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A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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COVID-19/inmunología , Megacariocitos/inmunología , Monocitos/inmunología , ARN Viral , SARS-CoV-2/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , China , Estudios de Cohortes , Citocinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , ARN Viral/aislamiento & purificación , Análisis de la Célula Individual , Transcriptoma/inmunología , Adulto JovenRESUMEN
Particles and crystals constitute a unique class of toxic agents that humans are constantly exposed to both endogenously and from the environment. Deposition of particulates in the body is associated with a range of diseases and toxicity. The mechanism by which particulates cause disease remains poorly understood due to the lack of mechanistic insights into particle-biological interactions. Recent research has revealed that many particles and crystals activate the NLRP3 inflammasome, an intracellular pattern-recognition receptor. Activated NLRP3 forms a supramolecular complex with an adaptor protein to activate caspase 1, which in turn activates IL-1ß and IL-18 to instigate inflammation. Genetic ablation and pharmacological inhibition of the NLRP3 inflammasome dampen inflammatory responses to particulates. Nonetheless, how particulates activate NLRP3 remains a challenging question. From this perspective, we discuss our current understanding of and progress on revealing the function and mode of action of the NLRP3 inflammasome in mediating adaptive and pathologic responses to particulates in health and disease.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamación , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Caspasa 1/metabolismoRESUMEN
The hippocampus is an important part of the limbic system in the human brain that has essential roles in spatial navigation and the consolidation of information from short-term memory to long-term memory1,2. Here we use single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis to illustrate the cell types, cell linage, molecular features and transcriptional regulation of the developing human hippocampus. Using the transcriptomes of 30,416 cells from the human hippocampus at gestational weeks 16-27, we identify 47 cell subtypes and their developmental trajectories. We also identify the migrating paths and cell lineages of PAX6+ and HOPX+ hippocampal progenitors, and regional markers of CA1, CA3 and dentate gyrus neurons. Multiomic data have uncovered transcriptional regulatory networks of the dentate gyrus marker PROX1. We also illustrate spatially specific gene expression in the developing human prefrontal cortex and hippocampus. The molecular features of the human hippocampus at gestational weeks 16-20 are similar to those of the mouse at postnatal days 0-5 and reveal gene expression differences between the two species. Transient expression of the primate-specific gene NBPF1 leads to a marked increase in PROX1+ cells in the mouse hippocampus. These data provides a blueprint for understanding human hippocampal development and a tool for investigating related diseases.
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Linaje de la Célula , Regulación del Desarrollo de la Expresión Génica/genética , Hipocampo/citología , Hipocampo/embriología , Animales , Proteínas Portadoras/metabolismo , Giro Dentado/citología , Giro Dentado/embriología , Giro Dentado/metabolismo , Evolución Molecular , Femenino , Hipocampo/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neurogénesis , Neuronas/citología , Neuronas/metabolismo , Factor de Transcripción PAX6/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/embriología , Corteza Prefrontal/metabolismo , Especificidad de la Especie , Transcriptoma/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1ß, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental exposures, and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small molecule inhibitors. New structural and mechanistic insights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease. SIGNIFICANCE STATEMENT: The NLRP3 inflammasome plays central role in innate immune sensing and control of inflammation. Pharmacological inhibition of NLRP3 demonstrated promising efficacy in a range of diseases in animal models. Recent elucidation of the structure and inhibitor binding of NLRP3 generated new insights into its mode of action and inhibitor-NLRP3 interaction at molecular levels, providing new framework for developing small chemical inhibitors of NLRP3 with improved efficacy and specificity against chronic disease that has become major health concerns worldwide.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estructura Molecular , Transducción de Señal , Inflamación/tratamiento farmacológico , Inflamación/metabolismoRESUMEN
Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without Phf8 knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. © 2024 The Pathological Society of Great Britain and Ireland.
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Factor de Transcripción E2F1 , Transición Epitelial-Mesenquimal , Histona Demetilasas , Neoplasias de la Próstata , Factores de Transcripción de la Familia Snail , Factores de Transcripción , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/enzimología , Animales , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Ratones , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Ratones Noqueados , Transducción de Señal , Metástasis de la Neoplasia , Ratones Transgénicos , Movimiento CelularRESUMEN
We report a study of thickness-dependent interband and intraband magnetic breakdown by thermoelectric quantum oscillations in ZrSiSe nanoplates. Under high magnetic fields of up to 30 T, quantum oscillations arising from degenerated hole pockets were observed in thick ZrSiSe nanoplates. However, when decreasing the thickness, plentiful multifrequency quantum oscillations originating from hole and electron pockets are captured. These multiple frequencies can be explained by the emergent interband magnetic breakdown enclosing individual hole and electron pockets and intraband magnetic breakdown within spin-orbit coupling (SOC) induced saddle-shaped electron pockets, resulting in the enhanced contribution to thermal transport in thin ZrSiSe nanoplates. These experimental frequencies agree well with theoretical calculations of the intriguing tunneling processes. Our results introduce a new member of magnetic breakdown to the field and open up a dimension for modulating magnetic breakdown, which holds fundamental significance for both low-dimensional topological materials and the physics of magnetic breakdown.
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BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer with high aggressive phenotype and poor prognosis. Accumulating evidence suggests that circRNAs have been identified as pivotal mediators in cancers. However, the role of circRNAs in ccRCC progression remains elusive. METHODS: The differentially expressed circRNAs in 4 paired human ccRCC and adjacent noncancerous tissues ccRCC were screened using circRNA microarrays and the candidate target was selected based on circRNA expression level using weighted gene correlation network analysis (WGCNA) and the gene expression omnibus (GEO) database. CircPDHK1 expression in ccRCC and adjacent noncancerous tissues (n = 148) were evaluated along with clinically relevant information. RT-qPCR, RNase R digestion, and actinomycin D (ActD) stability test were conducted to identify the characteristics of circPDHK1. The subcellular distribution of circPDHK1 was analyzed by subcellular fractionation assay and fluorescence in situ hybridization (FISH). Immunoprecipitation-mass spectrometry (IP-MS) and immunofluorescence (IF) were employed to evaluate the protein-coding ability of circPDHK1. ccRCC cells were transfected with siRNAs, plasmids or lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPDHK1 and its encoded peptide PDHK1-241aa. RNA-sequencing, western blot analysis, immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) assays were further employed to identify the underlying mechanisms regulated by PDHK1-241aa. RESULTS: CircPDHK1 was upregulated in ccRCC tissues and closely related to WHO/ISUP stage, T stage, distant metastasis, VHL mutation and Ki-67 levels. CircPDHK1 had a functional internal ribosome entry site (IRES) and encoded a novel peptide PDHK1-241aa. Functionally, we confirmed that PDHK1-241aa and not the circPDHK1 promoted the proliferation, migration and invasion of ccRCC. Mechanistically, circPDHK1 was activated by HIF-2A at the transcriptional level. PDHK1-241aa was upregulated and interacted with PPP1CA, causing the relocation of PPP1CA to the nucleus. This thereby inhibited AKT dephosphorylation and activated the AKT-mTOR signaling pathway. CONCLUSIONS: Our data indicated that circPDHK1-encoded PDHK1-241aa promotes ccRCC progression by interacting with PPP1CA to inhibit AKT dephosphorylation. This study provides novel insights into the multiplicity of circRNAs and highlights the potential use of circPDHK1 or PDHK1-241aa as a therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Ratones , Humanos , Carcinoma de Células Renales/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Circular/genética , Ratones Desnudos , Hibridación Fluorescente in Situ , Línea Celular Tumoral , Transducción de Señal/genética , Neoplasias Renales/genética , Serina-Treonina Quinasas TOR/metabolismo , Proliferación Celular/genética , Péptidos/genética , Regulación Neoplásica de la Expresión Génica , Proteína Fosfatasa 1/genética , Proteína Fosfatasa 1/metabolismoRESUMEN
Esophageal squamous cell carcinoma (ESCC) represents a frequently seen malignancy with high prevalence worldwide. Although current studies have shown that Wilms' tumor 1-associated protein (WTAP), a major part in the methyltransferase complex, is involved in various tumor pathological processes, its specific role in ESCC remains unclear. Therefore, the present work focused on exploring WTAP's function and mechanism in ESCC progression using clinical ESCC specimens, ESCC cells, and mammalian models. Firstly, we proved WTAP was significantly upregulated within ESCC, and WTAP mRNA expression showed a good diagnostic performance for ESCC. Functionally, WTAP positively regulated in-vivo and in-vitro ESCC cells' malignant phenotype through the AKT-mTOR signaling pathway. Meanwhile, WTAP positively regulated the N6-methyladenosine (m6A) modification levels in ESCC cells. Protein tyrosine phase type IVA member 1 (PTP4A1) was confirmed to be the m6A target of WTAP, and WTAP positively regulated the expression of PTP4A1. Further study revealed that PTP4A1 showed high expression within ESCC. Silencing PTP4A1 inhibited the AKT-mTOR signaling pathway to suppress ESCC cells' proliferation. Rescue experiments showed that silencing PTP4A1 partially reversed the WTAP-promoting effect on ESCC cells' proliferation ability. Mechanistically, WTAP regulated PTP4A1 expression to activate the AKT-mTOR pathway, promoting the proliferation of ESCC cells. Our study demonstrated that WTAP regulates the progression of ESCC through the m6A-PTP4A1-AKT-mTOR signaling axis and that WTAP is a potential target for diagnosing and treating ESCC.
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Adenosina , Proteínas de Ciclo Celular , Proliferación Celular , Epigénesis Genética , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Adenosina/análogos & derivados , Adenosina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Empalme de ARN , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Regulación hacia ArribaRESUMEN
Due to the ideal optical manipulation ability, the metasurface has broad prospects in the development of novel optical research. In particular, an active metasurface can control optical response through external stimulus, which has attracted great research interest. However, achieving effective modulation of the optical response is a significant challenge. In this work, we have developed a novel electrochemiluminescence (ECL) signal modulation strategy by an active magnetoplasmonic metasurface under an external magnetic field. The magnetoplasmonic metasurface was assembled based on yolk-shell Fe3O4@Au nanoparticles (Fe3O4@Au YS-NPs). On the one hand, the yolk-shell structure of Fe3O4@Au YS-NPs possessed the surface plasmon coupling effect and cavity-based Purcell effect, which provided high-intensity electromagnetic hot spots in the magnetoplasmonic metasurface. On the other hand, due to the strong magnetic response of the Fe3O4 core, the local magnetic field was induced by the external magnetic field, which further generated Lorentz force acting on the free electrons of Au nanoshells with strong optical anisotropy. The plasmon frequency of the metasurface can be effectively modulated by the Lorentz force effect. As a result, the ECL signal of nitrogen dots (N dots) was dynamically modulated and significantly enhanced at a specific polarization angle by the magnetoplasmonic metasurface under the variable external magnetic field. Based on the luminescence modulation ability and structure feature, the magnetoplasmonic metasurface was further established successfully as a sensing interface for gastric cancer (GC) extracellular vesicle (EV) detection. This study illustrated that the electromagnetic response of the active metasurface can effectively improve the optical modulation ability and luminescence sensing performance.
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Direct analysis in real time (DART) enables direct desorption and ionization of analytes, bypassing the time-consuming chromatographic separation traditionally required for mass spectrometry (MS) analysis. However, DART-MS suffers from matrix interference of complex samples, resulting in compromised detection sensitivity and quantitation accuracy. In this study, DART-MS was combined with differential mobility spectrometry (DMS) to provide an additional dimension of post-ionization ion mobility separation within a millisecond time scale, compensating for the lack of separation in DART-MS analysis. As proof-of-concept, primary aromatic amines (PAAs), a class of potentially hazardous chemicals, were analyzed in various toy products, including bubble solutions, finger paints, and plush toys. In addition to commercial Dip-it glass rod and metal mesh sampling tools, a customized rapid extractive evaporation device was designed for the accelerated extraction and sensitive analysis of solid toy samples. The incorporation of DMS in DART-MS analysis enabled the rapid separation and differentiation of isomeric analytes, leading to improved accuracy and reliability. The developed protocols were optimized and validated, achieving good linearity with correlation coefficients greater than 0.99 and acceptable repeatability with relative standard deviations less than 10%. Moreover, satisfactory sensitivity was realized with limits of detection and quantitation ranges of 0.2-5 and 1-20 µg/kg (µg/L) for the 11 PAA analytes. The established methodology was applied for the analysis of real toy samples (n = 18), which confirmed its appealing potential for toy safety screening and consumer health protection.
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Aminas , Juego e Implementos de Juego , Reproducibilidad de los Resultados , Espectrometría de Masas/métodos , Análisis Espectral , Aminas/análisisRESUMEN
BACKGROUND: According to former research, the atherosclerotic plaque is thought to be aggravated by intraplaque neovessels (IPN) and intraplaque hemorrhage (IPH). Intriguingly, a lower incidence of IPH was found in plaque treated with melatonin. In this study, we attempted to investigate the impact and underlying mechanism regarding the influences of melatonin upon IPN. METHODS: A mouse model was established by subjecting the high fat diet (HFD)-fed ApoE-/- mice to tandem stenosis (TS) surgery with melatonin and GW9662, a PPARγ antagonist, being given by gavage. In vitro experiment was conducted with HUVECs exposing to according treatments of VEGF, melatonin, GW9662, or Y27632. RESULTS: Plaque and IPN were attenuated by treatment with melatonin, which was then reversed by blocking PPARγ. Western blotting results showed that melatonin increased PPARγ and decreased RhoA/ROCK signaling in carotid artery. Elevated RhoA/ROCK signaling was observed in melatonin-treated mice when PPARγ was blocked. In accordance with it, experiments using protein and mRNA from HUVECs revealed that melatonin inhibited the RhoA/ROCK signaling by enhancing PPARγ. According to in vitro study, melatonin was able to inhibit cell migration and angiogenesis, which was aborted by GW9662. Blockage of ROCK using Y27632 was able to cease the effect of GW9662 and restored the suppression on cell migration and angiogenesis by melatonin. CONCLUSIONS: Our study demonstrates that melatonin is able to curb development of plaque and IPN formation by inhibiting the migration of endothelial cells via PPARγ- RhoA-ROCK pathway. That provides a therapeutic potential for both melatonin and PPARγ agonist targeting IPN, IPH, and atherosclerotic plaque.
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Amidas , Anilidas , Melatonina , Placa Aterosclerótica , Piridinas , Ratones , Animales , Placa Aterosclerótica/metabolismo , Melatonina/farmacología , Melatonina/uso terapéutico , PPAR gamma , Células Endoteliales/metabolismo , Ratones Noqueados para ApoE , Hemorragia , Apolipoproteínas ERESUMEN
Tumor-infiltrating lymphocytes (TILs) play a key role in regulating the host immune response and shaping tumor microenvironment. It has been previously shown that T cell infiltration in penile tumors was associated with clinical outcomes. However, few studies have reported the T cell receptor (TCR) repertoire in patients with penile cancer. In the present study, we evaluated the TCR repertoires in tumor and adjacent normal tissues from 22 patients with penile squamous cell carcinoma (PSCC). Analysis of the T cell receptor beta-variable (TRBV) and joining (TRBJ) genes usage and analysis of complementarity determining region 3 (CDR3) length distribution did not show significant differences between tumor and matched normal tissues. Moreover, analysis of the median Jaccard index indicated a limited overlap of TCR repertoire between these groups. Compared with normal tissues, a significantly lower diversity and higher clonality of TCR repertoire was observed in tumor samples, which was associated with clinical characteristics. Further analysis of transcriptional profiles demonstrated that tumor samples with high clonality showed increased expression of genes associated with CD8 + T cells. In addition, we analyzed the TCR repertoire of CD4 + T cells and CD8 + T cells isolated from tumor tissues. We identified that expanded clonotypes were predominantly in the CD8 + T cell compartment, which presented with an exhausted phenotype. Overall, we comprehensively compared TCR repertoire between penile tumor and normal tissues and demonstrated the presence of distinct T cell immune microenvironments in patients with PSCC.
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Carcinoma de Células Escamosas , Neoplasias del Pene , Masculino , Humanos , Receptores de Antígenos de Linfocitos T , Neoplasias del Pene/genética , Neoplasias del Pene/metabolismo , Regiones Determinantes de Complementariedad/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T CD8-positivos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Microambiente TumoralRESUMEN
With an estimated one million new cases reported annually, gastric cancer (GC) ranks as the fifth most diagnosed malignancy worldwide. The early detection of GC remains a major challenge, and the prognosis worsens either when patients develop resistance to chemotherapy or radiotherapy or when the cancer metastasizes. The precise pathogenesis underlying GC is not well understood, which further complicates its treatment. Circular RNAs (circRNAs), a recently discovered class of noncoding RNAs that originate from parental genes through "back-splicing", have been shown to play a key role in various biological processes in both eukaryotes and prokaryotes. CircRNAs have been linked to cardiovascular diseases, diabetes, hypertension, Alzheimer's disease, and the occurrence and progression of tumors. Prior studies have established that circRNAs play a crucial role in GC, impacting tumorigenesis, diagnosis, progression, and therapy resistance. This review aims to summarize how circRNAs contribute to GC tumorigenesis and progression, examine their roles in the development of drug resistance, discuss their potential as biotechnological drugs, and summarize their response to therapeutic drugs and microorganism in GC.
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ARN Circular , Neoplasias Gástricas , Humanos , ARN Circular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/diagnóstico , Pronóstico , Carcinogénesis/genética , Transformación Celular NeoplásicaRESUMEN
BACKGROUND: Gastric cancer (GC) ranks fifth in global cancer incidence and third in mortality rate among all cancer types. Circular RNAs (circRNAs) have been extensively demonstrated to regulate multiple malignant biological behaviors in GC. Emerging evidence suggests that several circRNAs derived from FNDC3B play pivotal roles in cancer. However, the role of circFNDC3B in GC remains elusive. METHODS: We initially screened circFNDC3B with translation potential via bioinformatics algorithm prediction. Subsequently, Sanger sequencing, qRT-PCR, RNase R, RNA-FISH and nuclear-cytoplasmic fractionation assays were explored to assess the identification and localization of circ0003692, a circRNA derived from FNDC3B. qRT-PCR and ISH were performed to quantify expression of circ0003692 in human GC tissues and adjacent normal tissues. The protein-encoding ability of circ0003692 was investigated through dual-luciferase reporter assay and LC/MS. The biological behavior of circ0003692 in GC was confirmed via in vivo and in vitro experiments. Additionally, Co-IP and rescue experiments were performed to elucidate the interaction between the encoded protein and c-Myc. RESULTS: We found that circ0003692 was significantly downregulated in GC tissues. Circ0003692 had the potential to encode a novel protein FNDC3B-267aa, which was downregulated in GC cells. We verified that FNDC3B-267aa, rather than circ0003692, inhibited GC migration in vitro and in vivo. Mechanistically, FNDC3B-267aa directly interacted with c-Myc and promoted proteasomal degradation of c-Myc, resulting in the downregulation of c-Myc-Snail/Slug axis. CONCLUSIONS: Our study revealed that the novel protein FNDC3B-267aa encoded by circ0003692 suppressed GC metastasis through binding to c-Myc and enhancing proteasome-mediated degradation of c-Myc. The study offers the potential applications of circ0003692 or FNDC3B-267aa as therapeutic targets for GC.
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Fibronectinas , Metástasis de la Neoplasia , Complejo de la Endopetidasa Proteasomal , Proteínas Proto-Oncogénicas c-myc , ARN Circular , Neoplasias Gástricas , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Fibronectinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Masculino , Proteolisis , Ratones Desnudos , Secuencia de Bases , Movimiento Celular/genética , Femenino , RatonesRESUMEN
Semliki Forest virus (SFV) viral replicon particles (VRPs) have been frequently used in various animal models and clinical trials. Chimeric replicon particles offer different advantages because of their unique biological properties. We here constructed a novel three-plasmid packaging system for chimeric SFV/SIN VRPs. The capsid and envelope of SIN structural proteins were generated using two-helper plasmids separately, and the SFV replicon contained the SFV replicase gene, packaging signal of SIN, subgenomic promoter followed by the exogenous gene, and 3' UTR of SIN. The chimeric VRPs carried luciferase or eGFP as reporter genes. The fluorescence and electron microscopy results revealed that chimeric VRPs were successfully packaged. The yield of the purified chimeric VRPs was approximately 2.5 times that of the SFV VRPs (1.38 × 107 TU/ml vs. 5.41 × 106 TU/ml) (p < 0.01). Furthermore, chimeric VRPs could be stored stably at 4°C for at least 60 days. Animal experiments revealed that mice immunized with chimeric VRPs (luciferase) had stronger luciferase expression than those immunized with equivalent amount of SFV VRPs (luciferase) (p < 0.01), and successfully expressed luciferase for approximately 12 days. Additionally, the chimeric VRPs expressed the RBD of SARS-CoV-2 efficiently and induced robust RBD-specific antibody responses in mice. In conclusion, the chimeric VRPs constructed here met the requirements of a gene delivery tool for vaccine development and cancer therapy.
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Virus de los Bosques Semliki , Virus Sindbis , Ratones , Animales , Virus de los Bosques Semliki/genética , Virus Sindbis/genética , Plásmidos/genética , Replicón , Luciferasas/genética , Vectores GenéticosRESUMEN
Polymer electrolyte membrane fuel cells (PEMFCs) represent a promising clean energy solution. However, their widespread adoption faces hurdles related to component optimization. This review explores the pivotal role of ionic liquids (ILs) in enhancing PEMFC performance, focusing on their role in polymer electrolyte membranes, catalyst modification, and other components. By addressing key obstacles, including proton conductivity, catalyst stability, and fuel crossover, ILs provide a pathway towards the widespread commercialization of PEMFCs. In the realm of PEMFC membranes, ILs have shown great potential in improving proton conductivity, mechanical strength, and thermal stability. Additionally, the utilization of ILs as catalyst modifiers has shown promise in enhancing the electrocatalytic activity of electrodes by serving as an effective stabilizer to promote the dispersion of metal nanoparticles, and reduce their agglomeration, thereby augmenting catalytic performance. Furthermore, ILs can be tailored to optimize the catalyst-support interaction, ultimately enhancing the overall fuel cell efficiency. Their unique properties, such as high oxygen solubility and low volatility, offer advantages in terms of reducing mass transport and water management issues. This review not only underscores the promising advancements achieved thus far but also outlines the challenges that must be addressed to unlock the full potential of ILs in PEMFC technology, offering a valuable resource for researchers and engineers working toward the realization of efficient and durable PEMFCs.
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BACKGROUND: Limonin shows promise in alleviating non-alcoholic fatty liver disease. We investigated the mechanisms of limonin against non-alcoholic steatohepatitis (NASH) using network pharmacology and molecular docking. METHODS: Public databases provided NASH- and limonin-associated targets. VennDiagram identified potential limonin targets for NASH. Enrichment analysis explored the limonin-NASH relationship. PPI network analysis, CytoHubba models, and bioinformatics identified hub genes for NASH treatment. Molecular docking assessed limonin's binding ability to hub targets. RESULTS: We found 37 potential limonin targets in NASH, involved in oxidative stress, inflammation, and signaling pathways. PPI network analysis revealed seven hub genes (STAT3, NFKBIA, MTOR, TLR4, CASP8, PTGS2, NFKB1) as NASH treatment targets. Molecular docking confirmed limonin's binding to STAT3, CASP8, and PTGS2. Animal experiments on high-fat diet mice showed limonin reduced hepatic steatosis, lipid accumulation, and expression of p-STAT3/STAT3, CASP8, and PTGS2. CONCLUSION: Limonin's therapeutic effects in NASH may stem from its antioxidant and anti-inflammatory properties. STAT3, CASP8, and PTGS2 are potential key targets for NASH treatment, warranting further investigation.
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Limoninas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Farmacología en Red , Ciclooxigenasa 2/uso terapéutico , Limoninas/farmacología , Limoninas/uso terapéutico , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: Cancer is still a leading cause of mortality. Over the years, cancer therapy has undergone significant advances driven by advancements in science and technology. A promising area of drug discovery in this field involves the development of therapeutic targets for cancer treatment. The urgent need to identify new pharmacological targets arises from the impact of tumor resistance on the effectiveness of current medications. Specifically, the RPS6KB2 gene on chromosome 11 has been implicated in cell cycle regulation and exhibits higher expression levels in tumor tissue. Given this association, there is a potential for this gene to serve as a target for cancer treatment. METHODS: We conducted an analysis using the GTEx, TCGA, and CCLE databases to explore the relationship between RPS6KB2 and immune infiltration, the tumor microenvironment (TME), microsatellite instability (MSI), and more. Cell proliferation was assessed using EDU detection, while cell invasion and migration were evaluated via wound healing and Transwell assays. Additionally, western blot analysis was employed to measure expression of Bax, Bcl-2, MMP2, MMP9, PCNA, and proinflammatory factors. RESULTS: Through data analysis and molecular biology methods, our study carefully examined the potential role of RPS6KB2 in cancer therapy. The data revealed that RPS6KB2 is aberrantly expressed in most cancers and is associated with poor prognosis. Further analysis indicated its involvement in cancer cell apoptosis and migration, as well as its role in cancer immune processes. We validated the significance of RPS6KB2 in hepatocellular carcinoma (HCC), highlighting its capacity to upregulate proinflammatory cytokines. CONCLUSION: Our research indicates that RPS6KB2 is a prognostic biomarker associated with immune infiltration in cancer that can affect antitumor immunity by increasing secretion of proinflammatory factors, providing a potential drug target for cancer treatment.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Quinasas S6 Ribosómicas 90-kDa , Humanos , Citocinas/genética , Inmunoterapia , Microambiente Tumoral/genéticaRESUMEN
D-ribose, an ubiquitous pentose compound found in all living cells, serves as a vital constituent of numerous essential biomolecules, including RNA, nucleotides, and riboflavin. It plays a crucial role in various fundamental life processes. Within the cellular milieu, exogenously supplied D-ribose can undergo phosphorylation to yield ribose-5-phosphate (R-5-P). This R-5-P compound serves a dual purpose: it not only contributes to adenosine triphosphate (ATP) production through the nonoxidative phase of the pentose phosphate pathway (PPP) but also participates in nucleotide synthesis. Consequently, D-ribose is employed both as a therapeutic agent for enhancing cardiac function in heart failure patients and as a remedy for post-exercise fatigue. Nevertheless, recent clinical studies have suggested a potential link between D-ribose metabolic disturbances and type 2 diabetes mellitus (T2DM) along with its associated complications. Additionally, certain in vitro experiments have indicated that exogenous D-ribose exposure could trigger apoptosis in specific cell lines. This article comprehensively reviews the current advancements in D-ribose's digestion, absorption, transmembrane transport, intracellular metabolic pathways, impact on cellular behaviour, and elevated levels in diabetes mellitus. It also identifies areas requiring further investigation.