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1.
Adv Sci (Weinh) ; 8(21): e2100974, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34514747

RESUMO

Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates FGF signaling. Various FGFR2 alterations are detected in breast cancer, yet it remains unclear if activation of FGFR2 signaling initiates tumor formation. In an attempt to answer this question, a mouse model berrying an activation mutation of FGFR2 (FGFR2-S252W) in the mammary gland is generated. It is found that FGF/FGFR2 signaling drives the development of triple-negative breast cancer accompanied by epithelial-mesenchymal transition that is regulated by FGFR2-STAT3 signaling. It is demonstrated that FGFR2 suppresses BRCA1 via the ERK-YY1 axis and promotes tumor progression. BRCA1 knockout in the mammary gland of the FGFR2-S252W mice significantly accelerated tumorigenesis. It is also shown that FGFR2 positively regulates PD-L1 and that a combination of FGFR2 inhibition and immune checkpoint blockade kills cancer cells. These data suggest that the mouse models mimic human breast cancers and can be used to identify actionable therapeutic targets.


Assuntos
Proteína BRCA1/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno B7-H1/metabolismo , Proteína BRCA1/antagonistas & inibidores , Proteína BRCA1/genética , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Imunoterapia , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Transgênicos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Fator de Transcrição YY1/metabolismo
2.
Mol Pharm ; 18(5): 1895-1904, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33886332

RESUMO

Intestinal efflux transporters affect the gastrointestinal processing of many drugs but further data on their intestinal expression levels are required. Relative mRNA expression and relative and absolute protein expression data of transporters are commonly measured by real-time polymerase chain reaction (RT-PCR), Western blot and mass spectrometry-based targeted proteomics techniques. All of these methods, however, have their own strengths and limitations, and therefore, validation for optimized quantification methods is needed. As such, the identification of the most appropriate technique is necessary to effectively translate preclinical findings to first-in-human trials. In this study, the mRNA expression and protein levels of the efflux transporter P-glycoprotein (P-gp) in jejunal and ileal epithelia of 30 male and female human subjects, and the duodenal, jejunal, ileal and colonic tissues in 48 Wistar rats were quantified using RT-PCR, Western blot and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A similar sex difference was observed in the expression of small intestinal P-gp in humans and Wistar rats where P-gp was higher in males than females with an increasing trend from the proximal to the distal parts in both species. A strong positive linear correlation was determined between the Western blot data and LC-MS/MS data in the small intestine of humans (R2 = 0.85). Conflicting results, however, were shown in rat small intestinal and colonic P-gp expression between the techniques (R2 = 0.29 and 0.05, respectively). In RT-PCR and Western blot, an internal reference protein is experimentally required; here, beta-actin was used which is innately variable along the intestinal tract. Quantification via LC-MS/MS can provide data on P-gp expression without the need for an internal reference protein and consequently, can give higher confidence on the expression levels of P-gp along the intestinal tract. Overall, these findings highlight similar trends between the species and suggest that the Wistar rat is an appropriate preclinical animal model to predict the oral drug absorption of P-gp substrates in the human small intestine.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Mucosa Intestinal/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Animais , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos/métodos , Duodeno/metabolismo , Feminino , Humanos , Íleo/metabolismo , Absorção Intestinal , Jejuno/metabolismo , Masculino , Pessoa de Meia-Idade , Ratos , Fatores Sexuais , Especificidade da Espécie , Espectrometria de Massas em Tandem
3.
Plant Physiol Biochem ; 149: 294-300, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32097848

RESUMO

Ethylene response factors (ERFs) are involved in the regulation of plant responses to biotic and abiotic stresses. Here we provide evidence for a role of ERF96, a member of the ERF transcription factor group IX, in selenite tolerance in Arabidopsis. ERF96 gene was rapidly up-regulated in response to selenite stress. Overexpression of ERF96 enhanced Arabidopsis resistance to selenite stress, while ERF96-silenced plants demonstrated wild-type (WT) resistance to selenite. In addition, the overexpression plants had significantly lower selenium (Se) content in shoots when subjected to selenite stress. Further investigation indicated that overexpression of ERF96 reduced transcript levels of selenite/phosphate transporters PHT1;1 and PHT2;1, which influenced Arabidopsis Se uptake and allocation in the presence of selenite. Moreover, our experiments showed that overexpression of ERF96 enhanced Arabidopsis antioxidant activity. Under selenite stress, ERF96-overexpressing lines exhibited the significant increases in catalase (CAT) and glutathione peroxidase (GPX) activities as well as the glutathione (GSH) content, while had a decrease in reactive oxygen species (ROS) accumulation compared to WT. Taken together, our results demonstrate that ERF96 plays a positive role in the regulation of selenite tolerance in Arabidopsis.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Selênio , Estresse Fisiológico , Fatores de Transcrição , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Expressão Gênica , Plantas Geneticamente Modificadas , Selênio/toxicidade , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
Sci Rep ; 8(1): 14608, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279587

RESUMO

Chitosan is an extremely valuable biopolymer and is usually obtained as a byproduct from the shells of crustaceans. In the current work, chitosan is obtained from an herbal source (Ganoderma lucidum spore powder (GLSP)) for the first time. To show this, both standard (thermochemical deacetylation, (TCD)) and emerging (ultrasound-assisted deacetylation (USAD)) methods of chitosan preparation were used. The obtained chitosan was characterized by elemental analysis, XRD (X-ray diffraction), FT-IR (Fourier transform infrared spectroscopy) and thermogravimetric measurements. The process resulted in chitosan possessing comparable values of DD, [η] and [Formula: see text] to the commercial product. Chitosan obtained via both processes (TCD and USAD) displayed excellent biocompatibility; although the USAD prepared biopolymer exhibited significantly improved fibroblast (L929 cell) viability and enhanced antibacterial zones for both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The findings of new herbal chitosan mark key developments of natural biomaterials; marking a potential shift from conventional sea-based organisms.


Assuntos
Quitosana/farmacologia , Reishi/química , Esporos Fúngicos/química , Acetilação , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quitosana/síntese química , Quitosana/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Pós , Sonicação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
5.
J Food Sci ; 82(6): 1412-1422, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28471056

RESUMO

A novel antimicrobial composite material was prepared by encapsulating orange essential oil (OEO) in zein prolamine (ZP) via the coaxial electrospinning (ES) technique. By manipulating process parameters, the morphological features of ZP/OEO fibers were modulated. Fine fibers with diameters ranging from 0.7 to 2.3 µm were obtained by regulating ZP solution concentration and process parameters during the ES process. Optimal loading capacity (LC) and encapsulation efficiency (EE) of OEO in fibrous ZP mats were determined to be 22.28% and 53.68%, respectively, and were achieved using a 35 w/v% ZP ES solution. The encapsulation of OEO was found to be reliant on ZP solution concentration (the enveloping medium). SEM analysis indicates the surface morphology of ZP/OEO electrospun fibers is dependent on ZP solution loading volume, with lower ZP concentrations yielding defective fibrous structures (for example, beaded and spindled-string like morphologies). Furthermore, this loading volume also influences OEO LC, EE, mat water contact angle and oil retention. CCK-8 assay and cell morphology assessment (HEK293T cells) indicate no significant change with electrospun ZP and ZP/OEO fibrous membranes over an 8 h period. Antimicrobial activity assessment using Escherichia coli, suggests composite nonwovens possess sterilization properties; elucidating potential application in active food packaging, food preservation and therefore sustainability.


Assuntos
Fenômenos Mecânicos , Membranas Artificiais , Óleos de Plantas/química , Antibacterianos/química , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Embalagem de Alimentos , Células HEK293 , Humanos , Óleos Voláteis/química , Fenilpropanolamina/química , Zeína/química
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