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1.
Angew Chem Int Ed Engl ; 62(23): e202302938, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37029469

RESUMO

Nanofluidic reverse electrodialysis provides an attractive way to harvest osmotic energy. However, most attention was paid to monotonous membrane structure optimization to promote selective ion transport, while the role of external fields and relevant mechanisms are rarely explored. Here, we demonstrate a Kevlar-toughened tungsten disulfide (WS2 ) composite membrane with bioinspired serosa-mimetic structures as an efficient osmotic energy generator coupling light. As a result, the output power could be up to 16.43 W m-2 under irradiation, outperforming traditional two-dimensional (2D) membranes. Both the experiment and simulation uncover that the generated photothermal and photoelectronic effects could synergistically promote the confined ion transport process. In addition, this membrane also possesses great anti-fouling properties, endowing its practical application. This work paves new avenues for sustainable power generation by coupling solar energy.

2.
Eur J Clin Pharmacol ; 77(6): 849-857, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33791828

RESUMO

BACKGROUND: Data on the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer are limited. Therefore, we conducted a meta-analysis to compare the efficacy and safety between NOACs and warfarin in this population. METHODS: A comprehensive search of the PubMed, Embase, and Cochrane databases for articles published through July 2020 was performed. An evaluation of each study was conducted, and data were extracted. Pooled odds ratio (OR) estimates and 95% CIs were calculated. RESULTS: Eight studies (3 randomized controlled trials (RCTs) and 5 retrospective cohort studies) involving a total of 24,665 patients were included. Among the RCTs, there were no significant differences in the rates of stroke or systemic embolism (OR=0.69; 95% CI, 0.45-1.06; P=0.09), venous thromboembolism (OR=0.91; 95% CI, 0.33-2.52; P=0.86), myocardial infarction (OR=0.74; 95% CI, 0.44-1.23; P=0.24), major bleeding (OR=0.81; 95% CI, 0.61-1.06; P=0.12), or major or nonmajor clinically relevant bleeding (OR= 0.98; 95% CI, 0.82-1.19; P=0.86) between the NOAC and warfarin groups. Among the observational studies, patients who used NOACs had a significantly lower risk than those who used warfarin. The prevalence rates of ischemic stroke (OR=0.51; 95% CI, 0.28-0.92; P=0.02), VTE (OR=0.50; 95% CI, 0.41-0.60; P<0.00001), major bleeding (OR=0.28; 95% CI, 0.14-0.55; P=0.0002), and intracranial or gastrointestinal bleeding (OR=0.59; 95% CI, 0.37-0.92; P=0.02) were significantly reduced in the NOAC group. CONCLUSION: Our meta-analysis confirms that NOACs are as safe and effective as warfarin and can be applied in the real world; this data can serve as a reference for clinical doctors for formulating treatment strategies.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Inibidores do Fator Xa/uso terapêutico , Neoplasias/epidemiologia , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Embolia/prevenção & controle , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico
3.
Cytometry A ; 95(6): 657-663, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30556307

RESUMO

Circulating tumor cells (CTCs) play a key role in cancer metastasis but are very difficult to detect. in vivo monitoring CTCs has been recognized as an important technique for cancer research and clinical diagnosis. Recently, a noninvasive method, in vivo flow cytometry (IVFC) has been developed to enable continuous, real-time, and long-duration detection of CTCs in animal models by detecting CTC fluorescence in blood vessels excited by lasers. In this study, we present a simple optical scheme for direct noninvasive CTC detection using confocal microscopes. We demonstrate that line scanning of confocal microscopy can provide effective and quantitative CTC detection in live mice during cancer development. Rare CTC signals can be acquired at the early stage of the tumor development after implantation of subcutaneous tumor and monitored continuously to the end. Signals from CTC clusters can also be acquired and distinguished from single CTCs. Our results suggest confocal microscopy is a simple and reliable method for biologists and doctors to use for cancer research. © 2018 International Society for Advancement of Cytometry.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Microscopia Confocal/métodos , Células Neoplásicas Circulantes/química , Animais , Biomarcadores Tumorais/sangue , Proteínas de Fluorescência Verde/química , Humanos , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/efeitos da radiação , Células PC-3
4.
Adv Mater ; 36(6): e2308639, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37923399

RESUMO

The quasi-solid electrolytes (QSEs) attract extensive attention due to their improved ion transport properties and high stability, which is synergistically based on tunable functional groups and confined solvent molecules among the polymetric networks. However, the trade-off effect between the polymer content and ionic conductivity exists in QSEs, limiting their rate performance. In this work, the epitaxial polymerization strategy is used to build the gradient hydrogel networks (GHNs) covalently fixed on zinc anode. Then, it is revealed that the asymmetric distribution of negative charges benefits GHNs with fast and selective ionic transport properties, realizing a higher Zn2+ transference number of 0.65 than that (0.52) for homogeneous hydrogel networks (HHNs) with the same polymer content. Meanwhile, the high-density networks formed at Zn/GHNs interface can efficiently immobilize free water molecules and homogenize the Zn2+ flux, greatly inhibiting the water-involved parasitic reactions and dendrite growth. Thus, the GHNs enable dendrite-free stripping/plating over 1000 h at 8 mA cm-2 and 1 mAh cm-2 in a Zn||Zn symmetric cell, as well as the evidently prolonged cycles in various full cells. This work will shed light on asymmetric engineering of ion transport channels in advanced quasi-solid battery systems to achieve high energy and safety.

5.
Nat Commun ; 15(1): 5876, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997277

RESUMO

Biological ion channels exhibit high selectivity and permeability of ions because of their asymmetrical pore structures and surface chemistries. Here, we demonstrate a biomimetic nanofluidic channel (BNC) with an asymmetrical structure and glycyl-L-proline (GLP) -functionalization for ultrafast, selective, and unidirectional Dy3+ extraction over other lanthanide (Ln3+) ions with very similar electronic configurations. The selective extraction mainly depends on the amplified chemical affinity differences between the Ln3+ ions and GLPs in nanoconfinement. In particular, the conductivities of Ln3+ ions across the BNC even reach up to two orders of magnitude higher than in a bulk solution, and a high Dy3+/Nd3+ selectivity of approximately 60 could be achieved. The designed BNC can effectively extract Dy3+ ions with ultralow concentrations and thereby purify Nd3+ ions to an ultimate content of 99.8 wt.%, which contribute to the recycling of rare earth resources and environmental protection. Theoretical simulations reveal that the BNC preferentially binds to Dy3+ ion due to its highest affinity among Ln3+ ions in nanoconfinement, which attributes to the coupling of ion radius and coordination matching. These findings suggest that BNC-based ion selectivity system provides alternative routes to achieving highly efficient lanthanide separation.


Assuntos
Disprósio , Disprósio/química , Íons , Biomimética/métodos , Nanotecnologia/métodos , Neodímio/química
6.
Dis Markers ; 2023: 5025868, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36726845

RESUMO

Esophageal cancer (ESCA), as a common cancer worldwide, is a main cause of cancer-related mortality. Long noncoding RNAs (lncRNAs) have been shown in an increasing number of studies to be capable of playing an important regulatory function in human malignancies. Our study is aimed at delving into the prognostic value and potential function of lncRNA SSTR5-AS1 (SSTR5-AS1) in ESCA. The gene expression data of 182 ESCA samples from TCGA and 653 nontumor specimens from GTEx. The expressions of SSTR5-AS1 were analyzed. We investigated whether there was a correlation between the expression of SSTR5-AS1 and the clinical aspects of ESCA. In order to compare survival curves, the Kaplan-Meier method together with the log-rank test was utilized. The univariate and multivariate Cox regression models were used to analyze the data in order to determine the SSTR5-AS1 expression's significance as a prognostic factor in ESCA patients. In order to investigate the level of SSTR5-AS1 expression in ESCA cells, RT-PCR was utilized. CCK-8 trials served as a model for the loss-of-function tests. In this study, we found that the expressions of SSTR5-AS1 were increased in ESCA specimens compared with nontumor specimens. According to the ROC assays, high SSTR5-AS1 expression had an AUC value of 0.7812 (95% CI: 0.7406 to 0.8217) for ESCA. Patients who had a high level of SSTR5-AS1 expression had a lower overall survival rate than those who had a low level of SSTR5-AS1 expression. In addition, multivariate analysis suggested that SSTR5-AS1 was an independent predictor of overall survival for ESCA patients. Moreover, RT-PCR experiments indicated that SSTR5-AS1 expression was distinctly increased in three ESCA cells compared with HET1A cells. CCK-8 experiments indicated that silence of SSTR5-AS1 distinctly inhibited the proliferation of ESCA cells. Overall, ESCA patients with elevated SSTR5-AS1 had a worse chance of survival, suggesting it could be used as a prognostic and diagnostic biomarker for ESCA.


Assuntos
Neoplasias Esofágicas , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Sincalida/metabolismo , Prognóstico , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica
7.
Chem Commun (Camb) ; 59(61): 9384-9387, 2023 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-37434494

RESUMO

A biomimetic hierarchical membrane consisting of ZIF-8 and MXene with controllable morphology could be fabricated by the facile electrochemical deposition method, well-realizing Li+/Mg2+ sieving. This membrane could work stably in real brine with perm-selectivity of Li+/Mg2+ up to 47.4.

8.
Adv Mater ; 35(6): e2208640, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36457170

RESUMO

Charge-governed ion transport is the vital property of nanofluidic channels for salinity-gradient energy harvesting and other electrochemical energy conversion technologies. 2D nanofluidic channels constructed by nanosheets exhibit great superiority in ion selectivity, but a high ion transport rate remains challenging due to the insufficiency of intrinsic surface charge density in nanoconfinement. Herein, extrinsic surface charge into nanofluidic channels composed of surfactant-assisted sulfonated covalent organic nanosheets (SCONs), which enable tunable ion transport behaviors, is demonstrated. The polar moiety of surfactant is embedded in SCONs to adjust in-plane surface charges, and the aggregation of nonpolar moiety results in the sol-to-gel transformation of SCON solution for membrane fabrication. The combination endows SCON/surfactant membranes with considerable water-resistance, and the designable extrinsic charges promise fast ion transport and high ion selectivity. Additionally, the SCON/surfactant membrane, serving as a power generator, exhibits huge potential in harvesting salinity-gradient energy where corresponding output power density can reach up to 9.08 W m-2 under a 50-fold salinity gradient (0.5 m NaCl|0.01 m NaCl). The approach to extrinsic surface charge provides new and promising insight into regulating ion transport behaviors.

9.
Nanomicro Lett ; 15(1): 130, 2023 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-37209189

RESUMO

The global carbon neutrality strategy brings a wave of rechargeable lithium-ion batteries technique development and induces an ever-growing consumption and demand for lithium (Li). Among all the Li exploitation, extracting Li from spent LIBs would be a strategic and perspective approach, especially with the low energy consumption and eco-friendly membrane separation method. However, current membrane separation systems mainly focus on monotonous membrane design and structure optimization, and rarely further consider the coordination of inherent structure and applied external field, resulting in limited ion transport. Here, we propose a heterogeneous nanofluidic membrane as a platform for coupling multi-external fields (i.e., light-induced heat, electrical, and concentration gradient fields) to construct the multi-field-coupled synergistic ion transport system (MSITS) for Li-ion extraction from spent LIBs. The Li flux of the MSITS reaches 367.4 mmol m-2 h-1, even higher than the sum flux of those applied individual fields, reflecting synergistic enhancement for ion transport of the multi-field-coupled effect. Benefiting from the adaptation of membrane structure and multi-external fields, the proposed system exhibits ultrahigh selectivity with a Li+/Co2+ factor of 216,412, outperforming previous reports. MSITS based on nanofluidic membrane proves to be a promising ion transport strategy, as it could accelerate ion transmembrane transport and alleviate the ion concentration polarization effect. This work demonstrated a collaborative system equipped with an optimized membrane for high-efficient Li extraction, providing an expanded strategy to investigate the other membrane-based applications of their common similarities in core concepts.

10.
Science ; 382(6670): 559-565, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37917701

RESUMO

Currently, electronics and iontronics in abiotic-biotic systems can only use electrons and single-species ions as unitary signal carriers. Thus, a mechanism of gating transmission for multiple biosignals in such devices is needed to match and modulate complex aqueous-phase biological systems. Here we report the use of cascade-heterogated biphasic gel iontronics to achieve diverse electronic-to-multi-ionic signal transmission. The cascade-heterogated property determined the transfer free energy barriers experienced by ions and ionic hydration-dehydration states under an electric potential field, fundamentally enhancing the distinction of cross-interface transmission between different ions by several orders of magnitude. Such heterogated or chemical-heterogated iontronics with programmable features can be coupled with multi-ion cross-interface mobilities for hierarchical and selective cross-stage signal transmission. We expect that such iontronics would be ideal candidates for a variety of biotechnology applications.


Assuntos
Eletrônica , Elétrons , Íons , Água , Biotecnologia
11.
Adv Mater ; 35(24): e2301285, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36930971

RESUMO

Ion-selective membranes act as the core components in osmotic energy harvesting, but remain with deficiencies such as low ion selectivity and a tendency to swell. 2D nanofluidic membranes as competitive candidates are still subjected to limited mass transport brought by insufficient wetting and poor stability in water. Here, an ionic-liquid-infused graphene oxide (GO@IL) membrane with ultrafast ion transport ability is reported, and how the confined ionic liquid mediates selective cation diffusion is revealed. The infusion of ionic liquids endows the 2D membrane with excellent mechanical strength, anti-swelling properties, and good stability in aqueous electrolytes. Importantly, immiscible ionic liquids also provide a medium, allowing partial dehydration for ultrafast ion transport. Through molecular dynamics simulation and finite element modeling, that GO nanosheets induce ionic liquids to rearrange, bringing in additional space charges, which can be coupled with GO synergistically, is proved. By mixing 0.5/0.01 m NaCl solution, the power density can achieve a record value of ≈6.7 W m-2 , outperforming state-of-art GO-based membranes. This work opens up a new route for boosting nanofluidic energy conversion because of the diversity of the ILs and 2D materials.

12.
Clin Sci (Lond) ; 123(6): 347-60, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22264240

RESUMO

The aim of the present study was to investigate whether CBSCs [(umbilical) cord blood stem cells] can be a new source of DCs (dendritic cells), which can generate more potent antigen-specific immune responses and anti-tumour effects. CBSCs and PBMCs (peripheral blood mononuclear cells) were collected, cultured and differentiated into DCs. Surface markers, secreting cytokines, antigen-presentation activity, antigen-specific cell-mediated immunity and cytotoxic killing effects induced by these two DC origins were evaluated and compared. CBSCs were expanded ~17-fold by ex vivo culture. The expression of surface markers in CBSC-derived DCs were higher than those in PBMC-derived DCs treated with LPS (lipopolysaccharide). The CBSC-derived DCs mainly secreted IL (interleukin)-6, IL-10 and TNF (tumour necrosis factor)-α, whereas PBMC-derived DCs mainly secreted IL-5 and IFN (interferon)-γ. The CBSC-derived DCs had better antigen-presentation abilities when stimulated with LPS or TNF-α, induced higher numbers of IFN-γ-secreting antigen-specific CD8+ T-cells, as assessed using an ELISpot (enzyme-linked immunosorbent spot) assay, and stimulated more potent antigen-specific CTL (cytotoxic T-cell) activities (P<0.01, one-way ANOVA). CBSC-derived DCs had quicker and greater ERK (extracellular-signal-regulated kinase) and Akt phosphorylation, and weaker p38 phosphorylation, than PBMC-derived DCs when stimulated with LPS. In conclusion, CBSC-derived DCs have the ability to induce stronger antigen-specific immunity and more potent anti-tumour effects and therefore could be a good source of DCs for use in DC-based cancer vaccines and immunotherapy.


Assuntos
Células Dendríticas/citologia , Sangue Fetal/citologia , Imunidade Celular , Neoplasias/terapia , Células-Tronco/citologia , Apresentação de Antígeno , Diferenciação Celular , Linhagem Celular Tumoral , Meios de Cultura , Citocinas/metabolismo , Células Dendríticas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sangue Fetal/imunologia , Células HeLa , Humanos , Imunoterapia , Células K562 , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células-Tronco/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Front Mol Biosci ; 9: 848105, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35155584

RESUMO

PIWI-interacting RNAs (piRNAs) are a novel type of small non-coding RNAs (sncRNAs), which are 26-31 nucleotides in length and bind to PIWI proteins. Although piRNAs were originally discovered in germline cells and are thought to be essential regulators for germline preservation, they can also influence gene expression in somatic cells. An increasing amount of data has shown that the dysregulation of piRNAs can both promote and repress the emergence and progression of human cancers through DNA methylation, transcriptional silencing, mRNA turnover, and translational control. Digestive cancers are currently a major cause of cancer deaths worldwide. piRNAs control the expression of essential genes and pathways associated with digestive cancer progression and have been reported as possible biomarkers for the diagnosis and treatment of digestive cancer. Here, we highlight recent advances in understanding the involvement of piRNAs, as well as potential diagnostic and therapeutic applications of piRNAs in various digestive cancers.

14.
Mol Immunol ; 151: 218-230, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36179604

RESUMO

Hepatocellular carcinoma (HCC) is one of the most severe malignant tumors that threaten human health, and its incidence is still on the rise recently. In spite of the current emerging treatment strategies, the overall prognosis of liver cancer remains worrying. Currently, immunotherapy has become a new research-active spot. The emergence of immune checkpoints and targeted immune cell therapy can significantly improve the prognosis of HCC. To a large extent, the effect of this immunotherapy depends on the tumor immune microenvironment (TME), an intricate system in which cancer cells and other non-cancer cells display various interactions. Understanding the immunosuppressive situation of these cells, along with the malignant behavior of cancer cells, can assist us to design new therapeutic approaches against tumors. Therefore, it is necessary to clarify the TME of HCC for further improvement of clinical treatment. This review discussed the functions of several immunosuppressive cells and exosomes in the latest research progress of HCC, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs) interacted actively to facilitate tumor progression. It further describes the treatment methods targeting them and the potential that needs to be explored in the future.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Supressoras Mieloides , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Humanos , Fatores Imunológicos/farmacologia , Imunoterapia/métodos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Microambiente Tumoral
15.
ACS Nano ; 16(7): 11092-11101, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35714284

RESUMO

Membrane separation provides effective methods for solving the global water crisis. Contemporary membrane systems depend on interfacial interactions between liquid and solid membrane matrixes. However, it may lead to a limiting permeate flux due to the large flow resistance at hydrophobic liquid-solid interfaces. Herein, the liquid-liquid interface with improved interface energy is reversibly introduced in membrane systems to boost wetting and reduce transport resistance. A series of interfaces were systematically explored to reveal mechanisms of wetting and boosted flow performances, which are further supported by simulations. Findings of this study highlight that interfacial liquids with lower surface energies, lower viscosities, and higher solubilities can effectively improve water flow without sacrificing rejection performance, achieving by transforming a solid-liquid interface into liquid-liquid interface interaction. It provides a concept to design advanced membrane systems for water purification (e.g., desalination and oil-water separation) and energy conversion processes.

16.
ACS Appl Mater Interfaces ; 14(11): 13223-13230, 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35262329

RESUMO

As a promising clean energy source, membrane-based osmotic energy harvesting has been widely investigated and developed through optimizing the membrane structure in recent years. For chasing higher energy conversion performance, various external stimuli have been introduced into the osmotic energy harvesting systems as assistant factors. Light as a renewable and well-tunable energy form has drawn great attention. Normally, it needs massive photoresponsive materials for improving the energy conversion performance and this hinders its wide applications. Herein, we fabricate a cellulose nanofiber (CNF) membrane with an ultrathin layer of low-dimensional carbon materials (LDCMs) for photothermal-enhanced osmotic energy conversion. The ultralow loading carbon quantum dot, carbon nanotube, and graphene oxide (LDCM/CNF = 1:200 wt) are used for light-to-heat conversion to build the heat gradient across the membrane. The output power density of the osmotic energy generator has increased from ∼3.55 to ∼7.67 W/m2 under a 50-fold concentration gradient with light irradiation. This work shows the great potential of the CNF as a nanofluidic platform and the photothermal enhancement in osmotic energy conversion, and the ultralow loading design provides a practical and economical way to fully utilize other energy resources for enhancing osmotic energy conversion.

17.
Biochim Biophys Acta Mol Basis Dis ; 1868(2): 166314, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34863896

RESUMO

The fundamental biological roles of a class of small noncoding RNAs (sncRNAs), derived from mature tRNAs or pre-tRNAs, in human diseases have received increasing attention in recent years. These ncRNAs are called tRNA-derived fragments (tRFs) or tRNA-derived small RNAs (tsRNAs). tRFs mainly include tRF-1, tRF-5, tRF-3 and tRNA halves (tiRNAs or tRHs), which are produced by enzyme-specific cleavage of tRNAs. Here, we classify tRF-5 and 5' tiRNAs into the same category: 5'-tRFs and review the biological functions and regulatory mechanisms of 5'-tRFs in cancer and other diseases (metabolic diseases, neurodegenerative diseases, pathological stress injury and virus infection) to provide a new theoretical basis for the diagnosis and treatment of diseases.


Assuntos
Regulação Neoplásica da Expressão Gênica , Doenças Metabólicas/patologia , Neoplasias/patologia , Doenças Neurodegenerativas/patologia , RNA de Transferência/genética , Viroses/patologia , Animais , Humanos , Doenças Metabólicas/genética , Neoplasias/genética , Doenças Neurodegenerativas/genética , Viroses/genética
18.
J Exp Clin Cancer Res ; 41(1): 267, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071480

RESUMO

BACKGROUND: Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mitochondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments. METHODS: A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC. RESULTS: The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell proliferation and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3'-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellular DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance. CONCLUSIONS: Our results demonstrated that circ_0000098 is an oncogenic circRNA that promotes HCC development through the miR-383/MCUR1 axis and targeting circ_0000098 with DOX/sh-1@PLT may be a promising and practical therapeutic strategy for preventing DOX resistance in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Trifosfato de Adenosina , Carcinogênese/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/genética , Doxorrubicina/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
19.
Small Methods ; 6(12): e2200932, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36300882

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies are shown to be effective therapeutics for providing coronavirus disease 2019 (COVID-19) protection. However, recurrent variants arise and facilitate significant escape from current antibody therapeutics. Bispecific antibodies (bsAbs) represent a unique platform to increase antibody breadth and to reduce neutralization escape. Herein, a novel immunoglobulin G-variable domains of heavy-chain-only antibody (IgG-VHH) format bsAb derived from a potent human antibody R15-F7 and a humanized nanobody P14-F8-35 are rationally engineered. The resulting bsAb SYZJ001 efficiently neutralizes wild-type SARS-CoV-2 as well as the alpha, beta, gamma, and delta variants, with superior efficacy to its parental antibodies. Cryo-electron microscopy structural analysis reveals that R15-F7 and P14-F8-35 bind to nonoverlapping epitopes within the RBD and sterically hindered ACE2 receptor binding. Most importantly, SYZJ001 shows potent prophylactic and therapeutic efficacy against SARS-CoV-2 in three established mouse models. Collectively, the current results demonstrate that the novel bsAb format is feasible and effective, suggesting great potential as an inspiring antiviral strategy.


Assuntos
Anticorpos Biespecíficos , COVID-19 , Camundongos , Animais , Humanos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Imunoglobulina G/genética , Anticorpos Biespecíficos/farmacologia , Microscopia Crioeletrônica , Anticorpos Antivirais/uso terapêutico
20.
Front Cell Dev Biol ; 9: 762588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34888309

RESUMO

Circular RNAs (circRNAs) are highly correlated with the progression and prognosis of hepatocellular carcinoma (HCC). In addition, mounting evidence has revealed that N6-methyladenosine (m6A) methylation, a common RNA modification, is involved in the progression of malignancies. In this research, a novel circRNA, hsa_circ_0058493, was proven to be upregulated in HCC, which was correlated with the prognosis of HCC patients. Experimentally, hsa_circ_0058493 knockdown suppressed the growth and metastasis of HCC cells in vivo and in vitro. On the contrary, the overexpression of hsa_circ_0058493 in HCC cells had the opposite effect in vitro. Mechanistic experiments revealed that hsa_circ_0058493 contained m6A methylation sites and that methyltransferase-like 3 (METTL3) mediated the degree of methylation modification of hsa_circ_0058493. Furthermore, YTH domain-containing protein 1 (YTHDC1) could bind to hsa_circ_0058493 and promote its intracellular localization from the nucleus to the cytoplasm. In addition, both si-METTL3 and si-YTHDC1 suppressed HCC cell growth and metastasis, whereas rescue experiments confirmed that overexpression of hsa_circ_0058493 inverted the inhibitory effects of si-METTL3 and si-YTHDC1 on HCC cells. Taken together, this study explored the oncogenic role of m6A-modified hsa_circ_0058493 and found to accelerate HCC progression via the METTL3-hsa_circ_0058493-YTHDC1 axis, indicating a potential therapeutic target for this deadly disease.

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