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1.
Comput Intell Neurosci ; 2021: 8387382, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34475949

RESUMO

Image style transfer can realize the mutual transfer between different styles of images and is an essential application for big data systems. The use of neural network-based image data mining technology can effectively mine the useful information in the image and improve the utilization rate of information. However, when using the deep learning method to transform the image style, the content information is often lost. To address this problem, this paper introduces L1 loss on the basis of the VGG-19 network to reduce the difference between image style and content and adds perceptual loss to calculate the semantic information of the feature map to improve the model's perceptual ability. Experiments show that the proposal in this paper improves the ability of style transfer, while maintaining image content information. The stylization of the improved model can better meet people's requirements for stylization, and the evaluation indexes of structural similarity, cosine similarity, and mutual information value have increased by 0.323%, 0.094%, and 3.591%, respectively.


Assuntos
Sistemas de Dados , Redes Neurais de Computação , Humanos , Semântica
2.
J Biol Chem ; 297(2): 100933, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34216622

RESUMO

Precursor messenger RNA (pre-mRNA) splicing is critical for cell growth and development, and errors in RNA splicing frequently cause cellular dysfunction, abnormal gene expression, and a variety of human diseases. However, there is currently a lack of reliable systems to noninvasively monitor the mRNA splicing efficiency in cells and animals. Here, we described the design of a genetically engineered ratiometric dual luciferase reporter to continuously quantify the changes in mRNA splice variants in vivo. This reporter system is encoded within a single polypeptide but on separate exons, thus generating two distinct luciferase signals derived from spliced and unspliced mRNAs. With this reporter, the two kinds of luciferase in the same individual can minimize the influence of indirect factors on splicing, and the ratio of these two luciferase intensities represents the dynamic splicing efficiency of pre-mRNA. Our study offers a convenient and robust tool for the screening and identification of small molecules or trans-acting factors that affect the efficiency of specific splicing reactions.

3.
Sci Rep ; 11(1): 13226, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168171

RESUMO

Lignosulfonate (LS) is a by-product obtained during sulfite pulping process and is commonly used as a growth enhancer in plant growth. However, the underlying growth promoting mechanism of LS on shoot growth remains largely unknown. Hence, this study was undertaken to determine the potential application of eco-friendly ion-chelated LS complex [sodium LS (NaLS) and calcium LS (CaLS)] to enhance recalcitrant indica rice MR 219 shoot growth and to elucidate its underlying growth promoting mechanisms. In this study, the shoot apex of MR 219 rice was grown on Murashige and Skoog medium supplemented with different ion chelated LS complex (NaLS and CaLS) at 100, 200, 300 and 400 mg/L The NaLS was shown to be a better shoot growth enhancer as compared to CaLS, with optimum concentration of 300 mg/L. Subsequent comparative proteomic analysis revealed an increase of photosynthesis-related proteins [photosystem II (PSII) CP43 reaction center protein, photosystem I (PSI) iron-sulfur center, PSII CP47 reaction center protein, PSII protein D1], ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), carbohydrate metabolism-related proteins (glyceraldehyde-3-phosphate dehydrogenase 3, fructose-bisphosphate aldolase) and stress regulator proteins (peptide methionine sulfoxide reductase A4, delta-1-pyrroline-5-carboxylate synthase 1) abundance in NaLS-treated rice as compared to the control (MSO). Consistent with proteins detected, a significant increase in biochemical analyses involved in photosynthetic activities, carbohydrate metabolism and protein biosynthesis such as total chlorophyll, rubisco activity, total sugar and total protein contents were observed in NaLS-treated rice. This implies that NaLS plays a role in empowering photosynthesis activities that led to plant growth enhancement. In addition, the increased in abundance of stress regulator proteins were consistent with low levels of peroxidase activity, malondialdehyde content and phenylalanine ammonia lyase activity observed in NaLS-treated rice. These results suggest that NaLS plays a role in modulating cellular homeostasis to provide a conducive cellular environment for plant growth. Taken together, NaLS improved shoot growth of recalcitrant MR 219 rice by upregulation of photosynthetic activities and reduction of ROS accumulation leading to better plant growth.

4.
Bioorg Med Chem ; 40: 116185, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965842

RESUMO

Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.

6.
Bioconjug Chem ; 32(1): 161-171, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33337872

RESUMO

Early identification and treatment of breast cancer is very important for breast conserving therapy and to improve the prognosis and survival rates of patients. Multifunctional nanotheranostic agents are of particular importance in the field of precise nanomedicine, since they can augment the visualization and treatment of cancer. We developed a novel Bi2S3 nanoparticle coated with a hyaluronic acid (HA)-modified tantalum oxide (TaOx) nanoshell (Bi2S3@TaOx-HA). The as-prepared core/shell nanoparticles exhibited a high Bi2S3 nanoparticle loading efficiency of (67 wt %). The TaOx nanoshell exhibited excellent biocompatibility and computed tomography imaging capacity, and the Bi2S3 nanoparticles exhibited an excellent photothermal transducing performance and computed tomography (CT) and photoacoustic imaging capacity. As a result of these merits, the Bi2S3@TaOx core-shell nanoparticles can act as a theranostic agent for CT/photoacoustically monitored enhanced photothermal therapy. These findings will evoke new interest in future cancer therapeutic strategies based on biocompatible functional nanomaterials.


Assuntos
Bismuto/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Óxidos/química , Medicina de Precisão , Sulfetos/química , Tantálio/química , Animais , Materiais Biocompatíveis , Linhagem Celular Tumoral , Feminino , Humanos , Técnicas Fotoacústicas , Fototerapia/métodos , Tomografia Computadorizada por Raios X
7.
Anal Chem ; 92(23): 15565-15572, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33201673

RESUMO

Pyroptotic cell death is a phenomenon that runs through all life activities and plays an important role in physiological and pathological processes of the body's metabolism. It is of big biological significance to understand the phenomenon and nature of cell pyroptosis. In the process of cell pyroptosis, the pore-forming effector gasdermin D (GSDMD) is cleaved to form oligomers, which are inserted into the cell membrane, causing rapid cell death. However, the effective cell death induced by GSDMD complicates our ability to understand the behavior of pyroptosis. In this work, we performed molecular mutagenesis to develop a genetically encoded pyroptotic reporter, where a secreted Gaussia luciferase (Gluc) was strategically placed in the p30-p20 tolerated junction of GSDMD to support natural pyrophosphorylation and promote live imaging of cell pyroptosis. In addition, we demonstrated that this fused Gluc-GSDMD reporter executed inflammatory body-dependent pyroptosis in response to extracellular stimuli, and that the lysed p30-GSDMD can be secreted out of the cell and can be detected in the culture medium and animal blood. Therefore, our study provides a valuable tool that not only noninvasive and real-time monitoring of cell pyroptosis, but also affords a high-throughput functional screening of pyroptosis-targeted compounds in cultured cells and animal models.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/sangue , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Ligação a Fosfato/sangue , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Animais , Linhagem Celular Tumoral , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Luciferases/genética , Imagem Molecular , Mutagênese , Proteínas de Ligação a Fosfato/genética , Fosforilação
8.
Mol Imaging Biol ; 22(3): 476-485, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31228075

RESUMO

PURPOSE: Hepatocellular carcinoma (HCC) is a common cancer worldwide, and complete surgical resection of diseased tissue is a reliable strategy to cure cancer. Fluorescence image-guided surgery is a promising tool for surgeons to identify and remove malignant lesions. While non-targeted fluorescent dyes have been used for HCC diagnosis and resection, insufficient specificity and false positive uptake from inflammatory tissue result in a high recurrence rate or excessive excision of healthy liver tissue. To circumvent these problems, we focused on developing novel tumor-specific targeting probe to selectively illuminate cancer region during surgery. Given overexpression of histone deacetylases (HDACs) in HCC and many other cancers, HDAC-targeted imaging has been emerged as a promising tool for tumor detection. PROCEDURES: Recently, high expression of HDACs, in particular HDAC6, has been observed in tumor samples of HCC patient, and a few HDAC inhibitors, including FDA-approved suberoylanilide hydroxamic acid (SAHA), display potent antitumor effect on HCC. Correspondingly, in this study, we utilized a small molecule SAHA with the high HDAC-binding affinity as the HCC-specific targeting ligand to develop HDAC-targeted fluorescence probe for HCC detection and fluorescence image-guided resection. RESULTS: In in vitro imaging, SAHA was labelled with fluorescein isothiocyanate (FITC) to evaluate targeting property, and the imaging results demonstrated that FITC-SAHA was specific uptake by HCC Bel-7402 cells. In in vivo imaging, near infrared fluorescence dye IRDye800CW-labelled SAHA (NIR probe IRDye800CW-SAHA) showed rapid tumor accumulation with high tumor-to-background contrast on both the subcutaneous and orthotopic HCC mouse tumor models. Furthermore, the orthotopic HCC was successfully resected by the IRDye800CW-SAHA fluorescence image-guided surgery. Moreover, IRDye800CW-SAHA showed no toxicity toward healthy tissues. CONCLUSIONS: Our results indicate that IRDye800CW-SAHA is a clinical translatable probe for HCC detection and resection.


Assuntos
Benzenossulfonatos/química , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Desacetilase 6 de Histona/metabolismo , Indóis/química , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Vorinostat/metabolismo , Animais , Apoptose/fisiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Corantes Fluorescentes/química , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Langmuir ; 35(46): 14833-14839, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31600446

RESUMO

Photodynamic therapy (PDT) and fluorescence imaging offer the possibility of precise and personalized treatment of cancer, but low singlet oxygen production of a commercial photosensitizer and the quenching effect of fluorescent dyes limit the further application of PDT treatment and fluorescence imaging. In addition, the single nanoplatform that simultaneously achieved singlet oxygen and fluorescence enhancement is rare. In this paper, a novel simultaneously enhanced singlet oxygen and fluorescence production nanoplatform of AuNR@mSiO2-Ce6-Cy5.5 has been successfully designed and synthesized by surface plasmon resonance coupling. The as-synthesized nanoplatform achieved a 1.8-fold enhancement of the singlet oxygen production of Ce6 and a 5.0-fold enhancement of the fluorescence production of Cy5.5 by surface plasmon resonance coupling. The as-synthesized nanoplatform simultaneously enhances the photodynamic therapy and fluorescence imaging of cancer, which will have great potential in biomedical applications.

10.
Anal Chem ; 91(13): 7973-7979, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31179690

RESUMO

Cell detection is of great significance for biomedical research. Surface enhanced Raman scattering (SERS) has been widely applied to the detection of cells. However, there is still a lack of a general, low-cost, rapid, and sensitive SERS method for cell detection. Herein, a dynamic liquid SERS platform, which combines label-free SERS technique with soft tubular microfluidics for cell detection, is proposed. Compared with common static solid and static liquid measurement, the dynamic liquid SERS platform can present dynamical mixing, precise control of the mixing time, and continuous spectra collection. By characterizing the model molecules, the proposed dynamic liquid SERS platform has successfully demonstrated good stability and repeatability with 1.90% and 4.98% relative standard deviation (RSD), respectively. Three cell lines including one normal breast cell line (MCF-10A) and two breast cancer cell lines (MCF-7 and MDA-MB-231) were investigated in this platform. 270 cell spectra were selected as the training set for the classification of the models based on the K-Nearest Neighbor (K-NN) algorithm. In three independent experiments, three types of cells were identified by a test set containing 180 cell spectra with sensitivities above 83.3% and specificities above 91.6%. The accuracy was 94.1 ± 1.14% among three independent cell identifications. The dynamic liquid SERS platform has shown higher signal intensity, better repeatability, less pretreatment, and obtainment of more spectra with less time consumption. It will be a powerful detection tool in the area of cell research, clinical diagnosis, and food safety.


Assuntos
Neoplasias da Mama/química , Mama/química , Técnicas Analíticas Microfluídicas/instrumentação , Análise Espectral Raman/instrumentação , Algoritmos , Mama/citologia , Mama/patologia , Neoplasias da Mama/diagnóstico , Linhagem Celular , Linhagem Celular Tumoral , Desenho de Equipamento , Feminino , Humanos
11.
Acupunct Med ; 37(1): 47-54, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30843418

RESUMO

BACKGROUND: Acupuncture has been recommended as an alternative therapy for migraine. Emerging evidence suggests that the 5-HT7 receptor (5-HT7R) plays a significant facilitatory role in descending modulation in migraine pathophysiology, and that activation of 5-HT7R in the descending pathway is involved in migraine central sensitisation. OBJECTIVE: To investigate the ability of electroacupuncture (EA) to ameliorate central sensitisation via modulation of 5-HT7R in the descending pain pathways using a rat model of migraine induced by repetitive dural electrical stimulation (DES). DESIGN: 64 male Sprague-Dawley rats were randomly divided into four groups: Normal group; DES group (receiving dural electrical stimulation only); DES+GB20 group (DES model group treated with EA at GB20); and DES+Sham group (DES model group treated with EA at a non-traditional (sham) acupuncture point). The presence of cutaneous allodynia was determined by measuring facial and hind-paw withdrawal latencies to electronic von-Frey. The expression of 5-HT7R in the descending pathways (periaqueductal grey, raphe magnus nucleus, and trigeminal nucleus caudalis) was assessed using immunofluorescence and Western blotting. RESULTS: Facial and hind-paw withdrawal thresholds were significantly increased in the DES+GB20 group compared with the untreated DES group. The expression of 5-HT7R was significantly decreased in the DES+GB20 group compared with the DES group (one-way analysis of variance (ANOVA), P<0.05). No significant differences in behaviour or expression were found between the rats in the DES+Sham group and the untreated DES group (one-way ANOVA, P>0.05). CONCLUSION: EA at GB20 may ameliorate central sensitisation in migraine by inhibiting the activation of 5-HT7 receptors in the descending pain pathway in a rat model of migraine.


Assuntos
Eletroacupuntura , Transtornos de Enxaqueca/terapia , Receptores de Serotonina/metabolismo , Pontos de Acupuntura , Animais , Humanos , Masculino , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Núcleo Magno da Rafe/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética
12.
Mol Pharm ; 15(10): 4702-4709, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30180594

RESUMO

The ability to detect breast cancer early in its progression is essential to improve patient survival and quality of life. The noninvasive and dynamic imaging and functional assessments of estrogen receptor-alpha (ERα), which is commonly expressed at high levels in breast cancer, are important for effective diagnosis and treatment. Hence, the development of a specific ERα-targeted probe is a major research goal. To that end, in the present study, we created a novel near-infrared (NIR) fluorescent probe, IRDye800CW-E2, for targeted ERα imaging in breast-tumor-bearing mice. IRDye800CW-E2 consisted of a cyanine dye IRDye800CW as the NIR fluorophore and the E2 analogue ethinyl estradiol amine as an ERα targeting ligand. The ethinyl estradiol amine was initially labeled with fluorescein isothiocyanate (FITC) to evaluate the binding specificity to human breast-tumor cells in vitro. Flow chamber and in vitro confocal laser endomicroscopy imaging experiments demonstrated that FITC-E2 was specifically taken up by MCF-7 cells. Furthermore, NIR fluorescence imaging revealed the ability of IRDye800CW-E2 to rapidly target tumors and to achieve good contrast between tumors and background signal 4-48 h postinjection. The fluorescent signal of IRDye800CW-E2 in tumors was successfully blocked by the coinjection of the endogenous ERα-ligand 17ß-estradiol (E2) and the probe. Ex vivo fluorescent imaging further confirmed high uptake of the probe by tumors. These results indicated that IRDye800CW-E2 has great potential as an ERα-targeted imaging probe for early breast-tumor detection and has potential for clinical translation.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Receptor alfa de Estrogênio/metabolismo , Animais , Feminino , Corantes Fluorescentes/química , Humanos , Células MCF-7 , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Med Chem ; 61(18): 8155-8173, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053783

RESUMO

In this work, we developed a small library of novel OBHS-RES hybrid compounds with dual inhibition activities targeting both the estrogen receptor α (ERα) and NF-κB by incorporating resveratrol (RES), a known inhibitor of NF-κB, into a privileged indirect antagonism structural motif (OBHS, oxabicycloheptene sulfonate) of estrogen receptor (ER). The OBHS-RES conjugates could bind well to ER and showed remarkable ERα antagonistic activity, and they also exhibited excellent NO inhibition in macrophage RAW 264.7 cells. Compared with 4-hydroxytamoxifen, some of them showed better antiproliferative efficacy in MCF-7 cell lines with IC50 up to 3.7 µM. In vivo experiments in a MCF-7 breast cancer model in Balb/c nude mice indicated that compound 26a was more potent than tamoxifen. Exploration of the compliancy of the structure against ER specificity utilizing these types of isomeric three-dimensional ligands indicated that one enantiomer had much better biological activity than the other.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/antagonistas & inibidores , Inflamação/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células Cultivadas , Antagonistas do Receptor de Estrogênio/química , Antagonistas do Receptor de Estrogênio/farmacologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Ligantes , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Resveratrol/química , Transdução de Sinais , Relação Estrutura-Atividade , Sulfonas/química
14.
Chem Commun (Camb) ; 54(31): 3887-3890, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29610818

RESUMO

Estrogen receptor ß (ERß) has recently been identified as a pharmaceutical target in hormone replacement therapy for breast cancers. However, the biological function of ERß in disease progression remains unclear. A highly ERß-selective fluorescent probe (FPNM) was discovered exhibiting nanomolar affinity for ERß with an ERß/ERα selectivity as high as 80, which allowed specific labeling of intracellular ERß. Moreover, distinct ERß dynamics in various cellular bio-settings such as prostate cancer (DU-145) or triple-negative breast cancer (MDA-MB-231) cells were directly observed for the first time viaFPNM staining.


Assuntos
Receptor beta de Estrogênio/metabolismo , Corantes Fluorescentes/química , Naftalenos/química , Nitrilas/química , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Corantes Fluorescentes/síntese química , Humanos , Simulação de Acoplamento Molecular , Imagem Molecular , Naftalenos/síntese química , Nitrilas/síntese química
15.
Eur J Pharmacol ; 828: 67-79, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29563065

RESUMO

Gastric cancer is the second leading cause of cancer-related deaths in the world. SAHA, one of the emerging HDAC inhibitor widely used for cancer treatment, has unignorable side effects, as it is a multi-target HDAC inhibitor. However, it is believed that specifically targeting against fewer HDACs might decrease this cytoxin effect. In our previous work, we have designed and synthesized a series of new compounds, which specifically targets to HDAC6, and TC24 was one of them. In this study, we further demonstrated that TC24 selectively inhibited the activity of HDAC6 other than class I HDACs. TC24 exhibited strong anti-proliferation and anti-motility ability toward gastric cancer cells but had no obvious cytoxin effect on gastric normal GES-1 cells. The anti-cancer effect of TC24 was triggered by G2/M cell cycle arrest, apoptosis and the loss of mitochondrial membrane potential. Bcl-2, cdc 2 and cyclin B1 were decreased while Bax and cleaved-PARP were increased. Also, TC24 suppressed tumor angiogenesis via the reduction of HIF-1α and VEGF. All the above data supported that TC24 was a selective inhibitor of HDAC6 and strongly suppressed the proliferation of gastric cancer cells via inducing cell cycle arrest and cell apoptosis and tumor angiogenesis inhibition, suggesting TC24 is potentially a novel therapeutic agent for gastric cancer and the research on chemical structure of TC24 would promote the understanding of the drug design of related compounds.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Fosforilação/efeitos dos fármacos , Conformação Proteica , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Front Immunol ; 8: 837, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28785263

RESUMO

Cellular metabolism has been known for its role in bioenergetics. In recent years, much light has been shed on the reprogrammable cellular metabolism underlying many vital cellular processes, such as cell activation, proliferation, and differentiation. Metabolic reprogramming in immune and endothelial cells (ECs) is being studied extensively. These cell compartments are implicated in inflammation and pathogenesis of many diseases but their similarities in metabolic reprogramming have not been analyzed in detail. One of the most notable metabolic reprogramming is the Warburg-like effect, famously described as one of the hallmarks of cancer cells. Immune cells and ECs can display this phenotype that is characterized by a metabolic switch favoring glycolysis over oxidative phosphorylation (OXPHOS) in aerobic conditions. Though energy-inefficient, aerobic glycolysis confers many benefits to the respiring cells ranging from higher rate of adenosine triphosphate production to maintaining redox homeostasis. Chemical and biological regulators either promote or perturb this effect. In this review, nitric oxide, hypoxia-inducible factor, and adenosine monophosphate-activated protein kinase have been discussed for their common involvement in metabolic reprogramming of both systems. From in vitro and animal studies, various discrepancies exist regarding the effects of those regulators on metabolic switch. However, it is generally accepted that glycolysis favors inflammatory reactions while OXPHOS favors anti-inflammatory processes. The reasons for such observation are currently subject of intense studies and not completely understood. Finally, metabolic reprogramming in immune cells and ECs does not limit to the physiological state in health but can also be observed in pathological states, such as atherosclerosis and cancer. These new insights provide us with a better understanding of the similarities in metabolic reprogramming across a number of cell types, which could pave the way for future research and possible metabolic-based therapeutics.

17.
Bioconjug Chem ; 28(7): 1925-1930, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28595014

RESUMO

Development of a chelator-free and biocompatible platform for the facile construction of gadolinium3+ (Gd3+)-loaded nanoparticle based probes for in vivo magentic resonance imaging (MRI) is still challenging. Herein, biocompatible Gd3+-loading melanin dots (Gd-M-dots) have been easily prepared and have exhibited good loading efficiency for Gd3+, high stability, and higher T1 relaxivity compared to the commercial Gd-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) agent. Furthermore, Gd-M-dots showed unique photoacoustic (PA) properties, and a high PA imaging signal could be observed in vivo 1 h after injection. Compared to the traditional Gd3+-loaded nanoparticles for single-modal MRI, Gd-M-dots can also be radiolabeled with 64Cu2+ for positron emission tomography. Overall, these attractive properties of Gd-M-dots render them a promising imaging agent for various biomedical applications.


Assuntos
Radioisótopos de Cobre/análise , Diagnóstico por Imagem/métodos , Melaninas/química , Sondas Moleculares/química , Nanopartículas/química , Materiais Biocompatíveis/química , Quelantes , Gadolínio/análise , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos
18.
Bioorg Med Chem ; 25(13): 3531-3539, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28506582

RESUMO

A strategy by integrating biological imaging into early stages of the drug discovery process can improve our understanding of drug activity during preclinical and clinical study. In this article, we designed and synthesized coumarin-based nonsteroidal type fluorescence ligands for drug-target binding imaging. Among these synthesized compounds, 3e, 3f and 3h showed potent ER binding affinity and 3e (IC50=0.012µM) exhibited excellent ERα antagonistic activity, its antiproliferative potency in breast cancer MCF-7 cells is equipotent to the approved drug tamoxifen. The fluorescence of compounds 3e and 3f depended on the solvent properties and showed significant changes when mixed with ERα or ERß in vitro. Furthermore, target molecule 3e could cross the cell membrane, localize and image drug-target interaction in real time without cell washing. Thus, the coumarin-based platform represents a promising new ER-targeted delivery vehicle with potential imaging and therapeutic properties.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Cumarínicos/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Corantes Fluorescentes/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Células MCF-7 , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Tamoxifeno/química , Tamoxifeno/farmacologia
19.
ChemMedChem ; 12(3): 235-249, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-27976818

RESUMO

The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERß. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERß-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERß. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERß antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.


Assuntos
Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/antagonistas & inibidores , Compostos Organosselênicos/química , Animais , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Humanos , Ligantes , Células MCF-7 , Conformação Molecular , Simulação de Acoplamento Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/toxicidade , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Células Vero
20.
Bioorg Med Chem ; 24(13): 3062-3074, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27240467

RESUMO

Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(-). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS-HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(-) breast cancer cells (MDA-MB-231). Thus, the FcOBHS-HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Sítios de Ligação , Neoplasias da Mama/fisiopatologia , Compostos Bicíclicos com Pontes/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade
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