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1.
J Clin Neurosci ; 90: 217-224, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275553

RESUMO

Postoperative delirium (POD) is a significant clinical problem in neurosurgical patients after intracranial surgery. Identification of high-risk patients may optimize perioperative management, but an adequate risk model for use at early phase after operation has not been developed. In the secondary analysis of a prospective cohort study, 800 adult patients admitted to the ICU after elective intracranial surgeries were included. The POD was diagnosed as Confusion Assessment Method for the ICU positive on postoperative day 1 to 3. Multivariate logistic regression analysis was used to develop early prediction model (E-PREPOD-NS) and the final model was validated with 200 bootstrap samples. The incidence of POD in this cohort was19.6%. We identified nine variables independently associated with POD in the final model: advanced age (OR 3.336, CI 1.765-6.305, 1 point), low education level (OR 2.528, 1.446-4.419, 1), smoking history (OR 2.582, 1.611-4.140, 1), diabetes (OR 2.541, 1.201-5.377, 1), supra-tentorial lesions (OR 3.424, 2.021-5.802, 1), anesthesia duration > 360 min (OR 1.686, 1.062-2.674, 0.5), GCS < 9 at ICU admission (OR 6.059, 3.789-9.690, 1.5), metabolic acidosis (OR 13.903, 6.248-30.938, 2.5), and neurosurgical drainage tube (OR 1.924, 1.132-3.269, 0.5). The area under the receiver operator curve (AUROC) of the risk score for prediction of POD was 0.865 (95% CI 0.835-0.895). The AUROC was 0.851 after internal validation (95% CI 0.791-0.912). The model showed good calibration. The E-PREPOD-NS model can predict POD in patients admitted to the ICU after elective intracranial surgery with good accuracy. External validation is needed in the future.


Assuntos
Craniotomia/efeitos adversos , Delírio do Despertar/diagnóstico , Fatores de Risco , Adulto , Idoso , Estudos de Coortes , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Delírio do Despertar/epidemiologia , Feminino , Humanos , Incidência , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
2.
Nat Prod Bioprospect ; 11(4): 459-464, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33978930

RESUMO

Three new diterpene alkaloids, tangutidines A-C (1-3), and four known alkaloids (4-7) were isolated from the whole plant of Aconitum tanguticum, from which amphoteric diterpene alkaloids (1-3) were obtained for the first time. The structures of 1-3 were elucidated by detailed interpretation of spectroscopic data, including MS and NMR data. All of them were evaluated for their cytotoxic activities.

3.
Nucleic Acids Res ; 49(2): 902-915, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33348378

RESUMO

Repair of covalent DNA-protein crosslinks (DPCs) by the metalloprotease SPRTN prevents genome instability, premature aging and carcinogenesis. SPRTN is specifically activated by DNA structures containing single- and double-stranded features, but degrades the protein components of DPCs promiscuously and independent of amino acid sequence. This lack of specificity is useful to target diverse protein adducts, however, it requires tight control in return, in order to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover the components and principles of a ubiquitin switch, which negatively regulates SPRTN. We demonstrate that monoubiquitylation is induced in an E3 ligase-independent manner and, in contrast to previous assumptions, does not control chromatin access of the enzyme. Data obtained in cells and in vitro reveal that monoubiquitylation induces inactivation of the enzyme by triggering autocatalytic cleavage in trans while also priming SPRTN for proteasomal degradation in cis. Finally, we show that the deubiquitylating enzyme USP7 antagonizes this negative control of SPRTN in the presence of DPCs.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Processamento de Proteína Pós-Traducional , Ubiquitina/fisiologia , Ubiquitinação , Catálise , Linhagem Celular , Cromatina/metabolismo , Adutos de DNA/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/química , Enzimas Desubiquitinantes/metabolismo , Técnicas de Inativação de Genes , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/metabolismo , Especificidade por Substrato , Peptidase 7 Específica de Ubiquitina/fisiologia
4.
J Clin Neurosci ; 80: 267-273, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33099359

RESUMO

BACKGROUND: Chordoid gliomas (CGs) are rare neuroepithelial tumors, which commonly arise from the anterior part of the third ventricle. Most studies on CGs included only one or two cases. To better understand the disease, we report 14 patients with pathologically confirmed CGs. METHOD: The clinical characteristics, including radiological and histological examination, operative records, and prognoses were analyzed and reviewed. RESULT: The case series included six male and eight female patients with an average age of 44.4 years. The most common preoperative symptom was headache (64.3%) and visual deterioration (57.1%). Radiological results showed that the third ventricle (12/14) was the most common site of the brain involved, and the lesions presented with solid (n = 9, 64.3%) or cystic-solid (n = 5, 35.7%) appearance. All patients were misdiagnosed as non-CG tumors. The operation approach was mainly determined by tumor location, thus trans-callosal approach (9/14) and trans-laminar terminalis approach were commonly used. Gross total resection (GTR) was achieved in all cases and none of them received any adjuvant therapy postoperatively. The most frequent postoperative complications were diabetes insipidus, electrolyte disturbance, hypopituitarism, cognitive dysfunction, and obstructive hydrocephalus. During an average follow-up period of 40.1 months, 2 cases (14.3%) were died of refractory hypopituitarism and pulmonary embolism, respectively. The preoperative symptoms and postoperative complications were all significantly improved in other 12 patients, and MRI showed no tumor recurrence. CONCLUSION: According to our experience, we recommend GTR as the primary goal, which is associated with improved rates of tumor control and without increasing rates of postoperative complications.


Assuntos
Neoplasias do Plexo Corióideo/diagnóstico por imagem , Glioma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Terceiro Ventrículo/diagnóstico por imagem , Adulto , Idoso , Neoplasias do Plexo Corióideo/patologia , Neoplasias do Plexo Corióideo/cirurgia , Feminino , Seguimentos , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terceiro Ventrículo/patologia , Terceiro Ventrículo/cirurgia
5.
Nat Commun ; 11(1): 4910, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978405

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Mol Cell ; 80(1): 102-113.e6, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853547

RESUMO

Repair of covalent DNA-protein crosslinks (DPCs) by DNA-dependent proteases has emerged as an essential genome maintenance mechanism required for cellular viability and tumor suppression. However, how proteolysis is restricted to the crosslinked protein while leaving surrounding chromatin proteins unharmed has remained unknown. Using defined DPC model substrates, we show that the DPC protease SPRTN displays strict DNA structure-specific activity. Strikingly, SPRTN cleaves DPCs at or in direct proximity to disruptions within double-stranded DNA. In contrast, proteins crosslinked to intact double- or single-stranded DNA are not cleaved by SPRTN. NMR spectroscopy data suggest that specificity is not merely affinity-driven but achieved through a flexible bipartite strategy based on two DNA binding interfaces recognizing distinct structural features. This couples DNA context to activation of the enzyme, tightly confining SPRTN's action to biologically relevant scenarios.


Assuntos
Reagentes para Ligações Cruzadas/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/química , Linhagem Celular , Proteínas de Ligação a DNA/química , Humanos , Espectroscopia de Ressonância Magnética , Modelos Biológicos , Domínios Proteicos , Relação Estrutura-Atividade
7.
Nat Commun ; 11(1): 3661, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694504

RESUMO

The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus (SLD) and exhibit REM sleep-related activation. In SLD, orexin directly excites orexin receptor-positive neurons (occupying ~3/4 of total-population) and increases gap junction conductance among neurons. Their interaction spreads the orexin-elicited partial-excitation to activate SLD network globally. Besides, the activated SLD network exhibits increased probability of synchronized firings. This synchronized excitation promotes the correspondence between SLD and its downstream target to enhance SLD output. Using optogenetics and fiber-photometry, we consequently find that orexin-enhanced SLD output prolongs REM sleep episodes through consolidating brain state activation/muscle tone inhibition. After chemogenetic silencing of SLD orexin signaling, a ~17% reduction of REM sleep amounts and disruptions of REM sleep muscle atonia are observed. These findings reveal a stabilization role of orexin in REM sleep.


Assuntos
Tronco Encefálico/fisiologia , Orexinas/metabolismo , Privação do Sono/fisiopatologia , Sono REM/fisiologia , Potenciais de Ação/fisiologia , Animais , Comportamento Animal , Tronco Encefálico/citologia , Modelos Animais de Doenças , Eletrodos Implantados , Eletroencefalografia , Eletromiografia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Tono Muscular/fisiologia , Neurônios/metabolismo , Optogenética , Receptores de Orexina/metabolismo , Orexinas/genética , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Vigília/fisiologia
8.
Ther Adv Med Oncol ; 11: 1758835919875324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632466

RESUMO

Background: Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer in Asia and demonstrates poor survival rates following a therapeutic regimen. Methods: Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and treatment failure in cancers. Therefore, identification and characterization of CSCs may help to improve clinical outcomes for ESCC patients. Tumor sphere formation assay are performed to isolate cancer stem-like ESCC cells. QRT-PCR, tumor initiation, metastasis, CCRT treatment are used to evaluate ESCC cells' stemness properties in vitro and in vivo. Results: The authors' data demonstrates that cancer stem-like ESCC cells harbored stemness characteristics including self-renewal, differentiation, and transdifferentiation, and possess tumor initiation, metastasis, and treatment inefficiency properties. For the identification of useful biomarkers of cancer stem-like ESCC cells, the authors further identified that CLDN4 was upregulated in cancer stem-like ESCC cells when compared with bulk cancer cells. High-CLDN4 cells harbored stemness and cisplatin/concurrent chemoradiation therapy (CCRT) resistance properties and a high level of CLDN4 was correlated with poor prognosis and poor CCRT response in ESCC patients. Importantly, thiamine tetrahydrofurfuryl disulfide (TTFD) decreased CLDN4 and attenuated stemness in ESCC cells, and TTFD combined with CCRT improved CCRT response in vivo. Conclusions: CLDN4 was suggested as prognostic and a CCRT response indicator for ESCC patients. TTFD combined with CCRT has potential to improve ESCC patient's clinical outcomes in the future.

9.
Oncogene ; 37(34): 4662-4678, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29755127

RESUMO

Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients.


Assuntos
Neoplasias Pulmonares/genética , MicroRNAs/genética , Metástase Neoplásica/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/patologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/patologia
10.
Breast Cancer Res ; 19(1): 133, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258605

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20-30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. METHODS: The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student's t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. RESULTS: miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/ß-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease. CONCLUSIONS: miR-105/93-3p activates Wnt/ß-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.


Assuntos
Biomarcadores Tumorais , MicroRNA Circulante , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Antineoplásicos/farmacologia , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/sangue , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Transcriptoma , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Via de Sinalização Wnt
11.
Oncotarget ; 8(18): 29699-29710, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-27447863

RESUMO

Trastuzumab is regarded as the primary therapy for patients with HER2-enriched breast cancer, but the pathological complete response for advanced cases is less than 30%. The underlying mechanism of trastuzumab resistance remains unclear and there are currently no conclusive biomarkers for patient response to trastuzumab. Identifying predictive biomarkers for trastuzumab response may allow treatments to be individually tailored and optimized multi-target therapies may be developed. CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance. In this study, we examined samples from 369 patients to investigate the correlation between CTMP expression level and patient outcome. Elevated CTMP expression was correlated with adverse outcomes in HER2-enriched patients including overall and disease-free survival as well as trastuzumab resistance. Ectopic expression of varying levels of CTMP in SkBR3 cells dose-dependently attenuated trastuzumab-mediated growth inhibition through AKT activation. In addition, inhibition of AKT signaling by AKT inhibitor IV and Rapamycin reversed CTMP-mediated trastuzumab resistance. In clinical samples, the high expression of CTMP was showed in trastuzumab non-responders and positively correlated with AKT activity. Taken together, we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2-enriched breast cancer. High CTMP expression not only predicted poor prognosis, but may also predict resistance to trastuzumab in HER2-enriched patients. Therefore, CTMP expression may be considered as a prognostic biomarker in HER2-enriched breast cancer and high expression may indicate a utility for AKT-inhibition in these patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Membrana/genética , Receptor ErbB-2/metabolismo , Tioléster Hidrolases/genética , Trastuzumab/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Recidiva , Tioléster Hidrolases/metabolismo , Trastuzumab/uso terapêutico
12.
Oncotarget ; 7(26): 39680-39693, 2016 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-27203740

RESUMO

Concurrent chemoradiation therapy (CCRT) is the predominant treatment in esophageal cancer, however resistance to therapy and tumor recurrence are exceedingly common. Elevated ERBB2/Her2 may be at least partially responsible for both the high rates of recurrence and resistance to CCRT. This receptor tyrosine kinase is upregulated in 10-20% of esophageal squamous cell carcinoma (ESCC) tissues, and amplification of ERBB2 has been correlated with poor prognosis in esophageal cancer. Tissues from 131 ESCC patients, along with cell and animal models of the disease were used to probe the underlying mechanisms by which ERBB2 upregulation occurs and causes negative outcomes in ESCC. We found that overexpression of ERBB2 inhibited radiosensitivity in vitro. Furthermore, miR-193a-5p reduced ERBB2 expression by directly targeting the 3'UTR. Increased miR-193a-5p enhanced radiosensitivity and inhibited tumorigenesis in vitro and in vivo. Additionally, low miR-193a-5p expression correlated with poor prognosis in ESCC patients, and ESCC patients with good CCRT response exhibited higher miR-193a-5p expression. Our data suggest that patients with high miR-193a-5p will likely benefit from CCRT treatment alone, however a combination of CCRT with Herceptin may be beneficial for patients with low miR-193a-5p expression.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Quimiorradioterapia/métodos , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Carcinogênese , Estudos de Casos e Controles , Linhagem Celular Tumoral , Regulação para Baixo , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/metabolismo , Fatores de Risco , Trastuzumab/metabolismo
13.
Sci Rep ; 5: 10686, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-26095534

RESUMO

Over the past decade, DNA has demonstrated remarkable potential in fabrication of molecular logic and arithmetic systems. In this work, a simple DNA-based system mimicking a full-subtractor that handles three inputs including one minuend and two subtrahends for eight input/output conditions is successfully designed. The whole system is established by one gate molecule and three input sequences, all made of single-stranded DNA sequences.


Assuntos
Computadores Moleculares , DNA de Cadeia Simples , Nanotecnologia/métodos
14.
Small ; 11(32): 3909-15, 2015 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25939740

RESUMO

Zinc sulfide nanosheet-based hybrid superlattices with tunable periodicities and rod-like or tubular morphologies are constructed by the spontaneous assembly of nanosheets as they grow in amine solution. The as-prepared architectures can be used as an enhanced electrode for photocurrent response and converted to other functional materials.

15.
Cell Cycle ; 14(3): 408-16, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25659037

RESUMO

WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.


Assuntos
Pontos de Checagem do Ciclo Celular , Ciclina D1/metabolismo , Fase G1 , Oxirredutases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Inativação Gênica , Humanos , Masculino , Camundongos Nus , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Oxidorredutase com Domínios WW
16.
Exp Biol Med (Maywood) ; 240(3): 403-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25662955

RESUMO

Pin1 is a peptidyl-prolyl isomerase which plays a critical role in many diseases including cancer and Alzheimer's disease. The essential role of Pin1 is to affect stability, localization or function of phosphoproteins by catalyzing structural changes. Among the collection of Pin1 substrates, many have been shown to be involved in regulating cell cycle progression. The cell cycle disorder caused by dysregulation of these substrates is believed to be a common phenomenon in cancer. A number of recent studies have revealed possible functions of several important Pin1-binding cell cycle regulators. Investigating the involvement of Pin1 in the cell cycle may assist in the development of future cancer therapeutics. In this review, we summarize current knowledge regarding the network of Pin1 substrates and Pin1 regulators in cell cycle progression. In G1/S progression, cyclin D1, RB, p53, p27, and cyclin E are all well-known cell cycle regulators that are modulated by Pin1. During G2/M transition, our lab has shown that Aurora A suppresses Pin1 activity through phosphorylation at Ser16 and cooperates with hBora to modulate G2/M transition. We conclude that Pin1 may be thought of as a molecular timer which modulates cell cycle progression networks.


Assuntos
Ciclo Celular/fisiologia , Peptidilprolil Isomerase/fisiologia , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Fosfoproteínas/fisiologia , Transdução de Sinais/fisiologia
17.
J Biol Chem ; 286(51): 43816-43829, 2011 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-21998300

RESUMO

Most studies on heat shock protein 90 (Hsp90) have focused on the involvement of Hsp90 in the interphase, whereas the role of this protein in the nucleus during mitosis remains largely unclear. In this study, we found that the level of the acetylated form of Hsp90 decreased dramatically during mitosis, which indicates more chaperone activity during mitosis. We thus probed proteins that interacted with Hsp90 by liquid chromatography/mass spectrometry (LC/MS) and found that nucleolin was one of those interacting proteins during mitosis. The nucleolin level decreased upon geldanamycin treatment, and Hsp90 maintained the cyclin-dependent kinase 1 (CDK1) activity to phosphorylate nucleolin at Thr-641/707. Mutation of Thr-641/707 resulted in the destabilization of nucleolin in mitosis. We globally screened the level of mitotic mRNAs and found that 229 mRNAs decreased during mitosis in the presence of geldanamycin. Furthermore, a bioinformatics tool and an RNA immunoprecipitation assay found that 16 mRNAs, including cadherin and Bcl-xl, were stabilized through the recruitment of nucleolin to the 3'-untranslated regions (3'-UTRs) of those genes. Overall, strong correlations exist between the up-regulation of Hsp90, nucleolin, and the mRNAs related to tumorigenesis of the lung. Our findings thus indicate that nucleolin stabilized by Hsp90 contributes to the lung tumorigenesis by increasing the level of many tumor-related mRNAs during mitosis.


Assuntos
Proteína Quinase CDC2/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Antibióticos Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Núcleo Celular/metabolismo , Cromatografia Líquida/métodos , Células HeLa , Humanos , Imunoprecipitação , Lactamas Macrocíclicas/farmacologia , Espectrometria de Massas/métodos , Mitose , Fosfoproteínas/química , Conformação Proteica , RNA/metabolismo , Interferência de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Espectrometria de Massas em Tandem/métodos
18.
J Med Chem ; 53(16): 6164-79, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20662543

RESUMO

Certain indeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferation, DNA binding affinity, and topoisomerases (topo I and topo II) inhibitory activities. The preliminary results are the following: (1) substituent of the aminoalkoxyimino side chain at C11 is important for antiproliferative activities in which the terminal amine preferred to be a tertiary or the cyclic five-membered pyrrolidino ring; (2) among the indeno[1,2-c]quinoline derivatives evaluated, (E)-6-hydroxy-9-methoxy-11H-indeno[1,2-c]quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime (8c) was found to be one of the most cytotoxic agents with a GI50 value of 0.84, 0.89, and 0.79 microM against SAS, A549, and BT483, respectively, which is more active than camptothecin; (3) substituent at C6 is crucial for the selective cytotoxicity in which the OH group is the most preferred while hydrogen or piperazine exhibited cytotoxicity on both cancer cells and Detroit-551; (4) a positive correlation of antiproliferative activity, DNA binding affinity, and topo I and topo II inhibitory activities has been observed for indeno[1,2-c]quinoline derivatives; (5) compound 8c induced DNA fragmentation may through caspase-3 activation, phosphorylation of the histone protein H2AX at Ser139 (gamma-H2AX), and PARP cleavage; (6) compound 8c demonstrated significant tumor regression in the human breast xenograft model; (7) indeno[1,2-c]quinoline derivatives are a new class of molecules that have the potential to be developed as dual topo I and topo II inhibitory agents.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Hidroxiquinolinas/síntese química , Indenos/síntese química , Oximas/síntese química , Quinolinas/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA/química , Fragmentação do DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Indenos/farmacocinética , Indenos/farmacologia , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Oximas/química , Oximas/farmacologia , Relação Quantitativa Estrutura-Atividade , Quinolinas/farmacocinética , Quinolinas/farmacologia , Estereoisomerismo , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Transplante Heterólogo
19.
Eur J Med Chem ; 44(6): 2552-62, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19246129

RESUMO

A series of 2-styrylchromone analogs were synthesized and examined for their antiproliferative effects on a panel of carcinoma cells. Among the tested agents, only 4m exhibited a moderate activity with an IC(50) value of 28.9 microM against PC-3 cells which indicates the selectivity of PC-3 cells in response to 2-styrylchromones. In addition, 4q demonstrated the most antiproliferative effect with an IC(50) value of 4.9 microM against HeLa cells. Flow cytometric analysis and DAPI staining revealed that HeLa cells exposed to 4q as low as 5 microM induced cell death through sub-G1 arrest and DNA fragmentation. Furthermore, CoMFA analysis of tested 2-styrylchromones resulted in a q(2) of 0.459 to generate a 3D-QSAR model on BT483 cell line. Together, these results suggest a potential structural optimization and pharmacological study of 2-styrylchromones.


Assuntos
Cromonas/síntese química , Cromonas/farmacologia , Desenho de Fármacos , Neoplasias da Próstata/tratamento farmacológico , Estirenos/síntese química , Estirenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromonas/classificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Imunofluorescência , Células HeLa , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/patologia , Relação Quantitativa Estrutura-Atividade , Estereoisomerismo , Estirenos/classificação , Fatores de Tempo
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