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1.
Proc Natl Acad Sci U S A ; 117(11): 6103-6113, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123069

RESUMO

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.

2.
Apoptosis ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31938895

RESUMO

Emerging evidence has indicated that microRNAs are involved in multiple processes of cancer development. Previous studies have demonstrated that microRNA-499a (miR-499a) plays both oncogenic and tumor suppressive roles in several types of malignancies, and genetic variants in miR-499a are associated with the risk of cervical cancer. However, the biological roles of miR-499a in cervical cancer have not been investigated. Quantitative real-time PCR was used to assess miR-499a expression in cervical cancer cells. Mimics or inhibitor of miR-499a was transfected into cervical cancer cells to upregulate or downregulate miR-499a expression. The effects of miR-499a expression change on cervical cancer cells proliferation, colony formation, tumorigenesis, chemosensitivity, transwell migration and invasion were assessed. The potential targets of miR-499a were predicted using online database tools and validated using real-time PCR, Western blot and luciferase reporter experiments. miR-499a was significantly upregulated in cervical cancer cells. Moreover, overexpression of miR-499a significantly enhanced the proliferation, cell cycle progression, colony formation, apoptosis resistance, migration and invasion of cervical cancer cells, while inhibiting miR-499a showed the opposite effects. Further exploration demonstrated that Sex-determining region Y box 6 was the direct target of miR-499a. miR-499a-induced SOX6 downregulation mediated the oncogenic effects of miR-499a in cervical cancer. Inhibiting miR-499a could enhance the anticancer effects of cisplatin in the xenograft mouse model of cervical cancer. Our findings for the first time suggest that miRNA-499a may play an important role in the development of cervical cancer and could serve as a potential therapeutic target.

3.
J Exp Clin Cancer Res ; 38(1): 402, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519193

RESUMO

BACKGROUND: Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. METHODS: Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. RESULTS: DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. CONCLUSIONS: Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Artemisininas/farmacologia , Glioma/metabolismo , Proteínas de Choque Térmico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Expressão Gênica , Humanos , Camundongos , Espécies Reativas de Oxigênio/metabolismo
4.
Molecules ; 24(19)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547150

RESUMO

As one of the most efficient pathways to provide clean energy, fuel cells have attracted great attention in both academic and industrial communities. Proton exchange membranes (PEMs) or proton-conducting electrolytes are the key components in fuel cell devices, which require the characteristics of high proton conductivity as well as high mechanical, chemical and thermal stabilities. Organic-inorganic hybrid PEMs can provide a fantastic platform to combine both advantages of two components to meet these demands. Due to their extremely high proton conductivity, good thermal stability and chemical adjustability, polyoxometalates (POMs) are regarded as promising building blocks for hybrid PEMs. In this review, we summarize a number of research works on the progress of POM-polymer hybrid materials and related applications in PEMs. Firstly, a brief background of POMs and their proton-conducting properties are introduced; then, the hybridization strategies of POMs with polymer moieties are discussed from the aspects of both noncovalent and covalent concepts; and finally, we focus on the performance of these hybrid materials in PEMs, especially the advances in the last five years. This review will provide a better understanding of the challenges and perspectives of POM-polymer hybrid PEMs for future fuel cell applications.

5.
ACS Appl Mater Interfaces ; 11(35): 31899-31908, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31407896

RESUMO

A novel ionic liquid-impregnated metal-organic-framework (IL@NH2-MIL-101) was prepared and introduced into sulfonated poly(arylene ether ketone) with pendent carboxyl groups (SPAEK) as the nanofiller for achieving hybrid proton exchange membranes. The nanofiller was anchored in the polymeric matrix by the formation of amido linkage between the pendent carboxyl group attached to the molecule chain of SPAEK and amino group belonging to the inorganic framework, thus leading to the enhancement in mechanical properties and dimensional stability. Besides, the hybrid membrane (IL@MOF-1) exhibits an enhanced proton conductivity up to 0.184 S·cm-1 because of the incorporation of ionic liquid in the nanocages of NH2-MIL-101. Moreover, the special structure of NH2-MIL-101 contributes to a low leakage of ionic liquid so as to retain the stable proton conductivity of hybrid membranes under fully hydrated conditions. Furthermore, as a result of a cross-linked structure formed by inorganic nanofiller, the IL@MOF-1 hybrid membrane shows a lower methanol permeability (7.53 × 10-7 cm2 s-1) and superior selectivity (2.44 × 105 S s cm-3) than the pristine SPAEK membrane. Especially, IL@MOF-1 performs high single-cell efficiency with a peak power density of 37.5 mW cm-2, almost 2.3-fold to SPAEK. Electrochemical impedance spectroscopy and scanning electron microscopy indicated that the nanofiller not only contributed to faster proton transfer but also resulted in a tighter bond between the membrane and catalyst. Therefore, the incorporation of IL@NH2-MIL-101 to prepare the hybrid membrane is proven to be suitable for application in direct methanol fuel cells.

6.
BMC Cancer ; 19(1): 851, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462277

RESUMO

BACKGROUND: Gradual loss of terminal differentiation markers and gain of stem cell-like properties is a major hall mark of cancer malignant progression. The stem cell pluripotent transcriptional factor SOX family play critical roles in governing tumor plasticity and lineage specification. This study aims to establish a novel SOX signature to monitor the extent of tumor dedifferentiation and predict prognostic significance in hepatocellular carcinoma (HCC). METHODS: The RNA-seq data from The Cancer Genome Atlas (TCGA) LIHC project were chronologically divided into the training (n = 188) and testing cohort (n = 189). LIRI-JP project from International Cancer Genome Consortium (ICGC) data portal was used as an independent validation cohort (n = 232). Kaplan-Meier and multivariable Cox analyses were used to examine the clinical significance and prognostic value of the signature genes. RESULTS: The SOX gene family members were found to be aberrantly expressed in clinical HCC patients. A five-gene SOX signature with prognostic value was established in the training cohort. The SOX signature genes were found to be closely associated with tumor grade and tumor stage. Liver cancer dedifferentiation markers (AFP, CD133, EPCAM, and KRT19) were found to be progressively increased while hepatocyte terminal differentiation markers (ALB, G6PC, CYP3A4, and HNF4A) were progressively decreased from HCC patients with low SOX signature scores to patients with high SOX signature scores. Kaplan-Meier survival analysis further indicated that the newly established SOX signature could robustly predict patient overall survival in both training, testing, and independent validation cohort. CONCLUSIONS: An oncogenic dedifferentiation SOX signature presents a great potential in predicting prognostic significance in HCC, and might provide novel biomarkers for precision oncology further in the clinic.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Perfilação da Expressão Gênica/métodos , Neoplasias Hepáticas/patologia , Fatores de Transcrição SOX/genética , Carcinoma Hepatocelular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Medicina de Precisão , Prognóstico , Análise de Sequência de RNA/métodos , Análise de Sobrevida
7.
ACS Nano ; 13(6): 7135-7145, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31184135

RESUMO

Multiscale hierarchical morphologies are greatly desired for fabricating nanocomposites with tunable macroscopic properties, but challenges remain in precisely manipulating the spatial arrangement of nanoparticles in polymer matrices across multiple length scales. Here, we demonstrate a class of mobile-ligand nanoparticle system built upon 1 nm anionic polyoxometalate molecular nanoparticles and cationic terminated polymer chains by electrostatic interaction. The highly rearrangeable polymer chains can serve as mobile ligands to direct the polyoxometalates to align into sub-10 nm anisotropic superlattice-like nanoarrays in the bulk state. Moreover, these nanoarrays can further serve as structural units to assemble into hierarchically ordered morphologies in polymer matrices, e.g., percolated networks over hundreds of micrometers which are comprised of cylindrically packed polyoxometalate superlattices down to sub-10 nm scale. These hierarchical morphologies enable the nanocomposites with reinforced mechanical performance. The presented mobile-ligand approach can provide a paradigm to design functional polymer nanocomposites with improved properties such as mechanical reinforcement and collective optical and electronic functions.

8.
Front Oncol ; 8: 594, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581773

RESUMO

Background: HOXA10 is a key transcriptional factor that regulates testis development as reported from previous transgenic mouse models and human inherited diseases. However, whether it also plays important roles in promoting the development of testicular cancer is not well-understood. Objective: To study the expression of HOXA10 and its regulated signaling pathways in testicular cancers. Design, Setting, and Participants: A tissue microarray was constructed with benign and cancerous testis. TCam2, NT-2, and NCCIT cell models were applied in this study. Intervention: Immunohistochemistry and immunofluorescence were performed to measure the expression and cellular localization of HOXA10 in testicular cancer tissues and cell models. Cell proliferation and cell cycling rates were determined by BrdU incorporation and flow cytometry assays. HOXA10 transcriptomes were profiled with Ampliseq RNA-seq in testicular cancer cells. Immunoblotting assays were used to detect HOXA10-regulated signaling. Results: HOXA10 is a nuclear protein in benign spermatocytes. Reduced nuclear expression and increased cytoplasmic expression of HOXA10 are associated with testicular cancers. These changes are consistent in both seminoma and non-seminoma. Enhanced HOXA10 expression in testicular cancer cell models inhibits cell proliferation and delays cell cycle progression through G2/M phases. These functions of HOXA10 mainly affect the TP53, cKit, STAT3, AKT, and ERK signaling pathways. Conclusions: Loss of nuclear functions of HOXA10 enhances proliferation of testicular cancer cells, suggesting that downregulation of HOXA10 transcription activity may promote the development of testicular cancers.

10.
Sci Rep ; 8(1): 10334, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985410

RESUMO

Membrane type 1 metalloproteinase (MT1-MMP) is an important regulator of cancer invasion, growth and angiogenesis, thus making it an attractive target for cancer imaging and therapy. A non-substrate peptide (MT1-AF7p) that bonded to the "MT-Loop" region of MT1-MMP was identified by using a phage-displayed peptide library and was used to image the MT1-MMP expression in vivo through optical imaging. However, the substrate in the screening did not have a 3D structure, thus resulting in a loose bonding of MT1-AF7p. To simulate the real conformation of the "MT-Loop" and improve the performance of MT1-AF7p, molecular simulations were performed, because this strategy provides multiple methods for predicting the conformation and interaction of proteinase in 3D. In view of the binding site of the receptor-ligand interactions, histidine 4 was selected for mutation to achieve an increased affinity effect. The optimized peptides were further identified and conformed by atomic force microscopy, isothermal titration calorimetry, cell fluorescence imaging in vitro, and near-infrared fluorescence tumor optical imaging in vivo. The results revealed that the optimized peptide with a mutation of histidine 4 to arginine has the highest affinity and specificity, and exhibited an increased fluorescence intensity in the tumor site in optical imaging.


Assuntos
Metaloproteinase 14 da Matriz/metabolismo , Peptídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Domínio Catalítico/genética , Linhagem Celular Tumoral , Humanos , Metaloproteinase 14 da Matriz/química , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Neoplasias/diagnóstico por imagem , Imagem Óptica , Peptídeos/síntese química , Peptídeos/química , Peptidomiméticos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Distribuição Tecidual , Transplante Heterólogo
11.
Cell ; 174(3): 758-769.e9, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30033370

RESUMO

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.


Assuntos
Variação Estrutural do Genoma/genética , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA2/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Variações do Número de Cópias de DNA , Exoma , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Sequências de Repetição em Tandem/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento Completo do Genoma/métodos
12.
Cell Death Dis ; 9(2): 137, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374168

RESUMO

Triple-negative breast cancer (TNBC) shows a higher malignant and poorer clinical outcome compared with other breast cancer subtypes. Albeit that chemotherapy is the first choice for TNBC treatment, rapid emergence of chemoresistance and variability of chemotherapeutic responses in TNBC patients call for novel therapeutic strategies. Here, we reported evidences highlighting that combination of BH3 mimetics and mTOR inhibitors could be a promising therapeutic strategy to improve TNBC treatment. Our results showed that combination of the BH3 mimetic ABT263 and typical mTOR inhibitors, BEZ235 or AZD8055, leads to efficient apoptosis in vitro. Tumor regression was significantly improved by combination therapy compared with either drug alone in the xenograft model. Further mechanistic investigations revealed that mTOR inhibitors induced the suppression of MCL-1; concomitantly, the expression level of PUMA was significantly upregulated in a FOXO3a-dependent manner. The specific changes of MCL-1 and PUMA facilitated the release of the apoptotic regulators, such as BIM, BAX, and BAK, to induce the activation of mitochondrial apoptotic pathway, thereby sensitizing the ABT263 activity in TNBC. Therefore, our findings provided evidences that mTOR inhibitors can enhance antitumor efficacy of BH3 mimetics via downregulating MCL-1 and upregulating PUMA in TNBC; it could be a promising therapeutic strategy to treat TNBC.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Regulação para Baixo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima , Compostos de Anilina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box O3/metabolismo , Humanos , Imidazóis/farmacologia , Camundongos Nus , Modelos Biológicos , Morfolinas/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima/efeitos dos fármacos
13.
Reprod Sci ; 25(1): 44-50, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28372536

RESUMO

A relaxed fundus (FUN) and a contracted lower uterine segment (LUS) of human myometrium are required for maintaining pregnancy. How this regional myometrium function is regulated remains unclear. We have previously reported that the homeobox protein A13 (HoxA13) is highly expressed in the LUS and can enhance the expression of contraction-associated proteins (CAPs). Here, we show that in contrast to HoxA13, HoxA10 and HoxA11 genes are expressed at significantly higher levels in myometrium tissues and primary myocytes from the FUN. When introduced exogenously into a human myometrial cell line, HoxA10 and HoxA11 suppress the messenger RNA (mRNA) levels of several CAP genes including interleukin-1 beta (IL-1ß), IL-6, connexin 43 (Cx43), and cyclooxygenase 2 (Cox2). Consistently, enhanced HoxA10 and HoxA11 expressions strongly inhibited IL-1ß and Cx43 protein levels. We further confirmed that higher expression of HoxA10 and HoxA11 genes in primary myocytes from the FUN compared to that from the LUS was associated with lower expression of IL-1ß, IL-6, Cox2, and Cx43 genes. We conclude that the expression patterns of HoxA10, HoxA11, and HoxA13 and their actions in regulating CAP genes in FUN and LUS create regionalized myometrium phenotypes in women that may be important to control regionalized myometrium contractility for maintaining pregnancy.


Assuntos
Proteínas de Homeodomínio/metabolismo , Miométrio/metabolismo , Contração Uterina/metabolismo , Adulto , Linhagem Celular , Conexina 43/genética , Conexina 43/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feminino , Proteínas de Homeodomínio/genética , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fenótipo , Contração Uterina/genética
14.
Apoptosis ; 22(11): 1321-1335, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28936716

RESUMO

Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O2·-), singlet oxygen (1O2) and hydrogen peroxide (H2O2). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules. Cancer cell death types induced by ROS include apoptotic, autophagic, ferroptotic and necrotic cell death. Since abnormal metabolism in cancer cells, they have higher ROS content compared to normal cells. The higher endogenous ROS levels in cancer cells endow them more susceptible to the ROS-induction treatment. Indeed, some anticancer drugs currently used in clinic, such as molecular targeted drugs and chemotherapeutic agents, effectively kill cancer cells by inducing ROS generation. In addition, photodynamic therapy (PDT) is mainly based on induction of ROS burst to kill cancer cells. The mechanism of cell death induced by radiotherapy using ionizing radiation also refers to ROS production. Moreover, ROS play an important role in tumor immune therapy. Altogether, combining above traditional treatments with ROS-induced agents will be considered as a promising strategy in cancer therapy. In this review, we focus on our current understanding of the anticancer effects of ROS.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Espécies Reativas de Oxigênio/agonistas , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Necrose/induzido quimicamente , Necrose/genética , Necrose/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Angew Chem Int Ed Engl ; 56(31): 9013-9017, 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28603944

RESUMO

A facile and electrostatically driven approach has been developed to prepare bicontinuous polymer nanocomposites that is based on the polyoxometalate (POM) macroion induced phase transition of PS-b-P2VP from an initial lamellar phase to a stable bicontinuous phase. The multi-charged POMs can electrostatically cross-link P2VP blocks and give rise to bicontinuous phases in which the POM hybrid conductive domains occupy a large volume fraction of more than 50 %. Furthermore, the POMs can give rise to high proton conductivity and serve as nanoenhancers, endowing the bicontinuous nanocomposites with a conductivity of 0.1 mS cm-1 and a Young's modulus of 7.4 GPa at room temperature; these values are greater than those of pristine PS-b-P2VP by two orders of magnitude and a factor of 1.8, respectively. This approach can provide a new concept based on electrostatic control to design functional bicontinuous polymer materials.

16.
Acc Chem Res ; 50(6): 1391-1399, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28508633

RESUMO

The combination of rational design of building components and suitable utilization of driving force affords spontaneous molecular assemblies with well-defined nanostructure and morphology over multiple length scales. The serious challenges in constructing assemblies with structural advantages for the realization of functions programmed into the building components usually lie ahead since the process that occurs does not always follow the expected roadmap in the absence of external intervention. Thus, prefabricated intermediates that help in governing the target self-assemblies are developed into a type of unique building blocks. Metal oxide cluster polyanions are considered as a type of molecular nanoclusters with size scale and structural morphology similar to those of many known inorganic particles and clusters but possess distinctive characteristics. Following the understanding of these clusters in self-assembly and the rationalization of their most efficient design strategy and approach, the obtained fundamental principles can also be applied in common nanoparticle- and cluster-based systems. On the other hand, the deliberate synergy offered by organic countercations that support the self-assembly of these clusters greatly expands the opportunity for the functionalization of complex building units via control of multiple interactions. The ionic combination of the inorganic clusters with hydrophilicity and the cationic organic component with hydrophobicity leads to discrete properties of the complexes. Significantly, the core-shell structure with rigid-flexible features and amphiphilicity will pave the way for hierarchical self-assemblies of the obtained complexes, while the intrinsic characteristics of the metal oxide clusters can be modulated through external physicochemical stimuli. Within this context, over the past decade we have extensively explored the ionic combination of inorganic polyanionic clusters with cationic organic amphiphiles and devoted our efforts to establishing the general rules and structure-property relationships of the formed complexes for constructing self-assemblies at the interface, in solution, and in solid matrixes. Specific interest has been focused on the functional synergy deriving from the incompatible components in highly organized self-assemblies. In this Account, we describe the recent progress on the ionic complexation of polyoxometalate clusters with cationic amphiphiles and the construction of diverse self-assembled nanostructures. First, the fundamental structural characteristics and molecular geometries of the prepared complexes are analyzed. The construction principle and diversity of the self-assembly based on the complexes and the smart stimuli response are then discussed, subject to the adjustment of various non-covalent interactions occurring in the assemblies. Subsequently, we enumerate the functional applications of the ionic complexes assembling into organic, inorganic, and even biological matrixes. The inspiration from the construction of ionic complexation and self-assembly in this Account provides vivid profiles for the design of hybrid materials involving nanoclusters and/or nanoparticles with rich potentials in addition to polyoxometalate chemistry.

17.
Cancer Res ; 76(22): 6701-6711, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27659047

RESUMO

Castration-resistant prostate cancer (CRPC) is characterized by a shift in androgen receptor (AR) signaling from androgen-dependent to androgen (ligand)-independent. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens has been reported in androgen-dependent prostate cancer, its roles in regulating AR signaling transformation and CRPC progression remain unknown. In this study, we show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis, and CRPC progression. UGT2B17 expression and activity were higher in androgen-independent compared to androgen-dependent cell lines. UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Gene microarray analysis indicated that UGT2B17 suppressed androgen-dependent AR transcriptional activity and enhanced of ligand-independent transcriptional activity at genes associated with cell mitosis. These UGT2B17 actions were mainly mediated by activation of the c-Src kinase. In CRPC tumors, UGT2B17 expression was associated positively with c-Src activation. These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling to activate cell mitosis in cancer cells. Cancer Res; 76(22); 6701-11. ©2016 AACR.


Assuntos
Glucuronosiltransferase/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Animais , Progressão da Doença , Humanos , Ligantes , Masculino , Camundongos , Camundongos Nus , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise Serial de Tecidos , Transfecção
18.
Endocrinology ; 157(5): 2129-39, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26982635

RESUMO

Bipedalism in humans requires regionalization of myometrial function with a contracted lower uterine segment and a relaxed fundus during pregnancy to prevent fetal pressure on the cervix and reversal of this phenotype during labor. The HoxA13 gene is highly expressed in the lower uterine segment before term labor and regulates the regionalization of myometrium contractility. However, how HoxA13 regulates signal pathways to exert its functions remains unclear. Using a gene microarray technique, we profiled HoxA13 transcriptome in myometrial cells containing immune response genes (eg, IL-1ß, IL-6, and IL-8) and contraction-associated proteins (CAPs) such as cyclooxygenase-2 (Cox-2) and connexin-43. IL-1ß is responsible for mediating HoxA13 actions in up-regulating IL-6, IL-8, Cox-2, and connexin-43 expression. Blocking IL-1ß with its inhibitor abolishes these HoxA13 actions. HoxA13-induced IL-1ß stimulates the recruitment of activated THP-1 monocytes to myometrial cells, which in turn amplify the secretion of IL-1ß, IL-6, and IL-8 through a mutual feed-forward loop between these cell types. As a result, Cox-2 expression is dramatically enhanced. These findings lead us to conclude that HoxA13 increases myometrial cell contractility by enhancing the secretion of IL-1ß, resulting in an up-regulation of CAP and other proinflammatory cytokine expression. HoxA13-induced IL-1ß in myometrial cells also prompts leukocyte recruitment and further amplifies CAP expression.


Assuntos
Conexina 43/metabolismo , Ciclo-Oxigenase 2/metabolismo , Proteínas de Homeodomínio/metabolismo , Interleucina-1beta/metabolismo , Miócitos de Músculo Liso/metabolismo , Miométrio/metabolismo , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Conexina 43/genética , Ciclo-Oxigenase 2/genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Interferência de RNA , Transcriptoma , Regulação para Cima
19.
Reprod Sci ; 23(2): 264-71, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26342051

RESUMO

BACKGROUND: The androgen receptor (AR) plays essential roles in female reproductive physiology. In vitro studies have shown that AR exerts 2 distinct but related functions in myometrial cells. The AR is required for myometrial cell cycling ligand independently, thereby controls myometrial cell proliferation. The AR also exerts antiapoptotic functions through myeloid cell leukemia 1 (MCL1) in both ligand-dependent and ligand-independent manners. However, these AR functions have not yet been confirmed in vivo. This study provides in vivo evidence that AR expression is associated with myometrial cell proliferation and apoptosis. METHODS: Myometrial tissue was collected on day 6 of pregnancy from mice bearing an intact AR (AR+/+) or mice with AR heterozygous (AR-/+) or homozygous (AR-/-) functional knockout. Human uterine leiomyoma and paired myometrial tissue biopsies (n = 14 patients) were collected during hysterectomy. Immunohistochemistry was used to assess the protein expression of AR, MCL1, and Ki-67 index, as well as the functional associations of AR with MCL1 and Ki-67 index. RESULTS: In AR-/- mice, MCL1 protein levels were reduced ∼50% in both circular and longitudinal myometrial cells when compared with that in AR+/+ and AR-/+ mice. By contrast, Ki-67 index remained unchanged. The AR protein expression and Ki-67 index in leiomyoma were ∼2- to 3-fold higher than that in normal myometrium. Although MCL1 expression was not coordinately increased in leiomyoma, strong positive correlations between AR and MCL1 expression were observed in leiomyoma but not in normal myometrium tissue. CONCLUSION: These results suggest that AR is an important regulator of myometrial growth in vivo during pregnancy and in leiomyoma.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Miométrio/metabolismo , Receptores Androgênicos/metabolismo , Animais , Feminino , Humanos , Leiomioma/genética , Leiomioma/metabolismo , Leiomioma/patologia , Camundongos , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Receptores Androgênicos/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
20.
J Clin Endocrinol Metab ; 100(12): E1512-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26485220

RESUMO

CONTEXT: Bipedalism separates humans from most other animal species, but results in significant physiologic challenges, particularly with respect to the maintenance of pregnancy and induction of parturition. A contracted lower uterine segment (LUS) and a relaxed uterine fundal myometrium (FUN) during pregnancy are required to prevent pressure on the cervix from the fetal head due to gravity. With the onset of labor, this regionalization of myometrial function must be reversed, allowing descent of the fetus, dilation of the cervix, and expulsion of the fetus through the birth canal. However, the molecular mechanisms remain unclear. OBJECTIVE AND DESIGN: This study sought to identify phenotypic regionalization of LUS and FUN during pregnancy, RNA sequencing was performed to analyze the human myometrial transcriptome. Real-time PCR and immunoblotting were applied to validate sequencing results. Cell contraction/adhesion assays and gene microarrays were used to study the cellular functions of the identified genes. RESULTS: Homeobox A13 (HoxA13), prostacyclin synthase (PTGIS), and periostin (POSTN) genes are more highly expressed in LUS than FUN of nonlaboring, but not laboring, myometrial cells at term. HoxA13 up-regulates transcription of PTGIS and POSTN genes. Elevated HoxA13 expression enhances myometrial cell contractility and cell-cell adhesion. Gene microarray studies show that HoxA13-regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy. CONCLUSION: The LUS expresses higher levels of HoxA13, PTGIS, and POSTN, and is more contractile than the FUN at term prior to labor. This pregnancy-maintaining regionalization of myometrial function may be mediated by HoxA13.


Assuntos
Proteínas de Homeodomínio/genética , Miométrio/anatomia & histologia , Adulto , Adesão Celular/genética , Moléculas de Adesão Celular/genética , Sistema Enzimático do Citocromo P-450/genética , Feminino , Junções Comunicantes/genética , Idade Gestacional , Humanos , Contração Muscular/genética , Fenótipo , Gravidez , RNA/genética , Contração Uterina/genética
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