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1.
Nat Commun ; 10(1): 5716, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844057

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of ß-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/ß-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/ß-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/ß-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , beta Catenina/metabolismo , Adulto , Idoso , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Regulação para Cima , Proteína Wnt3A/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
2.
J Mater Chem B ; 7(39): 5947-5955, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31517375

RESUMO

A detection and degradation platform was developed to optically quantify the 6-enolate, 8-keto-dG, an important tautomer of mitochondrial mutated DNA 8-oxo-dG. We first found that 6-enolate, 8-keto-dG offers particular fluorescence emission under the conditions between pH ∼ 7 and ∼11. Thus, a mitochondria-targeting photosensitizer NV-12P was prepared to offer simultaneously photoinduced electron transfer and fluorescence resonance energy transfer (FRET) with 6-enolate, 8-keto-dG. Furthermore, NV-12P can also generate a reactive oxygen species to degrade 6-enolate, 8-keto-dG under irradiation conditions. This is the first publication about optical characterization, concentration detection and photodegradation of 6-enolate, 8-keto-dG, either in biological or in vitro applications.

3.
Micromachines (Basel) ; 9(5)2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30424161

RESUMO

Transmembrane pressure across the glomerular filter barrier may underlie renal failure. However, studies of renal failure have been difficult owing to a lack of in vitro models to capture the transmembrane pressure in a controlled approach. Here we report a microfluidic platform of podocyte culture to investigate transmembrane pressure induced glomerular leakage. Podocytes, the glomerular epithelial cells essential for filtration function, were cultivated on a porous membrane supplied with transmembrane pressure ΔP. An anodic aluminum oxide membrane with collagen coating was used as the porous membrane, and the filtration function was evaluated using dextrans of different sizes. The results show that dextran in 20 kDa and 70 kDa can penetrate the podocyte membrane, whereas dextran in 500 kDa was blocked until ΔP ≥ 60 mmHg, which resembles the filtration function when ΔP was in the range of a healthy kidney (ΔP < 60 mmHg) as well as the hypertension-induced glomerular leakage (ΔP ≥ 60 mmHg). Additionally, analysis showed that synaptopodin and actin were also downregulated when ΔP > 30 mmHg, indicating that the dysfunction of renal filtration is correlated with the reduction of synaptopodin expression and disorganized actin cytoskeleton. Taking together, our microfluidic platform enables the investigation of transmembrane pressure in glomerular filter membrane, with potential implications for drug development in the future.

4.
Eur J Clin Invest ; 48(7): e12942, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29682734

RESUMO

BACKGROUND: Pericardial adipose tissue (PAT) volume is highly associated with the presence and severity of cardiometabolic diseases, but the underlying mechanism is unknown. We previously demonstrated that a high-fat diet (HFD) induced metabolic dysregulation, cardiac fibrosis and accumulation of more PAT in minipigs. This study used our obese minipig model to investigate the characteristics of PAT and omental visceral fat (VAT) induced by a HFD, and the potential link between PAT and HFD-related myocardial fibrosis. MATERIALS AND METHODS: Five-month-old Lee-Sung minipigs were made obese by feeding a HFD for 6 months. RESULTS: The HFD induced dyslipidemia, cardiac fibrosis and more fat accumulation in the visceral and pericardial depots. The HFD changes the fatty acid composition in the adipose tissue by decreasing the portion of linoleic acid in the VAT and PAT. No arachidonic acid was detected in the VAT and PAT of control pigs, whereas it existed in the same tissues of obese pigs fed the HFD. Compared with the control pigs, elevated levels of malondialdehyde and TNFα were exhibited in the plasma and PAT of obese pigs. HFD induced greater size of adipocytes in VAT and PAT. Higher levels of GH, leptin, OPG, PDGF, resistin, SAA and TGFß were observed in obese pig PAT compared to VAT. CONCLUSION: This study demonstrated the similarities and dissimilarities between PAT and VAT under HFD stimulus. In addition, this study suggested that alteration in PAT contributed to the myocardial damage.


Assuntos
Tecido Adiposo/fisiologia , Obesidade/fisiopatologia , Adipócitos/patologia , Adipocinas/metabolismo , Tecido Adiposo/patologia , Animais , Composição Corporal/fisiologia , Tamanho Celular , Dieta Hiperlipídica , Dislipidemias/etiologia , Dislipidemias/patologia , Dislipidemias/fisiopatologia , Ácidos Graxos/química , Feminino , Fibrose/fisiopatologia , Gordura Intra-Abdominal/patologia , Gordura Intra-Abdominal/fisiologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Miocárdio/patologia , Obesidade/patologia , Estresse Oxidativo/fisiologia , Pericárdio/fisiologia , Suínos , Porco Miniatura
5.
Org Biomol Chem ; 15(37): 7936-7943, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28901370

RESUMO

A water-soluble pH sensor, 2-(6-(4-aminostyryl)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N, N-dimethylethanamine (ADA), was synthesized based on the molecular design of photoinduced electron transfer (PET) and intramolecular charge transfer (ICT). The fluorescence emission response against a pH value is in the range 3-6, which is suitable for labelling intracellular pH-dependent microenvironments. After biological evolution, ADA is more than a pH biosensor because it is also an endocytosis pathway tracking biosensor that labels endosomes, late endosomes, and lysosome pH gradients. From this, the emissive aggregates of ADA and protonated-ADA in these organs were evaluated to explore how this probe stresses emission colour change to cause these unique cellular images.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica , Organelas/química , Células Cultivadas , Corantes Fluorescentes/síntese química , Humanos , Concentração de Íons de Hidrogênio , Estrutura Molecular
6.
ACS Appl Mater Interfaces ; 8(44): 29883-29892, 2016 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-27748578

RESUMO

Unlike traditional binary nanostructures that construct chemotherapy drugs and photodynamic therapy photosensitizers, we introduce a molecule with a chemo-photodynamic dual therapy function. A water-soluble aggregation-induced emission enhancement (AIEE) fluorogen, NV-12P, was designed and synthesized based on asymmetric 1,6-disubstituted naphthalene and can generate particular reactive oxygen species to undergo type I photodynamic therapy under irradiation. Furthermore, this compound can specifically localize in mitochondria and, after biological evaluation, can cause mitochondrial dysfunction and potent cytotoxicity to cancer cells but not normal cells. We conclude that this compound is a potential dual-toxic efficacy molecule because it exhibits selective dark cytotoxicity and efficient photodamage in cancer cells. Additionally, we also supported the optimal combinational treatment course for the best chemo-phototherapy efficacy.


Assuntos
Fármacos Fotossensibilizantes/química , Células HeLa , Humanos , Mitocôndrias , Fotoquimioterapia , Espécies Reativas de Oxigênio
7.
Biosens Bioelectron ; 47: 566-73, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23591020

RESUMO

The G-quadruplex structures in the telomere of a chromosome can not only protect the internal chromosome sequences by preventing the improper activation of DNA-damage-response pathways but also become targets for cancer treatments. In this manuscript, we wish to prove the existence of G-quadruplex structure formation, rather than G-quadruplex sequence, in chromosome of human cancer cells. Based on our studies, the fluorescent mapping of G-quadruplex structures in the chromosome is possible with the combination of G-quadruplex targeting fluorophore (BMVC, 3, 6-bis-(1-methyl-4-vinylpyridinium)-carbazole diiodide) and duplex-binding fluorophores (Hoechst or propidium iodide). By means of an applicable incubation time between cell cycle period and proper staining procedure to the chromosome, FRET (fluorescence resonance energy transfer) between G-quadruplex targeting fluorophore and duplex-binding fluorophore can increase the signal contrast of the fluorescent color and the fluorescent mapping of quadruplex structures can be easily observed using fluorescence microscopy. These observations are further supported by basic spectral analysis, titration binding assay, gel electrophoresis binding competition assay and confocal microscopy.


Assuntos
Cromossomos Humanos/ultraestrutura , Quadruplex G , Neoplasias/genética , Antineoplásicos/uso terapêutico , Carbazóis/química , Dano ao DNA/genética , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Humanos , Neoplasias/patologia , Telômero/ultraestrutura
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