to conventional hardware used for this similar purpose, the device avoids the need to carry multiple types and models of sensing devices, making it possible to target multi-sensor data-based street built environment research. Second, the device's power and storage capabilities make it portable, independent, and scalable, accelerating self-motivated development. Third, it dramatically reduces the cost. The device provides a methodological and technological basis for conceptualizing new research scenarios and potential applications.
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Human noroviruses (huNoVs) cause epidemic acute gastroenteritis using histo-blood group antigens (HBGAs) as host receptors or attachment factors to initiate an infection. While most huNoVs have been shown to bind HBGAs, some known clinical isolates, such as GI.3 DSV and VA115, do not recognize any HBGAs and thus the molecular mechanism behind their infections remains elusive. In this study, we provided both phenotypic and structural evidence to show that huNoV DSV and VA115 recognize a group of glycans with terminal galactoses as ligands. First, through glycan array we found that both DSV and VA115 protruding (P) domain proteins bound two oligosaccharides that share common terminal galactoses. Then, by determination of the crystal structures of DSV/VA115 P proteins in complex with Galα1-3Galß1-4Glc and/or NA2 N-Glycan, respectively, we showed that the terminal galactose is the main saccharide recognized by the two viral proteins. Our data demonstrated that GI huNoVs can interact with non-HBGA glycans through their conserved galactose binding site, shedding light on the mechanism of huNoV adaptation through recognizing new glycan receptors to facilitate their widespread nature in human population. These findings are also of significance in strategy development for huNoV control and prevention, as well as development of antiviral drugs. IMPORTANCE Human noroviruses (huNoVs) are the most important viral pathogens causing epidemic acute gastroenteritis worldwide. Previous studies indicated that histo-blood group antigens (HBGAs) are critical host-susceptibility factors affecting huNoV host susceptibility, host range, and probably prevalence. However, certain huNoVs, such as GI.3 DSV and VA115, do not recognize any HBGAs. This implies that other unknown host factors might exist and the molecular mechanism underlying their host receptor recognition or attachment remains elusive. In this study, we found that purified capsid protruding domain proteins from two GI.3 huNoVs specifically bind two glycans that contain a common terminal galactose. We solved the crystal structures of the complexes at atomic resolution and validated the vital amino acids involved in glycan recognition. Our findings elucidate the mechanism of GI.3 huNoV-non-HBGA glycan interaction, which explains why GI.3 virus strains could not bind human HBGAs, paving a way to the prevention and treatment of huNoV-associated diseases.
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Antígenos de Grupos Sanguíneos , Galactosa , Gastroenteritis , Norovirus , Sitios de Unión , Antígenos de Grupos Sanguíneos/metabolismo , Proteínas de la Cápside/metabolismo , Galactosa/metabolismo , Gastroenteritis/fisiopatología , Humanos , Norovirus/metabolismo , Unión ProteicaRESUMEN
OBJECTIVE: Our study aimed to investigate the correlations between microstructural changes of cingulum and patients with mild cognitive impairment (MCI) by diffusion kurtosis imaging (DKI) technique. METHOD: A total of 104 patients with cerebral small vessel diseases (cSVD) were retrospectively enrolled in this study. According to Montreal Cognitive Assessment Scale (MoCA) scores, these patients were divided into MCI group (n = 59) and non-MCI group (n = 45). The general clinical data was collected and analyzed. The regions of interests (ROIs) were selected for investigation in cingulum. The values of DKI parameters were measured in each ROI and compared between the two groups, the correlations between DKI parameters and MoCA scores were examined. RESULTS: Compared to non-MCI group, MCI patients had more severe white matter hyperintensities (WMHs) (P = 0.038) and lower MoCA scores (P < 0.01). MCI patients showed significantly decreased fractional anisotropy (FA), axial kurtosis (AK), mean kurtosis (MK), radial kurtosis (RK), and kurtosis fractional anisotropy (KFA) in the left cingulum in the cingulated cortex (CgC) region (all P < 0.0125). In the left CgC region, FA, AK, MK, RK, and KFA were positively correlated with MoCA scores (r = 0.348, 0.409, 0.310, 0.441, 0.422, all P < 0.001). Meanwhile, FA, AK, MK, RK, and KFA were also positively correlated with MoCA scores (r = 0.338, 0.352, 0.289, 0.380, 0.370, all P < 0.001) in the right CgC region. CONCLUSION: DKI technique could be used to explore the microstructural changes of cingulum in MCI patients and DKI-derived parameters might be feasible to evaluate MCI patients.
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Disfunción Cognitiva , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Estudios Retrospectivos , Imagen de Difusión Tensora/métodos , Corteza Cerebral , Disfunción Cognitiva/diagnóstico por imagenRESUMEN
The development of nanotechnology is becoming a major trend nowadays. Nanoparticles (NPs) have been widely used in fields including food, biomedicine, and cosmetics, endowing NPs more opportunities to enter the human body. It is well-known that the gut microbiome plays a key role in human health, and the exposure of intestines to NPs is unavoidable. Accordingly, the toxicity of NPs has attracted more attention than before. This review mainly highlights recent advances in the evaluation of NPs' toxicity in the gastrointestinal system from the existing cell-based experimental models, such as the original mono-culture models, co-culture models, three-dimensional (3D) culture models, and the models established on microfluidic chips, to those in vivo experiments, such as mice models, Caenorhabditis elegans models, zebrafish models, human volunteers, as well as computer-simulated toxicity models. Owing to these models, especially those more biomimetic models, the outcome of the toxicity of NPs acting in the gastrointestinal tract can get results closer to what happened inside the real human microenvironment.
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Microbioma Gastrointestinal , Nanopartículas del Metal , Modelos Biológicos , Animales , Humanos , Nanopartículas del Metal/toxicidad , Microbioma Gastrointestinal/efectos de los fármacosRESUMEN
Zearalenone (ZEA) is an estrogen-like mycotoxin, which mainly led to reproductive toxicity. The study aimed to investigate the molecular mechanism of ZEA-induced dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAM) in piglet Sertoli cells (SCs) via the endoplasmic reticulum stress (ERS) pathway. In this study, SCs were used as a research object that was exposed to ZEA, and ERS inhibitor 4-Phenylbutyrate acid (4-PBA) was used as a reference. The results showed that ZEA damaged cell viability and increased Ca2+ levels; damaged the structure of MAM; up-regulated the relative mRNA and protein expression of glucose-regulated protein 75 (Grp75) and mitochondrial Rho-GTPase 1 (Miro1), while inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel 1 (VDAC1), mitofusin2 (Mfn2) and phosphofurin acidic cluster protein 2 (PACS2) were down-regulated. After a 3 h 4-PBA-pretreatment, ZEA was added for mixed culture. The results of 4-PBA pretreatment showed that inhibition of ERS reduced the cytotoxicity of ZEA against piglet SCs. Compared with the ZEA group, inhibition of ERS increased cell viability and decreased Ca2+ levels; restored the structural damage of MAM; down-regulated the relative mRNA and protein expression of Grp75 and Miro1; and up-regulated the relative mRNA and protein expression of IP3R, VDAC1, Mfn2, and PACS2. In conclusion, ZEA can induce MAM dysfunction in piglet SCs via the ERS pathway, whereas ER can regulate mitochondria through MAM.
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Zearalenona , Masculino , Animales , Porcinos , Zearalenona/toxicidad , Células de Sertoli/metabolismo , Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estrés del Retículo EndoplásmicoRESUMEN
The assembly of molecules into hierarchical superstructures is ubiquitous in the construction of novel geometrically complex hierarchical superstructures, attracting great attention. Herein, a metal-ligand cross-linking strategy is developed for the fabrication of ferric ion-dopamine coordination hierarchical superstructures. A range of superstructures with highly complex morphologies, such as flower-like, octopus-like, and hedgehog-like superstructures, are synthesized. The mechanism for formation of hierarchical superstructures involves the pre-cross-linking of ferric ion with dopamine molecules, the fabrication of iron-dopamine precursors aggregated into the spherical aggregates, the nanoscale aggregates sintering and ordering themselves upon equilibration, the nanodots polymerizing into nanorods, and finally the nanorods self-assembling into hierarchical superstructures. In-depth research illustrates that as the permittivity (ξ) of the reaction system increases, the resulting hierarchical superstructures tend to converge into spherical shape. As a proof of concept, the 0D nanospheres, 1D nanorods, and 3D hierarchical superstructures are fabricated through adjusting system permittivity. The hierarchical superstructure is utilized as peroxidase-like ligase mimics to enhance the effect of tumor photothermal treatment. Further in vitro and in vivo assays demonstrate that the hierarchical superstructure can effectively ablate tumor cells. This work opens new horizons in hierarchical superstructures with complex architectures, and has great potential in nanozymology, biomedical science, and catalysis.
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Nanotubos , Neoplasias , Proteínas Hedgehog , Humanos , Ligasas , Nanotubos/química , Neoplasias/terapia , Terapia FototérmicaRESUMEN
Adhesion to many kinds of surfaces, including biological tissues, is important in many fields but has been proved to be extremely challenging. Furthermore, peeling from strong adhesion is needed in many conditions, but is sometimes painful. Herein, a mussel inspired hydrogel is developed to achieve both strong adhesion and trigger-detachment. The former is actualized by electrostatic interactions, covalent bonds, and physical interpenetration, while the latter is triggered, on-demand, through combining a thixotropic supramolecular network and polymer double network. The results of the experiments show that the hydrogel can adhere to various material surfaces and tissues. Moreover, triggered by shear force, non-covalent interactions of the supramolecular network are destroyed. This adhesion can be peeled easily. The possible mechanism involved is discussed and proved. This work will bring new insight into electronic engineering and tissue repair like skin care for premature infants and burn victims.
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Hidrogeles , Adhesivos Tisulares , Adhesivos , Humanos , Hidrogeles/química , Polímeros , Adhesivos Tisulares/química , Cicatrización de HeridasRESUMEN
PURPOSE: Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. METHODS: RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-ß signaling. RESULTS: We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-ß signaling pathway due to its inhibitory role on SMAD7. CONCLUSION: ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future.
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Neoplasias de la Mama , ARN Largo no Codificante , Proteína smad7 , Neoplasias de la Mama/genética , Línea Celular Tumoral , Femenino , Proteínas Activadoras de GTPasa/genética , Humanos , ARN Largo no Codificante/genética , Proteína smad7/genética , Ubiquitina-Proteína LigasasRESUMEN
The adaptation of tumour cells to hypoxic microenvironment is one of the most significant characteristics of many malignant tumour diseases including hepatocarcinoma. Recently, long non-coding RNAs (lncRNAs) have been reported to play important roles in the various levels of gene regulation thus functioning in growth and survival of tumour cells. Here, new hypoxia-related lncRNAs in hepatocarcinoma cells were screened and validated by lncRNA chip-array as well as real-time RT-PCR. Among them, a hypoxia-activated lncRNA that we identified and termed Hypoxia-Activated BNIP3 Overlapping Non-coding RNA (HABON), was not only regulated by hypoxic-induced factor-1α (HIF-1α) but its expression increased significantly under hypoxia in tumour cells. We deciphered the biological characteristics of HABON including its cell localization, genomic location, as well as its full-length sequence, and proved HABON could promote growth, proliferation and clone-formation of hepatocarcinoma cells under hypoxia. Then, we revealed that HABON was transcriptionally activated by HIF-1α in hypoxic cells, furthermore, it could interact with HIF-1α and promote its protein degradation, thus affecting transcription of HIF-1α's target genes to exert its effects on cells. Besides, the elevated expression of HABON under hypoxia could promote the transcriptional activation of BNIP3 through HIF-1α, and increasing the expression level of BNIP3. This research provides a novel clue for the adaptive survival and growth mechanism of tumour under hypoxia, and gives a way to reveal the nature of tumour cells' resistance characteristics to harsh microenvironment.
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Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/fisiopatología , Neoplasias Hepáticas/patología , ARN Largo no Codificante/genética , Apoptosis , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Comunicación Celular , Proliferación Celular , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
Checkpoint blockade therapy has been proven efficacious in lung cancer patients. However, primary/acquired resistance hampers its efficacy. Therefore, there is an urgent need to develop novel strategies to improve checkpoint blockade therapy. Here we tested whether dual inhibition of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) by flavonoid melafolone improves program death 1 (PD-1) checkpoint blockade therapy through normalizing tumor vasculature and PD-1 ligand (PD-L1) downregulation. Virtual screening assay, cellular thermal shift assay, and enzyme inhibition assay identified melafolone as a potential inhibitor of COX-2 and EGFR. In Lewis lung carcinoma (LLC) and CMT167 models, dual inhibition of COX-2 and EGFR by melafolone promoted survival, tumor growth inhibition, and vascular normalization, and ameliorated CD8+ T-cell suppression, accompanied by the downregulation of transforming growth factor-ß (TGF-ß), vascular endothelial growth factor (VEGF), and PD-L1 in the tumor cells. Mechanistically, dual inhibition of COX-2 and EGFR in lung cancer cells by melafolone increased the migration of pericyte, decreased the proliferation and migration of endothelial cells, and enhanced the proliferation and effector function of CD8+ T cells through VEGF, TGF-ß, or PD-L1 downregulation and PI3K/AKT inactivation. Notably, melafolone improved PD-1 immunotherapy against LLC and CMT167 tumors. Together, dual inhibition of COX-2 and EGFR by melafolone improves checkpoint blockade therapy through vascular normalization and PD-L1 downregulation and, by affecting vessels and immune cells, may be a promising combination strategy for the treatment of human lung cancer.
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Antígeno B7-H1/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Flavonoides/farmacología , Neoplasias Pulmonares/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Células A549 , Animales , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma Pulmonar de Lewis , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Flavonoides/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Estructura Secundaria de ProteínaRESUMEN
MicroRNAs (miRNAs) play critical roles in breast cancer cell biological processes, including proliferation and apoptosis by inhibiting the expression of their target genes. Herein, we reported that miR-630 overexpression initiates apoptosis, blocks cell cycle progression and suppresses cell proliferation in breast cancer cells. Furthermore, BMI1, a member of polycomb group family, was identified as a direct target of miR-630, and there was a negative correlation between the expression levels of BMI1 and miR-630 in human breast cancer samples. With a series of biology approaches, subsequently, we proved that BMI1 was a functional downstream target of miR-630 and mediated the property of miR-630-dependent inhibition of breast cancer progression. Taken together, these findings provide further evidence on the tumor-suppression function of miR-630 in breast cancer, and clarify BMI1 as a novel functional target gene of miR-630.
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Neoplasias de la Mama/genética , MicroARNs/genética , Proteína Quinasa 7 Activada por Mitógenos/genética , Apoptosis/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , HumanosRESUMEN
Tumor-associated macrophages (TAMs) are pivotal effector cells in angiogenesis. Here, we tested whether CYP4X1 inhibition in TAMs by flavonoid CH625 prolongs survival and normalizes glioma vasculature. CH625 was selected against the CYP4X1 3D model by virtual screening and showed inhibitory activity on the CYP4X1 catalytic production of 14,15-EET-EA in the M2-polarized human peripheral blood mononuclear cells (IC50 = 16.5 µM). CH625 improved survival and reduced tumor burden in the C6 and GL261 glioma intracranial and subcutaneous model. In addition, CH625 normalized vasculature (evidenced by a decrease in microvessel density and HIF-1α expression and an increase in tumor perfusion, pericyte coverage, and efficacy of temozolomide therapy) accompanied with the decreased secretion of 14,15-EET-EA, VEGF, and TGF-ß in the TAMs. Furthermore, CH625 attenuated vascular abnormalization and immunosuppression induced by coimplantation of GL261 cells with CYP4X1high macrophages. In vitro TAM polarization away from the M2 phenotype by CH625 inhibited proliferation and migration of endothelial cells, enhanced pericyte migration and T cell proliferation, and decreased VEGF and TGF-ß production accompanied with the downregulation of CB2 and EGFR-dependent downstream STAT3 expression. These effects were reversed by overexpression of CYP4X1 and STAT3 or exogenous addition of 14,15-EET-EA, VEGF, TGF-ß, EGF, and CB2 inhibitor AM630. These results suggest that CYP4X1 inhibition in TAMs by CH625 prolongs survival and normalizes tumor vasculature in glioma via CB2 and EGFR-STAT3 axis and may serve as a novel therapeutic strategy for human glioma.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Flavonoides/farmacología , Glioma/irrigación sanguínea , Macrófagos/efectos de los fármacos , Neovascularización Patológica/inmunología , Receptor Cannabinoide CB2/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Regulación hacia Abajo/efectos de los fármacos , Receptores ErbB/metabolismo , Glioma/patología , Humanos , Macrófagos/metabolismo , Neovascularización Patológica/metabolismo , Factor de Transcripción STAT3/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30â¯mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the synovial fluid macrophages. In addition, leonurine decreased representative M1 marker (iNOS and CD86) expression, NLRP3 inflammasome activation and M1 cytokine (TNF-α and IL-1ß) production. In the in vitro cultured RAW264.7 and human monocyte-derived macrophages (MDMs), blockade of COX-2/mPGES-1 and 5-LOX by leonurine inhibited macrophage M1 polarization and NLRP3 inflammasome activation in response to MSU crystals, and thus down-regulated IL-1ß and TNF-α with STAT1 and NF-κB inactivation. Conversely, these effects were partially abolished by overexpression of COX-2, mPGES-1, 5-LOX or STAT1. Furthermore, leonurine prevented a positive feedback loop between COX-2/mPGES-1/5-LOX and IL-1ß/TNF-α in MSU crystal-induced inflammation. Together, simultaneous down-regulation of COX-2/mPGES-1 and 5-LOX by leonurine ameliorates MSU crystal-induced inflammation through decreasing IL-1ß and TNF-α production. Our study may provide novel multi-target agents toward the arachidonic acid (AA) network for gouty arthritis therapy.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Artritis Gotosa/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Ácido Gálico/análogos & derivados , Prostaglandina-E Sintasas/metabolismo , Ácido Úrico/toxicidad , Animales , Artritis Gotosa/inducido químicamente , Artritis Gotosa/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Relación Dosis-Respuesta a Droga , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Simulación del Acoplamiento Molecular/métodos , Prostaglandina-E Sintasas/antagonistas & inhibidores , Estructura Secundaria de Proteína , Células RAW 264.7 , Ratas , Ratas WistarRESUMEN
Dengue is the most prevalent mosquito-borne viral disease in tropical and subtropical regions worldwide. Since its clinical symptoms are non-specific and easily mistaken as other kinds of infection, laboratory diagnosis is required to confirm dengue infections. In this study, ten peptides (E1-E10) from the envelope protein of dengue virus (DENV) were first identified using bioinformatic tool. The screened peptides were then synthesized for the peptide-based chemiluminescence enzyme immunoassay (CLEIA). Two peptides, E1 and E7, were found as the best candidate antigen and therefore used as downstream application in the development of low-cost peptide-based anti-DENV immunoglobulin M antibodies (IgM) indirect CLEIA. 176 serum samples were used to study the presence of anti-DENV IgM antibodies to evaluate the diagnostic ability of IgM-CLEIA. Receiver operating characteristic curve (ROC) was used to estimate the diagnostic cut-off value. The sensitivity and the specificity reached 82.5% and 94.6% respectively when peptide E1 was used, but declined to 79.2% and 92.9% respectively when peptide E7 was used. Therefore, the combination of E1 and E7 was used to improve the sensitivity and the specificity to 85.0% and 96.4% respectively in 1.5â¯h assay time, providing a potentially practical use for the diagnosis of DENV infections in patients' serum.
Asunto(s)
Anticuerpos Antivirales/sangre , Virus del Dengue/química , Dengue/sangre , Inmunoglobulina M/química , Mediciones Luminiscentes/métodos , Péptidos/química , Proteínas Virales/química , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , MasculinoRESUMEN
Inspired by the biological growth that takes place in time-varying external fields such as light or temperature, we design an open reaction-diffusion system in order to investigate growth dynamics. The system is composed of the Belousov-Zhabotinsky (BZ) oscillatory reaction coupled with a copolymer gel consisting of NIPAAm and a photosensitive ruthenium catalyst. When subject to a unidirectional flow of the BZ reactants, the system displays groups of chemical waves whose structure depends upon the period and amplitude of illumination. Simulations of a modified six-variable Oregonator model exhibit all the complex wave groups found in our experiments. Studying this growth structure may aid in understanding the influence of periodic environmental variation on complex growth processes in living systems.