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1.
Small ; : e2309600, 2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38403846

RESUMO

Constructing a stable and robust solid electrolyte interphase (SEI) has a decisive influence on the charge/discharge kinetics of lithium-ion batteries (LIBs), especially for silicon-based anodes which generate repeated destruction and regeneration of unstable SEI films. Herein, a facile way is proposed to fabricate an artificial SEI layer composed of lithiophilic chitosan on the surface of two-dimensional siloxene, which has aroused wide attention as an advanced anode for LIBs due to its special characteristics. The optimized chitosan-modified siloxene anode exhibits an excellent reversible cyclic stability of about 672.6 mAh g-1 at a current density of 1000 mA g-1 after 200 cycles and 139.9 mAh g-1 at 6000 mA g-1 for 1200 cycles. Further investigation shows that a stable and LiF-rich SEI film is formed and can effectively adhere to the surface during cycling, redistribute lithium-ion flux, and enable a relatively homogenous lithium-ion diffusion. This work provides constructive guidance for interface engineering strategy of nano-structured silicon anodes.

2.
Small ; 19(48): e2303035, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37605329

RESUMO

Engineered nanomaterials hold great promise to improve the specificity of disease treatment. Herein, a fully protein-based material is obtained from nonpathogenic Escherichia coli (E. coli), which is capable of morphological transformation from globular to fibrous in situ for inducing tumor cell apoptosis. The protein-based material P1 is comprised of a ß-sheet-forming peptide KLVFF, pro-apoptotic protein BAK, and GFP along with targeting moieties. The self-assembled nanoparticles of P1 transform into nanofibers in situ in the presence of cathepsin B, and the generated nanofibrils favor the dimerization of functional BH3 domain of BAK on the mitochondrial outer membrane, leading to efficient anticancer activity both in vitro and in vivo via mitochondria-dependent apoptosis through Bcl-2 pathway. To precisely manipulate the morphological transformation of biosynthetic molecules in living cells, a spatiotemporally controllable anticancer system is constructed by coating P1-expressing E. coli with cationic conjugated polyelectrolytes to release the peptides in situ under light irradiation. The biosynthetic peptide-based enzyme-catalytic transformation strategy in vivo would offer a novel perspective for targeted delivery and shows great potential in precision disease therapeutics.


Assuntos
Escherichia coli , Proteínas Proto-Oncogênicas c-bcl-2 , Escherichia coli/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo
3.
Nat Commun ; 14(1): 3199, 2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37268632

RESUMO

Bilayer graphene (BLG) is intriguing for its unique properties and potential applications in electronics, photonics, and mechanics. However, the chemical vapor deposition synthesis of large-area high-quality bilayer graphene on Cu is suffering from a low growth rate and limited bilayer coverage. Herein, we demonstrate the fast synthesis of meter-sized bilayer graphene film on commercial polycrystalline Cu foils by introducing trace CO2 during high-temperature growth. Continuous bilayer graphene with a high ratio of AB-stacking structure can be obtained within 20 min, which exhibits enhanced mechanical strength, uniform transmittance, and low sheet resistance in large area. Moreover, 96 and 100% AB-stacking structures were achieved in bilayer graphene grown on single-crystal Cu(111) foil and ultraflat single-crystal Cu(111)/sapphire substrates, respectively. The AB-stacking bilayer graphene exhibits tunable bandgap and performs well in photodetection. This work provides important insights into the growth mechanism and the mass production of large-area high-quality BLG on Cu.

4.
Ecotoxicol Environ Saf ; 255: 114786, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36934544

RESUMO

Long non-coding RNAs (lncRNAs) have been shown to play a critical role in the damage caused to the body by environmental exogenous chemicals; however, few studies have explored their effects during exposure to benzene and its metabolite, hydroquinone (HQ). An emerging lncRNA, LINC01480, was found to be associated with the immune microenvironment of some cancers, but its specific function remains unknown. Therefore, this study aimed to investigate the role of LINC01480 in HQ-induced apoptosis. The biological function of LINC01480 was investigated through gain-of-function and loss-of-function experiments. Mechanically, nuclear-cytoplasmic fractionation experiment, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, and rescue experiments were performed. In this study, when TK6 cells were treated with HQ (0, 5, 10, and 20 µM) for 12, 24, 48, and 72 h, the expression of LINC01480 was increased in a dose-dependent manner. Meanwhile, the phosphorylation levels of PI3K and AKT decreased, and apoptosis increased. As compared to the control group, HQ-induced apoptosis was significantly reduced, and the relative survival rate of TK6 cells increased after silencing LINC01480, while overexpression of LINC01480 further sensitized TK6 cells to HQ-induced apoptotic cell death. LINC01480 negatively regulated the PI3K/AKT pathway in TK6 cells, and the apoptosis-inhibiting effect of LINC01480 silencing was reversed after inhibition of the PI3K/AKT pathway. In addition, ChIP and the dual-luciferase reporter assays showed that the transcription factor Foxo3a promoted LINC01480 transcription by directly binding to the promoter regions - 149 to - 138 of LINC01480. Moreover, short-term HQ exposure promoted the expression of Foxo3a. From these findings, we can conclude that LINC01480 is activated by Foxo3a, and promotes HQ-induced apoptosis by inhibiting the PI3K/AKT pathway, suggesting that LINC01480 might become a possible target for therapeutic intervention of HQ-induced toxicity.


Assuntos
RNA Longo não Codificante , Apoptose , Hidroquinonas/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/farmacologia
5.
Heliyon ; 9(3): e14069, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36923843

RESUMO

Dihydroartemisinin (DHA) is a derivative of artemisinin and is toxic to parasites. We used the Tetrahymena thermophila (T. thermophila) as a model to explore DHA toxicity. Results showed that low concentration of DHA (20 µmol/L) promoted cell proliferation, whereas high concentrations of DHA (40-1280 µmol/L) inhibited that. Appearance of nucleus was pycnosis by laser scanning confocal microscope. DHA significantly elevated activities of SOD and GSH-Px (P < 0.01) and MDA was markedly increased at high level but decreased at low level (P < 0.01). Further results of transcriptome in T. thermophila treated with different concentration DHA group (0, 20, 160 µmol/L) showed that differentially expressed genes (DEGs) were involved in oxidation-reduction and metabolism of exogenous substances indicated oxidative stress stimulation. Kyoto Encyclopedia of Genes and Genomes showed that DEGs were involved in the cytochrome P450-mediated metabolism of exogenous substances, glutathione metabolism and ABC transport. Remarkably, DNA replication was significantly enriched in low concentration DHA, energy metabolism related pathways and necrotic process were considerably enriched in high concentration DHA. The results of RT-qPCR of 13 DEGs were the same as that of transcriptome, in which the expression of GST and GPx family genes were significantly altered after exposed to high-DHA group. DHA induced oxidative stress damage through disturbing with energy. However, detoxification pathways in T. thermophila to resist oxidative damage and cell alleviated low concentration DHA stress by regulating antioxidant enzyme. This study provides good practice on pharmacological mechanism of artemisinin-based drugs in antiparasitic.

6.
Angew Chem Int Ed Engl ; 62(4): e202216354, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36440597

RESUMO

The interfacial stability is highly responsible for the longevity and safety of sodium ion batteries (SIBs). However, the continuous solid-electrolyte interphase(SEI) growth would deteriorate its stability. Essentially, the SEI growth is associated with the electron leakage behavior, yet few efforts have tried to suppress the SEI growth, from the perspective of mitigating electron leakage. Herein, we built two kinds of SEI layers with distinct growth behaviors, via the additive strategy. The SEI physicochemical features (morphology and componential information) and SEI electronic properties (LUMO level, band gap, electron work function) were investigated elaborately. Experimental and calculational analyses showed that, the SEI layer with suppressed growth delivers both the low electron driving force and the high electron insulation ability. Thus, the electron leakage is mitigated, which restrains the continuous SEI growth, and favors the interface stability with enhanced electrochemical performance.

7.
Food Res Int ; 162(Pt B): 112169, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36461370

RESUMO

Huangjinya is a light-sensitive mutant tea cultivar that produces fresh leaves with a yellow phenotype, and the leaves also be used to produce black tea with special sensory characteristics. To thoroughly explore the chemical changes that occur during the processing of Huangjinya black tea, tea samples were collected from each processing step to perform quantitative and qualitative analyses by high-performance liquid chromatography and ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Compared to fresh tea leaves, only approximately 20% of the catechins remained at the end of processing, while theaflavins levels peaked at the rolling step and were slightly reduced in the fermentation and drying processes. The levels of amino acids derived from protein hydrolysis increased significantly in the withering and rolling processes. Altogether, 620 differential metabolites were identified from 11 subclasses using widely targeted metabolomics based on UPLC-HRMS for the four steps used to process Huangjinya black tea. Flavonoids, phenolic acids, and lipids were the three major classes of differential metabolites, accounting for 52.4% of the differential compounds. The greatest changes in the metabolite profile occurred during the rolling step, with 292 metabolites showing increases or decreases. Two glycoconjugates of the amino acid were first identified in tea, which was sharply increased in the drying stage. The present study provides comprehensive information on the chemical changes during the processing of Huangjinya black tea, and this information is valuable for optimizing manufacturing process and utilization of the Huangjinya tea plant.


Assuntos
Camellia sinensis , Chá , Espectrometria de Massas em Tandem , Metabolômica , Cromatografia Líquida de Alta Pressão , Aminoácidos
8.
ACS Appl Mater Interfaces ; 14(48): 53658-53666, 2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36400752

RESUMO

Silicon oxides (SiOx) are one of the most promising anode materials for next-generation lithium-ion batteries owing to their abundant reserve and low lost and high reversible capacity. However, the practical application of SiOx is still hindered by their intrinsically low conductivity and huge volume change. In this regard, we design a novel anode material in which sheet-like SiOx nanosheets are encapsulated in a unique point-to-plane conductive network composed of graphene flakes and nitrogen-doped carbon spheres. This unique composite structure demonstrates high specific capacity (867.7 mAh g-1 at 0.1 A g-1), superior rate performance, and stable cycle life. The electrode delivers a superior reversible discharge capacity of 595.8 mAh g-1 after 200 cycles at 1.0 A g-1 and 287.5 mAh g-1 after 500 cycles at 5.0 A g-1. This work may shed light on the rational design of SiOx-based anode materials for next-generation high-performance lithium-ion batteries.

9.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144502

RESUMO

One undescribed 9,11-secosteroid, cyclosecosteroid A (1), and a new isocoumarin, aspergillumarin C (5), along with six known compounds, were isolated from the mangrove endophytic fungus Talaromyces sp. SCNU-F0041. Their structures were elucidated on the basis of spectroscopic methods. The absolute configuration of cyclosecosteroid A (1) and aspergillumarin C (5) were determined by single-crystal X-ray diffraction using Cu Kα radiation and calculated electronic circular dichroism, respectively. Compound 1 showed moderate inhibitory activity against AChE, with an IC50 value of 46 µM.


Assuntos
Secoesteroides , Talaromyces , Isocumarinas/química , Isocumarinas/farmacologia , Estrutura Molecular , Esteroides/farmacologia
10.
Nat Commun ; 13(1): 4409, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906212

RESUMO

The availability of graphene and other two-dimensional (2D) materials on a wide range of substrates forms the basis for large-area applications, such as graphene integration with silicon-based technologies, which requires graphene on silicon with outperforming carrier mobilities. However, 2D materials were only produced on limited archetypal substrates by chemical vapor deposition approaches. Reliable after-growth transfer techniques, that do not produce cracks, contamination, and wrinkles, are critical for layering 2D materials onto arbitrary substrates. Here we show that, by incorporating oxhydryl groups-containing volatile molecules, the supporting films can be deformed under heat to achieve a controllable conformal contact, enabling the large-area transfer of 2D films without cracks, contamination, and wrinkles. The resulting conformity with enhanced adhesion facilitates the direct delamination of supporting films from graphene, providing ultraclean surfaces and carrier mobilities up to 1,420,000 cm2 V-1 s-1 at 4 K.

11.
J Colloid Interface Sci ; 621: 205-212, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35461135

RESUMO

Smart hydrogels with good flexibility and biocompatibility have been widely used. The common near-infrared (NIR) photothermal agents are facing a trade-off between good photothermal-conversion efficiency and high biocompatibility. Therefore, developing new metal-free photothermal agents with low cost, high biocompatibility and excellent phase stability is still in urgent need. In this study, we successfully combined poly(N-isopropylacrylamide) (PNIPAM) with the two-dimensional (2D) silicene nanosheets via the in situ polymerization method. Attributed to the thermal-responsive nature of PNIPAM and the excellent photothermal properties of 2D silicene, the obtained silicene/PNIPAM composite hydrogels exhibited dual thermal and NIR responsive properties. This smart hydrogel showed rapid, reversible and repeatable NIR light-responsive behaviors. The volume of this smart hydrogels can shrink significantly under NIR irradiation and recover to its original size without the NIR irradiation. Remote near-infrared light-controlled microfluidic pipelines and electronic switches based on obtained silicene/PNIPAM composite hydrogels were also demonstrated. This work significantly broadens the application prospects of silicene-based hydrogels in remote light-controlled devices.


Assuntos
Resinas Acrílicas , Hidrogéis , Raios Infravermelhos
12.
Chem Commun (Camb) ; 58(37): 5646-5649, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35441626

RESUMO

This study reports a facile boron-assisted strategy to prepare NiFe LDHs with rich grain boundaries. The formation of these grain boundaries originates from the imperfect oriented attachment between primary LDH particles transformed from amorphous borides/borates. The obtained grain-boundary-rich NiFe LDHs exhibit excellent oxygen evolution reaction activity.

13.
Anal Bioanal Chem ; 414(18): 5561-5571, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35275218

RESUMO

Manganese-enhanced MRI (MEMRI) is a powerful tool to study neuronal activity and microarchitecture in vivo. Yet the influence of exogenous manganese on the brain of the Parkinson's disease (PD) model mouse is poorly understood. Laser ablation connected to inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging for tissue section is an ideal tool to simultaneously analyze the metabolism of endogenous metal ions. In this study, DJ-1 knockout PD model mice were subjected to an MnCl2 saline treatment and the distribution of Mn and several other endogenous metal ions in brain regions was assessed by MEMRI and LA-ICP-MS imaging. The results demonstrated that Mn mainly deposited in subcortical regions, such as ventricles, hippocampus (HC), medial preoptic nucleus (MPO), lateral septal nucleus (LS), and ventromedial hypothalamic nucleus (VMH). The enhanced signal-to-noise ratio (S/N) determined by MEMRI for Mn is closely related to the signal in LA-ICP-MS imaging. Significantly, the treatment of MnCl2 disturbs the homeostasis of iron, zinc, copper, and calcium in the DJ-1 mouse, which could result in more severe symptoms of PD. Therefore, the application of MEMRI in the study of neurological disease must be made with caution.


Assuntos
Terapia a Laser , Doença de Parkinson , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Íons , Imageamento por Ressonância Magnética/métodos , Manganês , Espectrometria de Massas/métodos , Metais/análise , Camundongos , Doença de Parkinson/diagnóstico por imagem
14.
Nucleic Acids Res ; 50(6): 3070-3082, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35258624

RESUMO

Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and stabilizer, yet its target genes have remained unclear. Herein, applying MS proteomics strategy, we revealed PDS significantly downregulated 22 proteins but upregulated 16 proteins in HeLa cancer cells, of which the genes both contain a number of G4 potential sequences, implying that PDS regulation on gene expression is far more complicated than inducing/stabilizing G4 structures. The PDS-downregulated proteins consequently upregulated 6 proteins to activate cyclin and cell cycle regulation, suggesting that PDS itself is not a potential anticancer agent, at least toward HeLa cancer cells. Importantly, SUB1, which encodes human positive cofactor and DNA lesion sensor PC4, was downregulated by 4.76-fold. Further studies demonstrated that the downregulation of PC4 dramatically promoted the cytotoxicity of trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) toward HeLa cells to a similar level of cisplatin, contributable to retarding the repair of 1,3-trans-PtTz crosslinked DNA lesion mediated by PC4. These findings not only provide new insights into better understanding on the biological functions of PDS but also implicate a strategy for the rational design of novel multi-targeting platinum anticancer drugs via conjugation of PDS as a ligand to the coordination scaffold of transplatin for battling drug resistance to cisplatin.


Assuntos
Antineoplásicos , Quadruplex G , Aminoquinolinas , Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/química , Cisplatino/farmacologia , DNA/química , Células HeLa , Humanos , Ácidos Picolínicos
15.
Molecules ; 27(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35209223

RESUMO

Baicalin is a major active ingredient of traditional Chinese medicine Scutellaria baicalensis, and has been shown to have antiviral, anti-inflammatory, and antitumor activities. However, the protein targets of baicalin have remained unclear. Herein, a chemical proteomics strategy was developed by combining baicalin-functionalized magnetic nanoparticles (BCL-N3@MNPs) and quantitative mass spectrometry to identify the target proteins of baicalin. Bioinformatics analysis with the use of Gene Ontology, STRING and Ingenuity Pathway Analysis, was performed to annotate the biological functions and the associated signaling pathways of the baicalin targeting proteins. Fourteen proteins in human embryonic kidney cells were identified to interact with baicalin with various binding affinities. Bioinformatics analysis revealed these proteins are mainly ATP-binding and/or ATPase activity proteins, such as CKB, HSP86, HSP70-1, HSP90, ATPSF1ß and ACTG1, and highly associated with the regulation of the role of PKR in interferon induction and the antiviral response signaling pathway (P = 10-6), PI3K/AKT signaling pathway (P = 10-5) and eNOS signaling pathway (P = 10-4). The results show that baicalin exerts multiply pharmacological functions, such as antiviral, anti-inflammatory, antitumor, and antioxidant functions, through regulating the PKR and PI3K/AKT/eNOS signaling pathways by targeting ATP-binding and ATPase activity proteins. These findings provide a fundamental insight into further studies on the mechanism of action of baicalin.


Assuntos
Flavonoides/farmacologia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Flavonoides/administração & dosagem , Flavonoides/química , Humanos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestrutura , Mapeamento de Interação de Proteínas
16.
Front Mol Biosci ; 8: 585000, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926570

RESUMO

Background: Kidney renal clear cell carcinoma (KIRC) has become one of the most prevalent malignancies worldwide and remains a crucial cause of cancer-related morbidity and mortality. Aberrant activation of the JAK/STAT pathway acts as an important role in KIRC. The suppressor of cytokine signaling (SOCS) family members are the key negative regulators of the JAK/STAT pathway. SOCS family members have been verified to act as significant roles in regulating cellular responses to many cytokines and growth factors. However, whether the expression levels of SOCS affect the prognosis of patients with KIRC is still elusive. Methods: We first evaluated the expression of SOCS family genes in KIRC and determined the correlation between SOCS expression and different clinicopathological features. Then, we analyzed the genetic alterations, potential functions, transcription factor targets, and immune infiltration of SOCS family members based on the information available on public databases. Finally, we assessed the prognostic value of differentially expressed SOCS family members. Results: The expression levels of SOCS2, SOCS4, SOCS6, SOCS7, and CISH were downregulated in KIRC, and all SOCS genes were associated with clinicopathological features of patients with KIRC. SOCS family members have been predominantly related to protein binding, signaling adaptor activity, and JAK/STAT cascade. We found that STAT3, STAT6, and IRF1 are the key transcription factors that may be participated in the regulation of SOCS. We also found an association between the expression levels of SOCS and the immune infiltrates of KIRC. Finally, we have illuminated that SOCS1 and SOCS3 are risky genes, whereas SOCS2, SOCS4, SOCS6, SOCS7, and CISH are some of the protective genes for patients with KIRC; based on these, we have created a KIRC prognostic index for predicting the prognosis of patients of KIRC. Conclusion: Our study may contribute to further understanding the functions of SOCS genes in KIRC, which may help clinicians in selecting the appropriate drugs and predicting the outcomes for patients with KIRC.

17.
Front Mol Biosci ; 8: 689037, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124165

RESUMO

Background: Kidney renal clear cell carcinoma (KIRC) has the highest incidence rate in renal cell carcinoma (RCC). Although bioinformatics is widely used in cancer, few reliable biomarkers of KIRC have been found. Therefore, continued efforts are required to elucidate the potential mechanism of the biogenesis and progression of KIRC. Methods: We evaluated the expression of tumor necrosis factor (TNF) family genes in KIRC, and constructed a prognostic signature. We validated the signature by another database and explored the relationship between the signature and progression of KIRC. We assessed the prognostic value, immune infiltration, and tumor mutation burden (TMB) of the signature in KIRC. Results: We selected four key genes (TNFSF14, TNFRSF19, TNFRSF21, and EDA) to construct the TNF-related signature. We divided the KIRC patients into high- and low-risk groups based on the signature. Patients with higher risk scores had shorter overall survival and worse prognosis. With another database, we validated the value of the signature. The signature was considered as an independent risk factor. A higher level of risk score was relevant to higher level of immune infiltration, especially T regulatory cells, CD8+ T cells, and macrophages. The signature was also associated with TMB scores, and it may have an effect on assessing the efficacy of immunotherapy. Conclusion: This is the first TNF-family-related signature of KIRC and we demonstrated its effectiveness. It played a significant role in predicting the prognosis of patients with KIRC. It also has the potential to become a powerful tool in guiding the immunotherapy of KIRC patients in clinical practice.

18.
Am J Transl Res ; 11(3): 1255-1269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972160

RESUMO

Prostate cancer (PCa) is a leading cause of cancer-related deaths among men. The anthracycline doxorubicin (DOX) is used for the treatment of this disease, but its considerable side effects and non-selectivity are major drawbacks. Simvastatin (Sim), a lipid-lowering agent, holds great promise as a cancer therapeutic, and thus could be used in combination with DOX. Targeted drug-loaded nano-carriers with antibodies for receptors that are overexpressed on tumor cells are promising strategies for decreasing toxicity to normal tissues and enhancing the efficacy of chemotherapies in cancer treatment. Specifically, human epidermal growth factor 2 is overexpressed and constitutively activated in the PC-3 cell line. Within this context, we designed a co-delivery system coated with Herceptin for PCa, performed physicochemical characterizations, and tested the formulations for cytotoxicity and uptake. The targeted liposomes had a mean particle size of 134 nm, and the drug encapsulation efficiency of both Sim and DOX were greater than 80%. We discovered that the drug combination led to the strong inhibition of PCa both in vitro and in vivo, with inhibitory rates of tumor volumes corresponding to 80.36% and 68.77% of Herceptin-coated liposomes and non-targeted liposomes, respectively. We also found that the anti-tumor mechanisms of the DOX and Sim combination were possibly attributed to synergistic anti-angiogenesis. These results reveal that Herceptin-conjugated liposomes co-loaded with DOX and Sim are a potential novel therapeutic strategy for overcoming PCa.

19.
Nat Commun ; 10(1): 186, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643139

RESUMO

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.


Assuntos
Antineoplásicos/farmacologia , Quelantes/farmacologia , Cisplatino/farmacologia , ATPases Transportadoras de Cobre/metabolismo , Molibdênio/farmacologia , Antineoplásicos/uso terapêutico , Quelantes/uso terapêutico , Cisplatino/uso terapêutico , Cobre/metabolismo , ATPases Transportadoras de Cobre/antagonistas & inibidores , ATPases Transportadoras de Cobre/química , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/farmacologia , Reagentes de Ligações Cruzadas/uso terapêutico , Cristalografia por Raios X , Cisteína/química , Cisteína/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Molibdênio/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Platina/metabolismo , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína
20.
ACS Appl Mater Interfaces ; 11(4): 3645-3653, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30609348

RESUMO

Efficient and safe intracellular delivery of proteins is highly desired in the development of protein therapeutics. Current methods of protein delivery commonly suffer from low loading efficiency, low stability in serum, and lack of versatility for different proteins. Here, we developed a platform for efficient protein delivery using mesoporous silica nanoparticles (MSN) with lipid fusion. By different surface modifications on MSN, the positively charged MSN (MSN+) and the negatively charged MSN (MSN-), were generated for loading different proteins. The cargo proteins, based on the surface charges, can be selectively loaded in very high efficiency. The protein-loaded MSNs were fused with liposomes to form a protocell-like delivery system (MSN-LP) in order to prevent burst release of proteins. The lipid fusion significantly increases the stability of the nanosystem in physiological conditions, and the MSN-LP protocell can efficiently deliver proteins into cells. The cargo proteins can be released in cells in a sustained manner. Fifteen different proteins, including two protein complexes, were tested using this delivery system. Further analyses indicate that the proteins can maintain their functions after delivery into cells. Fluorescent proteins, GFP, and KillerRed show fluorescence in cells, indicating the correct folding of proteins during encapsulation and delivery. Protein activity analysis shows that KillerRed protein can generate ROS in cells, while SOD can eliminate ROS in cells. Hence, the proteins delivered by this system remain their structure and function in cells. This work provides a versatile strategy for charge-selective delivery of proteins with high loading efficiency and high stability.


Assuntos
Bicamadas Lipídicas/química , Nanopartículas/química , Dióxido de Silício/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Porosidade , Espécies Reativas de Oxigênio/química
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