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1.
Pharm Dev Technol ; 27(3): 357-371, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35350969

RESUMO

Direct delivery of drugs into the nucleus is a promising nanotechnology therapy, since the nucleus is one of the most important organelles controlling cell proliferation and apoptosis. Here, we report a nucleus-targeting nanocarrier for nuclear drug delivery using a pH/enzyme dual sensitive strategy. The specific ligand PGM (PKKKRKV-GFLG-Mp), composed of nuclear localization sequence (PKKKRKV), enzyme-sensitive tetrapeptide (Gly-Phe-Leu-Gly, GFLG), and pH-sensitive molecules morpholine (Mp), was modified on poly (amidoamine) (PAMAM) by maleimide active polyethylene glycol ester (NHS-PEG-MAL) to form PAMAM-PEG-PGM. Doxorubicin (DOX) was loaded into the cavity of PAMAM to prepare DOX/PAMAM-PEG-PGM. In vitro release study suggested DOX release from DOX/PAMAM-PEG-PGM nanoparticles followed pH and enzyme-triggered manner. In vitro studies showed DOX/PAMAM-PEG-PGM nanoparticles could not only promote cell internalization through the charge switching of morpholine, but also achieve nuclear internalization by the mediation of composite formed by NLS and importin α/ß receptor. Further, employing H22 tumour-bearing BALB/c mice as a model, the systemic distribution and anticancer effects of nanoparticles were studied in vivo. The results indicated the nanoparticles could preferentially accumulate in the tumour site in vivo, and the tumour inhibition rate was 88.47%. In short, the nanoparticles developed could be promising in application to nucleus-targeting therapy to enhance antitumour activity.


Assuntos
Dendrímeros , Nanopartículas , Animais , Linhagem Celular Tumoral , Dendrímeros/química , Doxorrubicina , Portadores de Fármacos/química , Concentração de Íons de Hidrogênio , Camundongos , Morfolinas , Nanopartículas/química , Polietilenoglicóis/química
2.
Mol Cell Proteomics ; 16(2): 147-156, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27777341

RESUMO

Behcet disease (BD) is a chronic systemic vasculitis and considered as an autoimmune disease. Although rare, BD can be fatal due to ruptured vascular aneurysms or severe neurological complications. To date, no known biomarker has been reported for this disease, making it difficult to diagnosis in the clinics. To undertake this challenge, we employed the HuProt arrays, each comprised of ∼20,000 unique human proteins, to identify BD-specific autoantibodies using a Two-Phase strategy established previously. In Phase I, we profiled the autoimmunity on the HuProt arrays with 75 serum samples collected from 40 BD patients, 15 diagnosed autoimmune patients who suffer from Takayasu arteritis (TA; n = 5)), ANCA associated vasculitis (AAV; n = 5), and Sjogren's syndrome (SS; n = 5), and 20 healthy subjects, and identified 20 candidate autoantigens that were significantly associated with BD. To validate these candidates, in Phase II we constructed a focused array with these 20 candidate BD-associated antigens, and use it to profile a much larger cohort, comprised of serum samples collected from 130 BD patients, 103 autoimmune patients (i.e. 40TA, 40 AAV and 23 SS), and 110 healthy controls. This allowed us to validate CTDP1 (RNA polymerase II subunit A C-terminal domain phosphatase)as a BD-specific autoantigen. The association of anti-CTDP1 with BD patients was further validated using the traditional Western blotting analysis. In conclusion, anti-CTDP1 antibody serves a novel autoantibody for Behcet disease and is expected to help more accurate clinical diagnosis.


Assuntos
Síndrome de Behçet/diagnóstico , Fosfoproteínas Fosfatases/metabolismo , Análise Serial de Proteínas/métodos , Proteômica/métodos , Adulto , Autoanticorpos/imunologia , Autoantígenos/metabolismo , Síndrome de Behçet/imunologia , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Clin Exp Rheumatol ; 33(5): 639-46, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26320593

RESUMO

OBJECTIVES: Our objective was to better understand the roles of single nucleotide polymorphisms (SNPs) in the CCL21, ERBB3, and TERT genes region in the development of idiopathic inflammatory myopathies (IIMs), we explored the associations between SNPs in the mentioned three genes and IIMs susceptibility in a Chinese Han population. METHODS: Chinese polymyositis (PM) patients (n =291), dermatomyositis (DM) patients (n=526) and ethnically-matched healthy controls (n =968) were genotyped for the CCL21 region SNPs (rs951005 and rs2492358), ERBB3 (rs2292239 and rs11171739), and TERT (rs2853676 and rs10069690), by using the Sequenom MassArray system. RESULTS: Our study indicated strong allele and genotype associations between rs951005 (OR: 1.65, 95%CI: 1.18-2.30, Pc=0.015; Pc=0.041, respectively) in CCL21 gene and PM patients. Additionally, rs951005 was associated with interstitial lung disease (ILD) in PM patients (Pc =0.01), and was associated with PM patients in additive model. However, the Chinese Han PM/DM patients and controls had statistically similar frequencies of alleles, genotypes and different genetic models (additive, dominant, and recessive) of ERBB3 and TERT polymorphisms. CONCLUSIONS: This was the first study to demonstrate that the CCL21 gene SNP (rs951005) might confer genetic predisposition to PM patients or such patients with ILD in a Chinese Han population.


Assuntos
Povo Asiático/genética , Quimiocina CCL21/genética , Doenças Pulmonares Intersticiais/genética , Polimorfismo de Nucleotídeo Único , Polimiosite/genética , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etnologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimiosite/diagnóstico , Polimiosite/etnologia , Receptor ErbB-3/genética , Fatores de Risco , Telomerase/genética
4.
Eur J Pharm Sci ; 159: 105693, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33383133

RESUMO

In the present study, the three functions, including enhanced permeability and retention (EPR) effect, deep penetration within tumor, and receptor-mediated endocytosis, were integrated into a single platform in order to improve antitumor efficiency. A novel nanoparticle (dendrigraft poly-L-lysine@glycyrrhetinic acid@cyclohexane dicarboxylic anhydride@doxorubicin@ hyaluronic acid composite) has been successfully developed and was denoted as DGL-GA-CDA-DOX-HA. The transmission electron microscope (TEM), dynamic light scattering (DLS), polymer dispersity index (PDI), fourier transform infrared spectrometer (FTIR), and zeta potentials were used to characterize the physicochemical properties of the nanoparticles. According to the results of TEM and DLS, the DGL-GA-CDA-DOX-HA nanoparticles could be rapidly degraded with a size shrink from 182.5 nm to 47.7 nm by hyaluronidase (HAase) added in the medium. The loading amount of DOX reached 252.03 ± 36.38 mg/g for DGL-GA-CDA-DOX nanoparticles. When the nanoparticles were in a medium with HAase at pH 5.0, the drug quickly released. However, when the nanoparticles were exposed to a medium without HAase at pH 5.0, or a neutral medium containing HAase, drug release slowed down. The modification of GA on nanoparticles significantly enhanced their affinity and cytotoxicity to hepatocellular carcinoma HepG2 cells. The study showed that the penetrability of DGL-GA-CDA-DOX and DGL-GA-CDA DOX-HA nanoparticles pre-degraded by HAase in vitro multicellular tumor spheroids were always better than that of DGL-GA-CDA-DOX-HA nanoparticles untreated by HAase. The imaging in vivo and ex vivo exhibited that DGL-GA-CDA-DOX-HA nanoparticles could preferentially accumulate in the tumor site. Correspondingly, the DGL-GA-CDA-DOX-HA displayed the preferable antitumor efficiency to other experimental groups in H22 tumor-bearing mice, with a tumor inhibition rate of 71.6%. In short, these results suggested that DGL-GA-CDA-DOX-HA nanoparticles could promote therapeutic effects by modulating particle size and GA receptor-mediated endocytosis.


Assuntos
Portadores de Fármacos , Ácido Glicirretínico , Nanopartículas , Neoplasias/tratamento farmacológico , Animais , Doxorrubicina , Liberação Controlada de Fármacos , Ácido Hialurônico , Camundongos , Proteína Quinase C-alfa
5.
Int J Ophthalmol ; 14(9): 1315-1320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540605

RESUMO

AIM: To explore the association of single nucleotide polymorphisms (SNPs) in the IL33/IL1RL1 gene region with the susceptibility to Behcet's disease (BD) in a Chinese Han population. METHODS: A total of eight SNPs in the candidate gene region (rs11792633, rs7025417, rs10975519 and rs1048274 in IL33; rs2310220, rs12712142, rs13424006 and rs3821204 in IL1RL1) were genotyped in783 BD patients and 701 healthy controls by the Sequenom Mass Array iPLEX platform. RESULTS: A statistically significant association was observed between IL1RL1 rs12712142 and BD patients. The frequency of IL1RL1 rs12712142 variant allele A was significantly lower in BD patients than that in controls (OR=0.8, 95%CI: 0.69-0.94, Pc=0.039); the genotype distribution (Pc=0.043) and additive and dominant genetic model analyses (OR=0.8, 95%CI: 0.69-0.94, Pc=0.040 and OR=0.72, 95%CI: 0.58-0.88, Pc=0.011) also indicated a strong association between rs12712142 and BD patients. CONCLUSION: This is the first study to reveal the association between IL1RL1 rs12712142 variant allele A and the decreased risk of BD in the Chinese Han population, indicating a protective role of IL1RL1 in the pathogenesis of BD.

6.
Chin Med J (Engl) ; 129(17): 2085-90, 2016 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-27569236

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. This study was conducted to examine whether the association of a proliferation-inducing ligand (APRIL), spermatogenesis associated 8 (SPATA8), platelet-derived growth factor receptor-alpha (PDGFRA), and DNA polymerase beta (POLB) with SLE can be replicated in a Chinese Han population. METHODS: Chinese SLE patients (n = 1247) and ethnically and geographically matched healthy controls (n = 1440) were genotyped for the APRIL, SPATA8, PDGFRA, and POLB single-nucleotide polymorphisms (SNPs), rs3803800, rs8023715, rs1364989, and rs12678588 using the Sequenom MassARRAY System. RESULTS: The Chinese Han SLE patients and controls had statistically similar frequencies of alleles and genotypes of four gene polymorphisms. Moreover, no association signal was detected on different genetic models (additive, dominant, and recessive, all, P> 0.05) or in SLE subgroups stratified by various clinical manifestations (all, P> 0.05). CONCLUSIONS: Different genetic backgrounds from different ancestries and various populations may result in different genetic risk factors for SLE. We did not detect any significant association with SNPs of APRIL, SPATA8, PDGFRA, and POLB.


Assuntos
DNA Polimerase II/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adulto , Alelos , Povo Asiático , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
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