RESUMEN
Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
Asunto(s)
Antineoplásicos , Ácido Ascórbico , Estructuras Metalorgánicas , Linfocitos T , Animales , Ratones , Estructuras Metalorgánicas/química , Ácido Ascórbico/química , Ácido Ascórbico/farmacología , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Inmunoterapia , Bortezomib/química , Bortezomib/farmacología , Bortezomib/uso terapéutico , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Escherichia coli/efectos de los fármacos , Dióxido de Silicio/química , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Magnesio/química , Nanopartículas/química , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Liberación de FármacosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis and a 5-year survival rate of less than 11%. As a member of the CAP superfamily of proteins, the role of peptidase inhibitor 16 (Pi16) in tumor progression is still unclear. Immunohistochemistry and quantitative RT-PCR methods were used to detect the expression levels of Pi16 protein and mRNA in PDAC patients. CRISPR/Cas9 technology was used to knock out the expression of Pi16 in PDAC cell lines. In vivo and in vitro experiments were used to verify the effect of Pi16 on PDAC proliferation ability. By RNA sequencing, we found that oligoadenylate synthetase L (OASL) can serve as a potential downstream target of Pi16. The expression of Pi16 was higher in PDAC tissues than in matched adjacent tissues. High expression of Pi16 was associated with PDAC progression and poor prognosis. Overexpression of Pi16 could promote the proliferation of PDAC cells in vitro and in vivo. Bioinformatics analysis and coimmunoprecipitation assays showed that Pi16 could bind to OASL. Moreover, the functional recovery test confirmed that Pi16 could promote the proliferation of PDAC via OASL. Our present study demonstrates that Pi16 might participate in the occurrence and development of PDAC by regulating cell proliferation by binding to OASL, indicating that Pi16 might be a promising novel therapeutic target for PDAC.
Asunto(s)
2',5'-Oligoadenilato Sintetasa , Nucleótidos de Adenina , Carcinoma Ductal Pancreático , Glicoproteínas , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Glicoproteínas/metabolismo , Proteínas Portadoras/metabolismo , 2',5'-Oligoadenilato Sintetasa/metabolismoRESUMEN
Microalgae act as the entrance of polybrominated diphenyl ethers (PBDEs) from abiotic to biotic environments, which controlled the environmental fate of PBDEs in aquatic environments. Combing with typical coastal environmental characteristics including extracellular polymer substances (EPS) enrichment, light limitation and nitrogen starvation, the changes of adsorption and absorption kinetics of BDE-47 by Chlorella sp. and the role of EPS therein were investigated. The results quantified the adsorption and absorption kinetics of BDE-47 by Chlorella sp. cells and fitted it by the Lagergren pseudo first order model. Furthermore, we found the adsorption and absorption kinetics could be changed by the above mentioned environmental factors. To be specific, the total BDE-47 adsorption amounts per microalgal cell were increased as the increase of ambient EPS (proteins or carbohydrates), attributing to the increase of soluble (SL)-EPS contents; increased total BDE-47 adsorption amounts but decreased absorption rates were found under light limitation and nitrogen starvation, which were attributed to increased bound (B)-EPS contents and protein/carbohydrates (P/C) ratios therein, respectively. Therefore, our study elucidated the adsorption and absorption kinetics of PBDEs by microalgae could be influenced by ambient environmental changes, clarified the roles of SL-EPS, B-EPS contents and P/C ratios, providing a solid basis for evaluating the environmental fate of PBDEs in the marine environments.
Asunto(s)
Chlorella , Microalgas , Éteres Difenilos Halogenados/metabolismo , Adsorción , Chlorella/metabolismo , Cinética , Microalgas/metabolismo , Nitrógeno , Carbohidratos , PolímerosRESUMEN
BACKGROUND: circular RNAs (circRNAs) have been reported to play crucial roles in the biology of different cancers. However, little is known about the function of circSTX6 (hsa_circ_0007905) in pancreatic ductal adenocarcinoma (PDAC). METHODS: circSTX6, a circRNA containing exons 4, 5, 6 and 7 of the STX6 gene, was identified by RNA sequencing and detected by quantitative reverse transcription PCR (qRT-PCR). The biological function of circSTX6 was assessed in vitro and in vivo. The relationship between circSTX6 and miR-449b-5p was confirmed by biotin-coupled circRNA capture, fluorescence in situ hybridization (FISH) and luciferase reporter assays. The interaction of circSTX6 with Cullin 2 (CUL2) was verified by RNA-protein RNA pull-down, RNA immunoprecipitation (RIP) and western blotting assays. RESULTS: circSTX6 was frequently upregulated in PDAC tissues, and circSTX6 overexpression promoted tumor proliferation and metastasis both in vitro and in vivo. Furthermore, circSTX6 expression was associated with tumor differentiation and N stage. Mechanistically, circSTX6 regulated the expression of non-muscle myosin heavy chain 9 (MYH9) by sponging miR-449b-5p. Moreover, circSTX6 was confirmed to participate in the ubiquitin-dependent degradation of hypoxia-inducible factor 1-alpha (HIF1A) by interacting with CUL2 and subsequently accelerating the transcription of MYH9. CONCLUSIONS: Our findings indicate that circSTX6 facilitates proliferation and metastasis of PDAC cells by regulating the expression of MYH9 through the circSTX6/miR-449b-5p axis and circSTX6/CUL2/HIF1A signaling pathway. Therefore, circSTX6 could serve as a potential therapeutic target for the treatment of PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Proteínas Cullin , MicroARNs , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proteínas Cullin/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , MicroARNs/genética , Neoplasias Pancreáticas/patología , Proteínas Qa-SNARE , ARN Circular/genética , Neoplasias PancreáticasRESUMEN
Newcastle disease virus (NDV), an avian paramyxovirus, possesses the ability to kill tumor cells. Here, we report the effects of NDV strain D90, which was isolated in China, against oral squamous cell carcinoma (OSCC) cells. In this study, we showed that the cell death induced by D90 was apoptotic. Furthermore, the apoptosis induced by D90 was dependent on the mitochondrial pathway, and the death receptor pathway may be not involved. Bax and Bcl-2 also played a role in the apoptosis induced by D90. Lymph node metastasis is a serious problem for oral cancer; we therefore evaluated the impact of D90 on the migration and invasion of OSCC cells. NDV D90 affected microtubules and microfilaments to inhibit the motility of OSCC prior to apoptosis. The effects of D90 on the migration and invasion rates of OSCC cells were evaluated by migration and invasion assays. Subsequently, the changes in sp1, RECK, MMP-2, and MMP-9 induced by a low concentration of D90 were detected by western blot and gelatin zymography. D90 significantly inhibited the invasion and metastasis of OSCC cells by decreasing the expression of sp1 and increasing the expression of RECK to suppress the expression and activity of MMP-2 and MMP-9.
Asunto(s)
Carcinoma de Células Escamosas/terapia , Proteínas Ligadas a GPI/biosíntesis , Metaloproteinasa 2 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/biosíntesis , Neoplasias de la Boca/terapia , Virus de la Enfermedad de Newcastle/genética , Animales , Apoptosis/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proteínas Ligadas a GPI/genética , Humanos , Metástasis Linfática , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Viroterapia Oncolítica , Factor de Transcripción Sp1/biosíntesisRESUMEN
As emerging pollutants in the aquatic environments, micro- and nano-plastics (MNPs) aroused widespread environmental concerns for their potential threats to the ecological health. Previous research has proved that microalgae growth could recover from the MNPs toxicities, in which the extracellular polymeric substances (EPS) might play the key role. In order to comprehensively investigate the recovery process of microalgae from MNPs stress and the effecting mechanisms of EPS therein, this study conducted a series of experiments by employing two sizes (0.1 and 1 µm) of polystyrene (PS) MNPs and the marine model diatom Thalassiosira pseudonana during 14 days. The results indicated: the pigments accumulations and photosynthetic recovery of T. pseudonana under MPs exposure showed in the early stage (4-5 days), while the elevation of reactive oxygen species (ROS) and EPS contents lasted longer time period (7-8 days). EPS was aggregated with MNPs particles and microalgal cells, corresponding to the increased settlement rates. More increase of soluble (SL)-EPS contents was found than bound (B)-EPS under MNPs exposure, in which the increase of the protein proportion and humic acid-like substances in SL-EPS was found, thus facilitating aggregates formation. ROS was the signaling molecule mediating the overproduction of EPS. The transcriptional results further proved the enhanced EPS biosynthesis on the molecular level. Therefore, this study elucidated the recovery pattern of microalgae from MNPs stress and linked "ROS-EPS production changes-aggregation formation" together during the growth recovery process, with important scientific and environmental significance.
Asunto(s)
Diatomeas , Microalgas , Contaminantes Químicos del Agua , Poliestirenos/toxicidad , Especies Reactivas de Oxígeno , Microplásticos/toxicidad , Matriz Extracelular de Sustancias Poliméricas , Contaminantes Químicos del Agua/toxicidad , PlásticosRESUMEN
A new class of noncoding RNAs, tsRNAs are not only abundant in humans but also have high tissue specificity. Recently, an increasing number of studies have explored the correlations between tsRNAs and tumors, showing that tsRNAs can affect biological behaviors of tumor cells, such as proliferation, apoptosis and metastasis, by modulating protein translation, RNA transcription or posttranscriptional regulation. In addition, tsRNAs are widely distributed and stably expressed, which endows them with broad application prospects in diagnosing and predicting the prognosis of tumors, and they are expected to become new biomarkers. However, notably, the current research on tsRNAs still faces problems that need to be solved. In this review, we describe the characteristics of tsRNAs as well as their unique features and functions in tumors. Moreover, we also discuss the potential opportunities and challenges in clinical applications and research of tsRNAs.
Asunto(s)
MicroARNs , Neoplasias , Humanos , Relevancia Clínica , MicroARNs/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Neoplasias/diagnóstico , Neoplasias/genética , ARN no TraducidoRESUMEN
A variety of studies have investigated the toxic effects of microplastics (MPs) on microalgae, but few of them considered their influence on dinoflagellate toxins production, which could cause significant ecological safety concerns in coastal areas. This research investigated the impacts of 5 µg L-1 and 5 mg L-1 polystyrene (PS) MPs on the changes of paralytic shellfish toxins (PSTs) production and their relationship with cellular oxidative stress of Alexandrium tamarense, a common harmful algal blooms causative dinoflagellate. The results showed elevation of reactive oxygen species (ROS) levels, activation of antioxidant system and overproduction of PSTs were positively correlated under PS MPs exposure (especially under 5 mg L-1 PS MPs), and the PSTs changes were eliminated by the ROS inhibitor. Further transcriptomic analysis revealed that ROS could enhance biosynthesis of glutamate, providing raw materials for PSTs precursor arginine, accompanied with enhanced acetyl-CoA and ATP production, finally leading to the overproduction of PSTs. Moreover, the oxidative intracellular environments might block the reduction process from STX to C1&C2, leading to the increase of STX and decrease of C1&C2 proportions. This work brings the first evidence that ROS could mediate PSTs production and compositions of Alexandrium under MPs exposure, with important scientific and ecological significance.
Asunto(s)
Dinoflagelados , Plásticos , Plásticos/farmacología , Especies Reactivas de Oxígeno , Microplásticos/toxicidad , Toxinas Marinas/toxicidad , MariscosRESUMEN
Microplastics (MPs) in marine environments simultaneously affect microalgae with UV-B radiation, while their joint effecting mechanisms remain largely unknown. To fill this research gap, the joint effects of polymethyl methacrylate (PMMA) MPs and UV-B radiation (natural environments intensity) on the model marine diatom Thalassiosira pseudonana were investigated. Antagonism was found between the two factors with regards to population growth. Furthermore, we found more inhibited population growth and photosynthetic parameters when pre-treated with PMMA MPs compared to pre-treated with UV-B radiation before joint-treated by the two factors. Transcriptional analysis elucidated that UV-B radiation could alleviate the down-regulation of photosynthetic (PSII, cyt b6/f complex and photosynthetic electron transport) and chlorophyll biosynthesis genes caused by PMMA MPs. Besides, the genes encoding carbon fixation and metabolisms was up-regulated under UV-B radiation, which could provide extra energy for the enhanced anti-oxidative activities and DNA replication-repair processes. These consequences showed that the toxicity of PMMA MPs was comprehensively alleviated when T. pseudonana was jointed treated by UV-B radiation. Our results reveled the underlying molecular mechanisms of antagonistic effects between PMMA MPs and UV-B radiation. This study provides important information that environmental factors like UV-B radiation should be considered when accessing the ecological risks of MPs on marine organisms.
Asunto(s)
Diatomeas , Microplásticos/metabolismo , Plásticos/metabolismo , Polimetil Metacrilato/toxicidad , Polimetil Metacrilato/metabolismo , FotosíntesisRESUMEN
China is the largest planting country of asparagus (Asparagus officinalis L.) in the world. Caoxian, as the famous asparagus township in China, enjoys a reputation for producing asparagus with high yield and good quality, due to its unique geological characteristic. In this study, a method of reverse-phase ultraperformance liquid chromatography coupled with electrospray tandem mass spectrometry (RP-UPLC-ESI-MS/MS) was established for profiling metabolites from three segments (tip, mid, and base) of 'Caoxian white and green Asparagus'. A total of 114 metabolites were identified, among them, 43 were found for the first time in this vegetable. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) was applied to provide an overview of the metabolite profiles of Caoxian asparagus and to separate different segments of spears. The variables most decisive to discriminate among segments included 9 of the metabolites tentatively identified. This study will help to improve the protection of Caoxian asparagus geographical indication.