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1.
J Biol Chem ; 298(2): 101563, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34998823

RESUMO

The cytidine deaminase APOBEC3B (A3B) is an endogenous inducer of somatic mutations and causes chromosomal instability by converting cytosine to uracil in single-stranded DNA. Therefore, identification of factors and mechanisms that mediate A3B expression will be helpful for developing therapeutic approaches to decrease DNA mutagenesis. Arsenic (As) is one well-known mutagen and carcinogen, but the mechanisms by which it induces mutations have not been fully elucidated. Herein, we show that A3B is upregulated and required for As-induced DNA damage and mutagenesis. We found that As treatment causes a decrease of N6-methyladenosine (m6A) modification near the stop codon of A3B, consequently increasing the stability of A3B mRNA. We further reveal that the demethylase FTO is responsible for As-reduced m6A modification of A3B, leading to increased A3B expression and DNA mutation rates in a manner dependent on the m6A reader YTHDF2. Our in vivo data also confirm that A3B is a downstream target of FTO in As-exposed lung tissues. In addition, FTO protein is highly expressed and positively correlates with the protein levels of A3B in tumor samples from human non-small cell lung cancer patients. These findings indicate a previously unrecognized role of A3B in As-triggered somatic mutation and might open new avenues to reduce DNA mutagenesis by targeting the FTO/m6A axis.


Assuntos
Arsênio , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Arsênio/toxicidade , Carcinoma Pulmonar de Células não Pequenas/genética , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Desmetilação , Humanos , Neoplasias Pulmonares/genética , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Mutagênese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Cell Biosci ; 11(1): 217, 2021 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-34924003

RESUMO

BACKGROUND: Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth. METHODS: Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets. RESULTS: In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo. CONCLUSIONS: Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.

3.
Nat Commun ; 12(1): 6653, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789768

RESUMO

BRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. Dysfunction of the BRCA1 pathway enhances the therapeutic efficiency of poly-(ADP-ribose) polymerase inhibitors (PARPi) in cancers, but the molecular mechanisms underlying this sensitization to PARPi are not fully understood. Here, we show that cancer cell sensitivity to PARPi is promoted by the ring between ring fingers (RBR) protein RNF19A. We demonstrate that RNF19A suppresses HR by ubiquitinating BARD1, which leads to dissociation of BRCA1-BARD1 complex and exposure of a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in the export of BARD1 to the cytoplasm. We provide evidence that high RNF19A expression in breast cancer compromises HR and increases sensitivity to PARPi. We propose that RNF19A modulates the cancer cell response to PARPi by negatively regulating the BRCA1-BARD1 complex and inhibiting HR-mediated DNA repair.


Assuntos
Proteína BRCA1/metabolismo , Recombinação Homóloga , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteína BRCA1/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinogênese , Dano ao DNA , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ligação Proteica , Multimerização Proteica , Domínios RING Finger , Proteínas Supressoras de Tumor/química , Ubiquitina-Proteína Ligases/química
4.
ACS Appl Mater Interfaces ; 13(38): 45335-45345, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34543000

RESUMO

Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive "cold tumor" to an immunogenic "hot tumor," thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Membrana Eritrocítica/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias/tratamento farmacológico , Protoporfirinas/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Cobre/química , Cobre/uso terapêutico , Humanos , Imunidade/efeitos dos fármacos , Imunoterapia , Luz , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/metabolismo , Peróxidos/química , Peróxidos/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/química , Protoporfirinas/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos
5.
Nano Lett ; 20(2): 1280-1285, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31904971

RESUMO

Elemental phosphorus nanostructures are notorious for a large number of allotropes, which limits their usefulness as semiconductors. To limit this structural diversity, we synthesize selectively quasi-1D phosphorus nanostructures inside carbon nanotubes (CNTs) that act both as stable templates and nanoreactors. Whereas zigzag phosphorus nanoribbons form preferably in CNTs with an inner diameter exceeding 1.4 nm, a previously unknown square columnar structure of phosphorus is observed to form inside narrower nanotubes. Our findings are supported by electron microscopy and Raman spectroscopy observations as well as ab initio density functional theory calculations. Our computational results suggest that square columnar structures form preferably in CNTs with an inner diameter around 1.0 nm, whereas black phosphorus nanoribbons form preferably inside CNTs with a 4.1 nm inner diameter, with zigzag nanoribbons energetically favored over armchair nanoribbons. Our theoretical predictions agree with the experimental findings.

6.
Angew Chem Int Ed Engl ; 59(3): 1074-1080, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31713959

RESUMO

Black phosphorene has attracted much attention as a semiconducting two-dimensional material. Violet phosphorus is another layered semiconducting phosphorus allotrope with unique electronic and optoelectronic properties. However, no confirmed violet crystals or reliable lattice structure of violet phosphorus had been obtained. Now, violet phosphorus single crystals were produced and the lattice structure has been obtained by single-crystal x-ray diffraction to be monoclinic with space group of P2/n (13) (a=9.210, b=9.128, c=21.893 Å, ß=97.776°). The lattice structure obtained was confirmed to be reliable and stable. The optical band gap of violet phosphorus is around 1.7 eV, which is slightly larger than the calculated value. The thermal decomposition temperature was 52 °C higher than its black phosphorus counterpart, which was assumed to be the most stable form. Violet phosphorene was easily obtained by both mechanical and solution exfoliation under ambient conditions.

7.
Chempluschem ; 84(2): 203-209, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31950692

RESUMO

Graphene-coated silicon nanoparticles with polydopamine buffers have been designed and successfully fabricated as anodes for lithium ion batteries, where the polydopamine was grown on the silicon nanoparticles and then coated with graphene layers. The expansion cavities for silicon nanoparticles during charging and discharging process are provided by the polydopamine buffer layers. The outermost graphene coating layers not only keep the pulverized silicon particles together without disintegration, but also improve the electric conductivity of silicon nanoparticles. Silicon nanoparticles of an industrial product level with different size distributions and oxidation layers were used in this work. High electrochemical performances with specific capacities of 1100 mAh g-1 were achieved by the designed silicon composites with polydopamine and graphene after 550 cycles at a current rate of 200 mA g-1 .

8.
Natl Sci Rev ; 6(4): 767-774, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34691932

RESUMO

Many different phase structures have been discovered for silver iodides. The ß and γ phases were found to be the most common ones at ambient conditions, while the rock-salt phase was found to be stable under pressures between 400 MPa and 11.3 GPa. Recently, the α phase was demonstrated to be stable under ambient conditions when the particle sizes were reduced to below 10 nm. However, no other phase has been reported to be stable for silver iodides under ambient conditions. Rock-salt and helix structures have been found to be stable under ambient conditions in this study. The structures have been characterized by elemental mapping, Raman scattering, and high-resolution transmission electron microscopy. The stabilities of these structures were also confirmed by molecular dynamics and density functional theory.

9.
Mol Cell ; 68(1): 171-184.e6, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28985503

RESUMO

A substantial fraction of eukaryotic transcripts are considered long non-coding RNAs (lncRNAs), which regulate various hallmarks of cancer. Here, we discovered that the lncRNA HOXB-AS3 encodes a conserved 53-aa peptide. The HOXB-AS3 peptide, not lncRNA, suppresses colon cancer (CRC) growth. Mechanistically, the HOXB-AS3 peptide competitively binds to the ariginine residues in RGG motif of hnRNP A1 and antagonizes the hnRNP A1-mediated regulation of pyruvate kinase M (PKM) splicing by blocking the binding of the ariginine residues in RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, ensuring the formation of lower PKM2 and suppressing glucose metabolism reprogramming. CRC patients with low levels of HOXB-AS3 peptide have poorer prognoses. Our study indicates that the loss of HOXB-AS3 peptide is a critical oncogenic event in CRC metabolic reprogramming. Our findings uncover a complex regulatory mechanism of cancer metabolism reprogramming orchestrated by a peptide encoded by an lncRNA.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Peptídeos/genética , RNA Longo não Codificante/genética , Processamento Alternativo , Motivos de Aminoácidos , Animais , Ligação Competitiva , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Éxons , Células HeLa , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Peptídeos/antagonistas & inibidores , Peptídeos/metabolismo , Ligação Proteica , Mapeamento de Interação de Proteínas , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
10.
Oncotarget ; 8(27): 44082-44095, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28489585

RESUMO

Despite recent efforts to understand activities of POU domain class 2 transcription factor 1 (POU2F1), little is known about the roles of POU2F1 in hepatocellular carcinoma (HCC) tumorigenesis and its correlation with any clinicopathological feature of HCC. In this study, we found that POU2F1 was significantly up-regulated in HCC specimens compared with adjacent non-cancerous liver specimens. The high POU2F1 protein expression level positively correlated with large tumor size, high histological grade, tumor metastasis and advanced clinical stage, and HCC patients with high POU2F1 levels exhibited poor prognoses. We further demonstrated that POU2F1 over-expression promoted HCC cell proliferation, colony formation, epithelial-to-mesenchymal transition (EMT), migration and invasion, while silencing of POU2F1 inhibited these malignant phenotypes. POU2F1 induced the expression of Twist1, Snai1, Snai2 and ZEB1 genes which are involved in the regulation of EMT. Furthermore, POU2F1 was up-regulated by AKT pathway in HCC, and POU2F1 over-expression reversed the inhibition of malignant phenotypes induced by AKT knock-down, indicating POU2F1 is a key down-stream effector of AKT pathway. Collectively, our results indicate that POU2F1 over-expression is positively associated with aggressive phenotypes and poor survival in patients with HCC, and POU2F1 regulated by AKT pathway promotes HCC aggressive phenotypes by regulating the transcription of EMT genes. POU2F1 may be employed as a new prognostic factor and therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Fator 1 de Transcrição de Octâmero/genética , Adulto , Idoso , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Inativação Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carga Tumoral
11.
Angew Chem Int Ed Engl ; 56(7): 1850-1854, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28074606

RESUMO

A phosphorus allotrope that has not been observed so far, ring-shaped phosphorus consisting of alternate P8 and P2 structural units, has been assembled inside multi-walled carbon nanotube nanoreactors with inner diameters of 5-8 nm by a chemical vapor transport and reaction of red phosphorus at 500 °C. The ring-shaped nanostructures with surrounding graphene walls are stable under ambient conditions. The nanostructures were characterized by high-resolution transmission electron microscopy, scanning transmission electron microscopy, energy-dispersive X-ray spectroscopy, Raman scattering, attenuated total reflectance Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy.

12.
ACS Nano ; 10(10): 9509-9515, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-27732777

RESUMO

The morphology and hybridization of nanostructures are crucial to achieve properties for various applications. An in situ grown three-dimensional (3D) MoS2 nanomask has been adopted to control the morphology and hybridization of molybdenum compounds. The in situ generated MoS2 mask on MoO3 nanobelt surfaces allowed us to fabricate a 3D c-MoO2@MoS2 hybrid nanostructure, in which c-MoO2 is a carved MoO2 nanobelt with a well-distributed hole pattern. The nanomasks have been controlled by adjusting the alignments of MoS2. The exposed MoO2 surfaces of c-MoO2@MoS2 were further sulfurated to give cw-MoO2@MoS2, in which all surfaces of MoO2 are wrapped by a few layers of MoS2. The structure synergistically enhanced the electrochemical performances of MoO2 and MoS2, especially at high current rates. Reversible capacities of 1418 and 295 mAh/g after 115 and 300 cycles still remained for the cw-MoO2@MoS2 anodes at current rates of 1 and 10 A/g, respectively.

13.
Nano Lett ; 15(8): 5268-72, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26226386

RESUMO

Molybdenum disulfides and carbides are effective catalysts for hydrogenation and hydridesulfurization, where MoS2 nanostructures are also highly promising materials for lithium ion batteries. High surface-to-volume ratio and strong interactions with conducting networks are crucial factors for their activities. A new hybrid structure of multiwalled carbon nanotube (MWCNT) with alternate MoC nanoparticles and MoS2 nanosheets (MoS2 + MoC-MWCNT) has been synthesized by controlled carburization of core-shell MoS2-MWCNT hybrid nanotubes and demonstrated by HRTEM, FFT, XRD, and Raman scattering. The MoS2 nanosheets (∼10 nm) remain tightly connected to MWCNT surfaces with {001} planes in parallel to MWCNT walls and the highly crystallized α-MoC particles (∼10 nm) are adhered to MWCNTs at angles of 60-80° between {111} planes and MWCNT walls. The electrochemical performances of the hybrid structures have been demonstrated as anodes for lithium ion batteries to be significantly increased by breaking MoS2 nanotubes into nanosheets (patches) on MWCNT surfaces, especially at high current rates. The specific capacities of MoS2 + MoC-MWCNT sample with ∼23% MoS2 have been demonstrated to be higher than those of MoS2-MWCNTs containing ∼70% MoS2.

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