Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nano Lett ; 20(2): 1117-1123, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32003222

RESUMO

Endosomal escape is a key step for intracellular drug delivery of nucleic acids, but reliable and sensitive methods for its quantitation remain an unmet need. In order to rationally optimize the mRNA transfection efficiency of a library of polymeric materials, we designed a deactivated Renilla luciferase-derived molecular probe whose activity can be restored only in the cytosol. This probe can be coencapsulated with mRNA in the same delivery vehicle, thereby accurately measuring its endosomal escape efficiency. We examined a library of poly(amine-co-ester) (PACE) polymers with different end groups using this probe and observed a strong correlation between endosomal escape and transfection efficiency (R2 = 0.9334). In addition, we found that mRNA encapsulation efficiency and endosomal escape, but not uptake, were determinant factors for transfection efficiency. The polymers with high endosomal escape/transfection efficiency in vitro also showed good transfection efficiency in vivo, and mRNA expression was primarily observed in spleens after intravenous delivery. Together, our study suggests that the luciferase probe can be used as an effective tool to quantitate endosomal escape, which is essential for rational optimization of intracellular drug delivery systems.

2.
Inorg Chem ; 58(21): 14325-14330, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31622085

RESUMO

The photoluminescence of lanthanide ions inside fullerenes is usually very weak due to the quenching effect of the fullerene cage. In the case of Er@C82, the near-infrared emission from the Er3+ ion is completely quenched by the C82 fullerene cage. It remains challenging to turn on the photoluminescence of Er@C82 and other monometallofullerenes. In this work, we adopt a covalent modification strategy to alter the electronic structure of the fullerene cage for sensitizing the near-infrared emission of Er3+ ions in metallofullerenes Er@C2n (2n = 72, 76, and 82). After covalent modification with trifluoromethyl, phenyl, or dichlorophenyl groups, the erbium metallofullerenes exhibit photoluminescence at 1.5 µm, which is the characteristic emission of the Er3+ ion. Particularly, the otherwise nonfluorescent metallofullerene Er@C82 is transformed into fluorescent derivatives by using this strategy. The photoluminescence from the Er3+ ion is ascribed to energy transfer from the fullerene cage to the Er3+ ion. According to theoretical calculations, the sensitization of the Er3+ ion by the fullerene cage is associated with the large HOMO-LUMO gap and the closed-shell electronic structure of the metallofullerene derivatives. This work provides useful guidance for the design and synthesis of new fluorescent metallofullerenes.

3.
J Proteomics ; 207: 103468, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374362

RESUMO

In this study, two susceptible strains and two multi-drug resistant clinical Escherichia coli strains were obtained by Kirby-Bauer method, and then a GC-MS-based metabolomics method was used to compare the differential expression of metabolites between two drug sensitive (CK1 and CK2) and two multidrug-resistant (MDR1 and MDR2) clinical strains of E. coli. We characterized a total of 273 metabolites, including 77 commonly altered metabolites, between MDR vs. antibiotic sensitive strains. Interestingly, the PCA score plot clearly discriminated drug sensitive and MDR strains. The following bioinformatics analysis showed that biosynthesis of amino acids, biosynthesis of phenylpropanoids and purine metabolism were commonly enriched in MDR strains. Moreover, microbial metabolism in diverse environments, carbon metabolism,and pyrimidine metabolism pathways were more likely to be enriched MDR1 strain, while ABC transporters, and cysteine and methionine metabolism pathways were enriched in MDR2 strains. The enzyme activities in several involved metabolic pathways were further measured and metabolite candidates were validated by GC-MS-SIM method. These results indicated that antibiotic resistance affects the metabolite profiles of bacteria. In general, our study provides evidence on the study and prediction of MDR characteristics and mechanisms in bacteria at the metabolite level. BIOLOGICAL SIGNIFICANCE: Overuse and abuse of antibiotics has led to the emergence of antibiotic-resistant strains of bacteria; however, relatively little is known about their resistance mechanisms. In this study, metabolomics method was used to compare the differential expression of metabolites between sensitive and multidrug-resistant clinical strains of E. coli. Results show that the PCA score plot clearly discriminated sensitive and MDR strains, indicating that they had different metabolic profiles. Further, bioinformatics analysis showed that biosynthesis of amino acids, biosynthesis of phenylpropanoids and purine metabolism may be related to resistance. Finally, the enzyme activities in several involved metabolic pathways were further measured and metabolite candidates were validated by GC-MS-SIM method. In general, our study provides evidence on the study and prediction of MDR characteristics and mechanisms in bacteria at the metabolite level.

4.
Nature ; 573(7772): 91-95, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31365921

RESUMO

Bilayer graphene can be modified by rotating (twisting) one layer with respect to the other. The interlayer twist gives rise to a moiré superlattice that affects the electronic motion and alters the band structure1-4. Near a 'magic angle' of twist2,4, where the emergence of a flat band causes the charge carriers to slow down3, correlated electronic phases including Mott-like insulators and superconductors were recently discovered5-8 by using electronic transport. These measurements revealed an intriguing similarity between magic-angle twisted bilayer graphene and high-temperature superconductors, which spurred intensive research into the underlying physical mechanism9-14. Essential clues to this puzzle, such as the symmetry and spatial distribution of the spectral function, can be accessed through scanning tunnelling spectroscopy. Here we use scanning tunnelling microscopy and spectroscopy to visualize the local density of states and charge distribution in magic-angle twisted bilayer graphene. Doping the sample to partially fill the flat band, we observe a pseudogap phase accompanied by a global stripe charge order that breaks the rotational symmetry of the moiré superlattice. Both the pseudogap and the stripe charge order disappear when the band is either empty or full. The close resemblance to similar observations in high-temperature superconductors15-21 provides new evidence of a deeper link underlying the phenomenology of these systems.

5.
Nat Commun ; 10(1): 2935, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270335

RESUMO

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Histonas/química , Histonas/imunologia , Imunidade Humoral , Lisina/imunologia , Animais , Linfócitos B/química , Linfócitos B/citologia , Ciclo Celular , Células Cultivadas , Ciclina E/genética , Ciclina E/imunologia , Desmetilação , Proteínas F-Box/genética , Proteínas F-Box/imunologia , Histonas/genética , Ferro/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/imunologia , Ativação Linfocitária , Lisina/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Regiões Promotoras Genéticas , Linfócitos T/citologia , Linfócitos T/imunologia
6.
Anticancer Res ; 39(6): 2729-2737, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177108

RESUMO

BACKGROUND/AIM: Salivary adenoid cystic carcinoma (SACC) is the most common malignancy of the salivary gland with a poor prognosis and survival. The present study aimed to investigate the role of histone methyltransferase WHSC1 in SACC. MATERIALS AND METHODS: Human SACC specimens were evaluated for WHSC1 expression by RT-PCR and immunohistochemistry. The effects of WHSC1 knockdown on SACC cells proliferation, cell cycle, clone and tumorsphere formation, and apoptosis as well as on the expression of related genes were examined. A xenograft mouse model of SACC was used to evaluate the in vivo effects of WHSC1 knockdown on SACC tumorigenesis. RESULTS: WHSC1 expression was up-regulated in human SACC tissues (p<0.01). WHSC1 knockdown in SACC cells significantly inhibited cell proliferation, clone and tumorsphere formation (p<0.05). Cell distribution at the S and G2/M phases was significantly reduced by WHSC1 knockdown (p<0.05). WHSC1 knockdown significantly increased apoptosis of SACC cells (p<0.05). c-Myc, survivin, Bcl-2 and cyclin B1 genes were significantly down-regulated by WHSC1 knockdown cells (p<0.05). WHSC1 knockdown significantly reduced H3K36me2 modification of the MYC gene promoter in SACC cells and tumorigenesis of SACC cells in vivo (p<0.05). CONCLUSION: Knockdown of WHSC1 inhibited cell proliferation, induced apoptosis and affected tumorigenesis in SACC.


Assuntos
Carcinoma Adenoide Cístico/patologia , Técnicas de Silenciamento de Genes/métodos , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Neoplasias das Glândulas Salivares/patologia , Regulação para Cima , Animais , Apoptose , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/metabolismo , Transdução de Sinais
7.
J Mol Cell Biol ; 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31065671

RESUMO

Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft (PDX) model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.

8.
Anticancer Res ; 39(4): 1711-1718, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952710

RESUMO

BACKGROUND/AIM: Osteosarcoma (OS) is a diagnosed primary cancer of the bone. Despite the great advances that have been made during the past decades in OS therapy, drug resistance and tumor recurrence are still major problems. It is urgent to find novel strategies to overcome drug resistance in order to prolong the survival time of OS patients. MATERIALS AND METHODS: Cell viability was investigated by the cell count kit-8 (CCK-8) and colony formation assays. P-Glycoprotein (P-gp) expression was analyzed by RT-qPCR and western blot. A xenograft mouse model was used to identify the synergistic efficacy of a P-gp inhibitor with cisplatin. Student's t-test was used to determine statistically significant differences. RESULTS: P-gp expression levels were associated with cisplatin efficacy in OS patients. OS cells with higher P-gp expression were more resistant to cisplatin. Knockdown or inhibition of P-gp sensitized OS cells to cisplatin. CONCLUSION: Down-regulating the expression of P-gp in OS maybe a promising strategy to overcome cisplatin resistance.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Biol Macromol ; 131: 925-932, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30914370

RESUMO

Interferon-inducible transmembrane protein 3 (IFITM3) inhibits the replication of multiple pathogenic viruses by blocking their entry. In this study, we constructed a shuttle plasmid, harboring human IFITM3. Thereafter, recombinant adenovirus rAd5-IFITM3 was obtained by co-transfection of the linearized viral backbone vector pAd5 and the shuttle plasmid. The results showed that human IFITM3 did not affect the assembly and morphogenesis of progeny adenovirus. Human IFITM3 can be expressed in both A549 and MDCK cells in a time dependent manner. Furthermore, cells infected with rAd5-IFITM3 at a multiplicity of infection (MOI) of 100 for 24 h were challenged with avian influenza virus (AIV) H5N1 at an MOI of 1 for 6, 12 and 24 h. Rates of H5N1 infection in rAd5-IFITM3 cells were significantly decreased at 24 h post-infection (hpi), in a time dependent manner, compared with that of wild type wtAd5-infected cells. The expressions of viral genes were significantly inhibited at transcriptional and translational levels at 6 and 12 hpi. These results suggest that IFITM3 can suppress H5N1 replication in the early stage of the infection, which may be used as a promise agent against H5N1 infection in vivo.


Assuntos
Adenoviridae/genética , Clonagem Molecular , Expressão Gênica , Vetores Genéticos/genética , Proteínas de Membrana/genética , Proteínas de Ligação a RNA/genética , Adenoviridae/ultraestrutura , Animais , Linhagem Celular , Cães , Ordem dos Genes , Humanos , Virus da Influenza A Subtipo H5N1 , Células Madin Darby de Rim Canino , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo
10.
Cell Death Dis ; 10(2): 65, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683853

RESUMO

Osteosarcoma (OS) is a primary malignant bone tumour. However, the genetic basis for the pathogenesis of OS remains elusive. In this study, we uncovered the role of the histone methyltransferase NSD2 in regulating tumourigenesis and chemosensitivity in OS. We show that NSD2 knockdown leads to increased apoptosis in OS cells in vitro and in vivo. Additionally, NSD2 knockdown significantly enhances the efficacy of cisplatin against OS cells and accordingly inhibits properties associated with cancer stem cells (CSCs). Furthermore, RNA sequencing (RNAseq) and Gene Ontology (GO) analysis revealed that NSD2 promotes transcription of genes associated with negative regulation of apoptotic signalling pathways and CSC properties. The results of chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) assays indicated that NSD2 knockdown leads to decreased H3K36me2 modification at BCL2 and SOX2 loci, thus inhibiting the transcription of these two genes that are closely correlated with apoptosis, CSC properties and chemosensitivity in OS cells. Pathway analysis demonstrated that the ERK and AKT pathways mediate the regulation of OS progression and chemosensitivity by NSD2. Overall, our study is the first to uncover the function of NSD2 in OS chemosensitivity. NSD2 regulates the expression of the apoptosis regulatory proteins BCL2 and SOX2 through the ERK and AKT pathways. Our results suggest that NSD2 is a new target for combined chemotherapy and is a prognostic factor for OS.

11.
Clin Epigenetics ; 11(1): 8, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651137

RESUMO

BACKGROUND: In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, the mechanisms of drug resistance remain elusive, limiting therapeutic efficacy. Here, we set out to explore the relationship between dynamic histone changes and the efficacy of cisplatin against OS. RESULTS: First, we found two histone demethylases associated with histone H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, and KDM6B that were upregulated after cisplatin treatment. Consistent with the clinical data, cisplatin-resistant OS specimens showed lower H3K27me3 levels than sensitive specimens. Then, we evaluated the effects of H3K27me3 alteration on OS chemosensitivity. In vitro inhibition of the histone methyltransferase EZH2 in OS cells decreased H3K27me3 levels and led to cisplatin resistance. Conversely, inhibition of the demethylases KDM6A and KDM6B increased H3K27me3 levels in OS and reversed cisplatin resistance in vitro and in vivo. Mechanistically, with the help of RNA sequencing (RNAseq), we found that PRKCA and MCL1 directly participated in the process by altering H3K27me3 on their gene loci, ultimately inactivating RAF/ERK/MAPK cascades and decreasing phosphorylation of BCL2. CONCLUSIONS: Our study reveals a new epigenetic mechanism of OS resistance and indicates that elevated H3K27me3 levels can sensitize OS to cisplatin, suggesting a promising new strategy for the treatment of OS.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Cisplatino/administração & dosagem , Histonas/metabolismo , Osteossarcoma/tratamento farmacológico , Regulação para Cima , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Masculino , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Proteína Quinase C-alfa/genética , Análise de Sequência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Proteomics ; 194: 148-159, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30521976

RESUMO

Previously, a maltose-specific channel porin, LamB was found to be associate with multi-drug resistance in a lamB deleted strain, but the exact mechanisms require further elucidation. Herein, differential protein expression between the Escherichia coli mutant strain ΔlamB and the wild type strain BW25113, with and without ciprofloxacin (CFLX), was identified using iTRAQ based liquid chromatography-tandem mass spectrometry (LC-MS/MS); while differential metabolite expression was examined using gas chromatography-mass spectrometry (GC-MS). Further Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that lamB deletion leads to a decrease in several key metabolic pathways such as tricarboxylic acid (TCA) cycle, pentose phosphate pathway and glycolysis/gluconeogenesis. When examining the ΔlamB strain without CFLX, many aminoacyl-tRNA biosynthesis and pyrimidine metabolism-related proteins were unaltered, but the addition of CFLX resulted in reduced levels. These findings indicate that a lamB deletion may confer antibiotic resistance by relieving the pressure of protein translation and DNA replication. To further examine antibiotic resistance, exogenous metabolites, including maltose, and several amino acids metabolites were evaluated to determine whether the resistance level could be reduced in the presence of CFLX. The obtained results indicate that lamB knockout may increase bacterial antibiotics resistance by decreasing metabolic pathway activity levels. BIOLOGICAL SIGNIFICANCE: An integrated metabonomic-proteomic method was performed to systematically compare the profiles of metabolites and proteins between ΔlamB and its wild type strain, with and without ciprofloxacin (CFLX) treatment. Following bioinformatics analysis showed that lamB deletion in CFLX stress leads to the decreasing of several key metabolic pathways. Many amino acid-tRNA biosynthesis and pyrimidine metabolism related proteins didn't change in ΔlamB strain but largely decreased after treated with CFLX. Further exogenous metabolites addition assay reveals that maltose and several amino acids metabolites contribute to the CFLX resistance mediated by LamB. Our results indicate that the down-regulation of LamB may increase bacterial antibiotics resistance by decreasing the intracellular metabolism pathways.

13.
Acta Biochim Biophys Sin (Shanghai) ; 50(11): 1141-1149, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30289427

RESUMO

Bcl-3 is an established oncogene in diverse malignant tumors. In this study, we investigated a dual role of Bcl-3 in BL1-subtype triple-negative breast cancer (TNBC). The BL1-subtype TNBC is featured by increasing cell cycle gene expression and the highest sensitivity to chemotherapy among all subtypes. Bcl-3 is associated with a better prognosis in BL1 patients. Bcl-3 knockdown in BL1 cell MDA-MB-468 induces the inhibition of cell proliferation and the G1/S transition arrest by promoting p27 and reducing the expressions of c-Myc and skp2 at mRNA and protein levels. Meanwhile, Bcl-3 enhances the sensitivity of MDA-MB-468 to chemotherapeutics ABX and PTX. Furthermore, the regulation mechanisms are restricted to BL1 cell and do not occur in SUM159PT, a typical MSL subtype of TNBC cell. These data suggest that Bcl-3 may be a potential clinical biomarker for diagnosis, treatment, and prognosis of patients with BL1-subtype TNBC.


Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
14.
Chemphyschem ; 19(22): 2995-3000, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30230199

RESUMO

In this work, we theoretically designed a new class of fullerene derivatives, metallofullerene heterodimers, through cross dimerization of metallofullerene monomers Li@C60 , Y@C82 and Y2 @C80 . The molecular structures, electronic structures, linear and nonlinear optical properties of the heterodimers were studied by using density functional theory calculations. We found that two fullerene cages are connected through a relatively weak carbon-carbon single bond. Inter-cage electron transfer takes place in the heterodimers because of the different electron accepting abilities of the metallofullerene moieties. The first hyperpolarizability of the metallofullerenes increases remarkably as a result of dimerization. Time-dependent density functional theory calculations reveal that the enhanced first hyperpolarizability of the dimer is associated with charge-transfer transitions. This study demonstrates that covalent dimerization is an efficient means to improve the nonlinear optical response of metallofullerenes.

15.
Biomacromolecules ; 19(9): 3861-3873, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30110158

RESUMO

Gene therapy promises to treat diseases that arise from genetic abnormalities by correcting the underlying cause of the disease rather than treating the associated symptoms. Successful transfer of nucleic acids into cells requires efficient delivery vehicles that protect the cargo and can penetrate the appropriate cellular barriers before releasing their contents. Many viral vectors and synthetic polycationic vectors for nucleic acid delivery do not translate well from in vitro to in vivo applications due to their instability and toxicity. We synthesized and characterized a library of biocompatible low charge density polymers from a family of poly(amine- co-ester) (PACE) terpolymers produced via enzyme catalyzed polymerization. PACE polymers are highly customizable; we found that the terpolymer composition can be optimized to produce efficient transfection of various nucleic acids-including DNA plasmids, mRNA, and siRNA-in specific cell types with low toxicity. Our findings suggest that the unique tunability of PACEs offers new tools for gene therapy and other biomedical applications.


Assuntos
Técnicas de Transferência de Genes , Nanopartículas/química , 3,4-Metilenodioxianfetamina/análogos & derivados , 3,4-Metilenodioxianfetamina/química , Células 3T3 , Animais , Ácidos Decanoicos/química , Ácidos Dicarboxílicos/química , Ésteres/química , Células HEK293 , Humanos , Macrolídeos/química , Camundongos , Poliaminas/química , Polimerização
16.
Oncogene ; 37(44): 5887-5900, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29973688

RESUMO

Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-κB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-κB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-κB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27Kip1 protein level, which inhibits CRC cell proliferation and retards CRC xenograft growth. Conversely, overexpression of RelB increases proliferation of CRC cells. In addition, we revealed a significant correlation between Bcl-3 and RelB in CRC tissues. The expression of RelB was consistent with the expression of Bcl-3 and the phosphorylation of Bcl-3 downstream proteins p-Akt (S473) and p-GSK3ß (S9). Bcl-3 overexpression can restore the phenotype changes caused by RelB knockdown. Importantly, we demonstrated that alternative NF-κB transcriptional factor (p52:RelB) can directly bind to the promoter region of Bcl-3 gene and upregulate its transcription. Moreover, the expression of RelB, NF-κB2 p52, and Bcl-3 was associated with poor survival of CRC patients. Taken together, these results represent that alternative NF-κB signaling may function as an oncogenic driver in CRC, and also provide new ideas and research directions for the pathogenesis, prevention, and treatment of other inflammatory-related diseases.


Assuntos
Neoplasias Colorretais/metabolismo , Subunidade p52 de NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Fator de Transcrição RelB/metabolismo , Fatores de Transcrição/genética , Animais , Carcinogênese , Linhagem Celular Tumoral , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição RelB/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/metabolismo , Transcrição Genética , Regulação para Cima
17.
Nat Commun ; 9(1): 2349, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29904129

RESUMO

In normal metals the magnetic moment of impurity-spins disappears below a characteristic Kondo temperature which marks the formation of a cloud of conduction-band electrons that screen the local-moment. In contrast, moments embedded in insulators remain unscreened at all temperatures. What then is the fate of magnetic-moments in intermediate, pseudogap systems, such as graphene? Theory predicts that coupling to the conduction-band electrons will drive a quantum phase transition between a local-moment phase and a Kondo-screened phase. However, attempts to experimentally confirm this prediction and its intriguing consequences, such as electrostatically tunable magnetic-moments, have been elusive. Here we report the observation of Kondo-screening and the quantum phase-transition between screened and unscreened phases of vacancy magnetic moments in graphene. Using scanning tunneling spectroscopy and numerical renormalization-group calculations we show that this transition enables to control the screening of local moments by tuning the gate voltage and the local curvature of the graphene membrane.

18.
Biomaterials ; 176: 122-130, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29879653

RESUMO

Gene delivery is known to be a complicated multi-step biological process. It has been observed that subtle differences in the structure and properties of polymeric materials used for gene delivery can lead to dramatic differences in transfection efficiency. Therefore, screening of properties is pivotal to optimizing the polymer. So far, most polymeric materials are built in a "bottom-up" manner, i.e. synthesized from monomers that allow modification of polymer composition or structural factors. With this method, we previously synthesized and screened a library of biodegradable poly(amine-co-ester) (PACE) terpolymers for optimized DNA delivery. However, it can be tedious and time consuming to synthesize a polymer library for screening, particularly when small changes of a factor need to be tested, when multiple factors are involved, and when the effects of different factors are synergistic. In the present work, we evaluate the potential of PACE to deliver mRNA. After observing that mRNA transfection efficiency was highly dependent on both end group composition and molecular weight (MW) of PACE in a synergistic manner, we developed a "top-down" process we called actuation, to simultaneously vary these two factors. Some of the actuated PACE (aPACE) materials presented superior mRNA delivery properties compared to regular PACE, with up to a 106-fold-increase in mRNA transfection efficiency in vitro. Moreover, when aPACE was used to deliver mRNA coding for erythropoietin (EPO) in vivo, it produced high levels of EPO in the blood for up to 48 h without inducing systemic toxicity. This polymer constitutes a new delivery vehicle for mRNA-based treatments that provides safe yet potent protein production.


Assuntos
Poliaminas/química , Poliésteres/química , RNA Mensageiro/administração & dosagem , Animais , Linhagem Celular , Sobrevivência Celular , Eritropoetina/genética , Feminino , Técnicas de Transferência de Genes , Humanos , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Peso Molecular , Nanopartículas/química , Polimerização , Bibliotecas de Moléculas Pequenas , Transfecção
19.
Adv Funct Mater ; 28(6)2018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29785179

RESUMO

Brain-derived neurotrophic factor (BDNF) is identified as a potent neuroprotective and neuroregenerative agent for many neurological diseases. Regrettably, its delivery to the brain is hampered by poor serum stability and rapid brain clearance. Here, a novel nanoformulation is reported composed of a bio-compatible polymer, poly(ethylene glycol)-b-poly(L-glutamic acid) (PEG-PLE), that hosts the BDNF molecule in a nanoscale complex, termed here Nano-BDNF. Upon simple mixture, Nano-BDNF spontaneously forms uniform spherical particles with a core-shell structure. Molecular dynamics simulations suggest that binding between BDNF and PEG-PLE is mediated through electrostatic coupling as well as transient hydrogen bonding. The formation of Nano-BDNF complex stabilizes BDNF and protects it from nonspecific binding with common proteins in the body fluid, while allowing it to associate with its receptors. Following intranasal administration, the nanoformulation improves BDNF delivery throughout the brain and displays a more preferable regional distribution pattern than the native protein. Furthermore, intranasally delivered Nano-BDNF results in superior neuroprotective effects in the mouse brain with lipopolysaccharides-induced inflammation, indicating promise for further evaluation of this agent for the therapy of neurologic diseases.

20.
Oncotarget ; 8(57): 97206-97216, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29228604

RESUMO

Progressive renal fibrosis in chronic kidney disease (CKD) greatly contributes to end-stage renal failure and is associated with high mortality. The identification of renal fibrosis biomarkers for the diagnosis and the monitoring of disease progression in CKD is urgently needed. Whole-transcriptomic analysis of renal tissues in a unilateral ureteral obstruction (UUO) mouse model revealed that the mRNA level of Bcl-3, an atypical member of the IκB family, was induced 6.3-fold 2 days after UUO. Compared with renal tissues in sham-operated mice, increases in Bcl-3 mRNA and protein in the renal tissues in the UUO model were accompanied with increases in other markers of renal fibrosis, including human epididymis protein 4 (HE4), a recently identified biomarker of renal fibrosis. Immunohistochemical analysis revealed that both Bcl-3 and HE4 were located in the plasma of renal tubule cells. Serum protein levels of Bcl-3 and HE4 rose with the development of renal fibrosis in UUO mouse model. We found that the serum protein levels of both HE4 and Bcl-3 were elevated in CKD patients compared with healthy controls. Moreover, a significant positive correlation between Bcl-3 and HE4 (r = 0.939, p < 0.0001) was observed in CKD patients. These data suggest that Bcl-3 can serve as a novel valuable biomarker of renal fibrosis in CKD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA