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Purpose: Various laboratory sources have recently achieved progress in implementing deep learning models on biomedical optical imaging of soft biological tissues. The highly scattered nature of tissues at specific optical wavelengths results in poor spatial resolution. This opens up opportunities for diffuse optical imaging to improve the spatial resolution of obtained optical properties suffering from artifacts. This study aims to investigate a dual-encoder deep learning model for successfully detecting tumors in different phantoms w.r.t tumor size on diffuse optical imaging. Approach: Our proposed dual-encoder network extends U-net by adding a parallel branch of signal data to get information directly from the base source. This allows the trained network to localize the inclusions without degrading or merging with the background. The signals from the forward model and the images from the inverse problem are combined in a single decoder, filling the gap between existing direct processing and post-processing. Results: Absorption and reduced scattering coefficients are well reconstructed in both simulation and phantom test datasets. The proposed and implemented dual-encoder networks characterize better optical-property images than the signal-encoder and image-encoder networks, and the contrast-and-size detail resolution of the dual-encoder networks outperforms the other two approaches. From the measures of performance evaluation, the structural similarity and peak signal-to-noise ratio of the reconstructed images obtained by the dual-encoder networks remain the highest values. Conclusions: In this study, we synthesized the advantages of boundary data direct reconstruction, namely the extracted signals and iterative methods, from the obtained images into a unified network architecture.
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Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial-mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators-twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPß. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPß toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPß and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.
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Neoplasias Colorrectales , Interleucina-6 , Humanos , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal/genética , Interleucina-6/metabolismo , Transducción de Señal , Genes srcRESUMEN
Hepatocellular carcinoma is the third most common cause of cancer-related death according to the International Agency for Research on Cancer. Dihydroartemisinin (DHA), an antimalarial drug, has been reported to exhibit anticancer activity but with a short half-life. We synthesized a series of bile acid-dihydroartemisinin hybrids to improve its stability and anticancer activity and demonstrated that an ursodeoxycholic-DHA (UDC-DHA) hybrid was 10-fold more potent than DHA against HepG2 hepatocellular carcinoma cells. The objectives of this study were to evaluate the anticancer activity and investigate the molecular mechanisms of UDCMe-Z-DHA, a hybrid of ursodeoxycholic acid methyl ester and DHA via a triazole linkage. We found that UDCMe-Z-DHA was even more potent than UDC-DHA in HepG2 cells with IC50 of 1 µM. Time course experiments and stability in medium determined by cell viability assay as well as HPLC-MS/MS analysis revealed that UDCMe-Z-DHA was more stable than DHA, which in part accounted for the increased anticancer activity. Mechanistic studies revealed that UDCMe-Z-DHA caused G0/G1 arrest and induced reactive oxygen species (ROS), mitochondrial membrane potential loss and autophagy, which may in turn lead to apoptosis. Compared to DHA, UDCMe-Z-DHA displayed much lower cytotoxicity toward normal cells. Thus, UDCMe-Z-DHA may be a potential drug candidate for hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Ácido Ursodesoxicólico , Neoplasias Hepáticas/patología , Espectrometría de Masas en Tándem , Apoptosis , Arteméter , Línea Celular TumoralRESUMEN
Significance: The machine learning (ML) approach plays a critical role in assessing biomedical imaging processes especially optical imaging (OI) including segmentation, classification, and reconstruction, intending to achieve higher accuracy efficiently. Aim: This research aims to develop an end-to-end deep learning framework for diffuse optical imaging (DOI) with multiple datasets to detect breast cancer and reconstruct its optical properties in the early stages. Approach: The proposed Periodic-net is a nondestructive deep learning (DL) algorithm for the reconstruction and evaluation of inhomogeneities in an inverse model with high accuracy, while boundary measurements are calculated by solving a forward problem with sources/detectors arranged uniformly around a circular domain in various combinations, including 16 × 15 , 20 × 19 , and 36 × 35 boundary measurement setups. Results: The results of image reconstruction on numerical and phantom datasets demonstrate that the proposed network provides higher-quality images with a greater amount of small details, superior immunity to noise, and sharper edges with a reduction in image artifacts than other state-of-the-art competitors. Conclusions: The network is highly effective at the simultaneous reconstruction of optical properties, i.e., absorption and reduced scattering coefficients, by optimizing the imaging time without degrading inclusions localization and image quality.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Algoritmos , Imagen Óptica , Fantasmas de Imagen , Aprendizaje Automático , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
The medicinal properties of natural/edible plant products and their use are popular in traditional practice owing to their nutritional contents with little to no side effects. Lepista nuda (L. nuda), an edible mushroom (Clitocybe nuda, commonly known as blewit), has attracted researchers to evaluate its contents and the mechanism of its activities. In the current study, we focused on evaluating the antiangiogenic effects of L. nuda water extract on zebrafish development and in vitro human umbilical vein endothelial cell (HUVEC) tube formation. Bioactive components such as ergothioneine, eritadenine, and adenosine were identified and quantified by HPLC analysis. The L. nuda extract showed antiangiogenic properties and inhibited intersegmental vessel (ISV), caudal vein plexus (CVP), hyaloid vessel (HV), and subintestinal vessel (SIV) development in Tg (fli1: EGFP) zebrafish embryos. The expression of angiogenesis-related genes (vegfaa, kdrl, vegfba, flt1, kdr) was affected following L. nuda extract treatment. L. nuda extract attenuated in vitro HUVEC tube formation, migration, and invasion. Furthermore, inhibition of MAPK/p38 signaling and depletion of proangiogenic genes, including growth factors (fgf, ang2, and vegfa); primary and accessory receptors (tie2, vegfr2, and eng); MMPs (mmp1 and mmp2); and cytokines (il-1α, il-1ß, il-6, and tnf-α) was observed in HUVECs following L. nuda treatment. An in vivo zebrafish xenograft assay showed that L. nuda extract inhibited HuCCT1 cell-induced SIV sprouting in HuCCT1-injected embryos. Collectively, the results suggest that L. nuda could be a potential inhibitor of angiogenesis limiting cancer progression.
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Agaricales , Pez Cebra , Animales , Humanos , Pez Cebra/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Neovascularización Fisiológica , Inhibidores de la Angiogénesis , Proliferación Celular , Movimiento CelularRESUMEN
Imaging tasks today are being increasingly shifted toward deep learning-based solutions. Biomedical imaging problems are no exception toward this tendency. It is appealing to consider deep learning as an alternative to such a complex imaging task. Although research of deep learning-based solutions continues to thrive, challenges still remain that limits the availability of these solutions in clinical practice. Diffuse optical tomography is a particularly challenging field since the problem is both ill-posed and ill-conditioned. To get a reconstructed image, various regularization-based models and procedures have been developed in the last three decades. In this study, a sensor-to-image based neural network for diffuse optical imaging has been developed as an alternative to the existing Tikhonov regularization (TR) method. It also provides a different structure compared to previous neural network approaches. We focus on realizing a complete image reconstruction function approximation (from sensor to image) by combining multiple deep learning architectures known in imaging fields that gives more capability to learn than the fully connected neural networks (FCNN) and/or convolutional neural networks (CNN) architectures. We use the idea of transformation from sensor- to image-domain similarly with AUTOMAP, and use the concept of an encoder, which is to learn a compressed representation of the inputs. Further, a U-net with skip connections to extract features and obtain the contrast image, is proposed and implemented. We designed a branching-like structure of the network that fully supports the ring-scanning measurement system, which means it can deal with various types of experimental data. The output images are obtained by multiplying the contrast images with the background coefficients. Our network is capable of producing attainable performance in both simulation and experiment cases, and is proven to be reliable to reconstruct non-synthesized data. Its apparent superior performance was compared with the results of the TR method and FCNN models. The proposed and implemented model is feasible to localize the inclusions with various conditions. The strategy created in this paper can be a promising alternative solution for clinical breast tumor imaging applications.
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Procesamiento de Imagen Asistido por Computador , Tomografía Óptica , Procesamiento de Imagen Asistido por Computador/métodos , Redes Neurales de la ComputaciónRESUMEN
In this article we describe four previous Tai-Chi models based on the I-Ching (Book of Changes) and their limitations. The I-Ching, the most important ancient source of information on traditional Chinese culture and cosmology, provides the metaphysical foundation for this culture, especially Confucian ethics and Taoist morality. To overcome the limitations of the four previous Tai-Chi models, we transform I-Ching cultural system into a psychological theory by applying the cultural system approach. Specifically, we propose the Jun-zi () Self-Cultivation Model (JSM), which argues that an individual (, xiao-ren) can become an ideal person, or jun-zi, through the process of self-cultivation, leading to good fortune and the avoidance of disasters (, qu-ji bi-xiong). The state of jun-zi is that of the well-functioning self, characterized by achieving one's full potential and an authentic, durable sense of wellbeing. In addition, we compare egoism (xiao-ren) and jun-zi as modes of psychological functioning. The JSM can be used to as a framework to explain social behavior, improve mental health, and develop culturally sensitive psychotherapies in Confucian culture. Finally, an examination of possible theoretical directions, clinical applications, and future research is provided.
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We demonstrate a working prototype of an optical breast imaging system involving parallel-plate architecture and a dual-direction scanning scheme designed in combination with a mammography machine; this system was validated in a pilot study to demonstrate its application in imaging healthy and malignant breasts in a clinical environment. The components and modules of the self-developed imaging system are demonstrated and explained, including its measuring architecture, scanning mechanism, and system calibration, and the reconstruction algorithm is presented. Additionally, the evaluation of feature indices that succinctly demonstrate the corresponding transmission measurements may provide insight into the existence of malignant tissue. Moreover, five cases are presented including one subject without disease (a control measure), one benign case, one suspected case, one invasive ductal carcinoma, and one positive case without follow-up treatment. A region-of-interest analysis demonstrated significant differences in absorption between healthy and malignant breasts, revealing the average contrast between the abnormalities and background tissue to exceed 1.4. Except for ringing artifacts, the average scattering property of the structure densities was 0.65-0.85 mm-1.
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Breast cancer remains the most frequently diagnosed cancer and is the leading cause of neoplastic disease burden for females worldwide, suggesting that effective therapeutic and/or diagnostic strategies are still urgently needed. In this study, a type of indocyanine green (ICG) and camptothecin (CPT) co-loaded perfluorocarbon double-layer nanocomposite named ICPNC was developed for detection and photochemotherapy of breast cancer. The ICPNCs were designed to be surface modifiable for on-demand cell targeting and can serve as contrast agents for fluorescence diffuse optical tomography (FDOT). Upon near infrared (NIR) irradiation, the ICPNCs can generate a significantly increased production of singlet oxygen compared to free ICG, and offer a comparable cytotoxicity with reduced chemo-drug dosage. Based on the results of animal study, we further demonstrated that the ICPNCs ([ICG]/[CPT] = 40-/7.5-µM) in association with 1-min NIR irradiation (808 nm, 6 W/cm2) can provide an exceptional anticancer effect to the MDA-MB-231 tumor-bearing mice whereby the tumor size was significantly reduced by 80% with neither organ damage nor systemic toxicity after a 21-day treatment. Given a number of aforementioned merits, we anticipate that the developed ICPNC is a versatile theranostic nanoagent which is highly promising to be used in the clinic.
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There is increasing evidence that statins, which are widely used in lowering serum cholesterol and the incidence of cardiovascular diseases, also exhibits anti-tumour properties. The underlying mechanisms by which statins-induced cancer cell death, however, remain incompletely understood. In this study, we explored the anti-tumour mechanisms of a lipophilic statin, lovastatin, in MCF-7 breast cancer cells. Lovastatin inhibited cell proliferation and induced cell apoptosis. Lovastatin caused p21 elevation while reduced cyclin D1 and survivin levels. Lovastatin also increased p53 phosphorylation, acetylation and its reporter activities. Results from chromatin immunoprecipitation analysis showed that p53 binding to the survivin promoter region was increased, while Sp1 binding to the region was decreased, in MCF-7 cells after lovastatin exposure. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation. Lovastatin's enhancing effects on p53 activation, p21 elevation and survivin reduction were significantly reduced in the presence of p38MAPK signalling inhibitor. Furthermore, LKB1-AMPK signalling blockade abrogated lovastatin-induced p38MAPK and p53 phosphorylation. Together these results suggest that lovastatin may activate LKB1-AMPK-p38MAPK-p53-survivin cascade to cause MCF-7 cell death. The present study establishes, at least in part, the signalling cascade by which lovastatin induces breast cancer cell death.
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Proteínas Quinasas Activadas por AMP/metabolismo , Lovastatina/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Survivin/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Humanos , Células MCF-7 , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Background and purpose: Angiogenesis and lymphangiogenesis are major routes for metastatic spread of tumor cells. It thus represent the rational targets for therapeutic intervention of cancer. Recently, we showed that a novel aliphatic hydroxamate-based compound, WMJ-S-001, exhibits anti-angiogenic, anti-inflammatory and anti-tumor properties. However, whether WMJ-S-001 is capable of suppressing lymphangiogenesis remains unclear. We are thus interested in exploring WMJ-S-001's anti-lymphangiogenic mechanisms in lymphatic endothelial cell (LECs). Experimental approach: WMJ-S-001's effects on LEC proliferation, migration and invasion, as well as signaling molecules activation were analyzed by immunoblotting, flow-cytometry, MTT, BrdU, migration and invasion assays. We performed tube formation assay to examine WMJ-S-001's ex vivo anti-lymphangiogenic effects. Key results: WMJ-S-001 inhibited serum-induced cell proliferation, migration, invasion in murine LECs (SV-LECs). WMJ-S-001 reduced the mRNA and protein levels of survivin. Survivin siRNA significantly suppressed serum-induced SV-LEC invasion. WMJ-S-001 induced p53 phosphorylation and increased its reporter activities. In addition, WMJ-S-001 increased p53 binding to the promoter region of survivin, while Sp1 binding to the region was decreased. WMJ-S-001 induced p38 mitogen-activated protein kinase (p38MAPK) activation. p38MPAK signaling blockade significantly inhibited p53 phosphorylation and restored survivin reduction in WMJ-S-001-stimulated SV-LCEs. Furthermore, WMJ-S-001 induced survivin reduction and inhibited cell proliferation, invasion and tube formation of primary human LECs. Conclusions and Implications: These observations indicate that WMJ-S-001 may suppress lymphatic endothelial remodeling and reduce lymphangiogenesis through p38MAPK-p53-survivin signaling. It also suggests that WMJ-S-001 is a potential lead compound in developing novel agents for the treatment of lymphangiogenesis-associated diseases and cancer.
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Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. However, the precise mechanisms underlying hydroxamate derivative-induced cancer cell death remain incomplete understood. In this study, we explored the anti-tumor mechanisms of a novel aliphatic hydroxamate-based compound, WMJ-J-09, in FaDu head and neck squamous cell carcinoma (HNSCC) cells. WMJ-J-09 induced G2/M cell cycle arrest and apoptosis in FaDu cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, transcription factor p63 phosphorylation, as well as modulation of p21 and survivin. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J-09's enhancing effects in p63 phosphorylation, p21 elevation and survivin reduction. Moreover, WMJ-J-09 caused an increase in α-tubulin acetylation and interfered with microtubule assembly. Furthermore, WMJ-J-09 suppressed the growth of subcutaneous FaDu xenografts in vivo. Taken together, WMJ-J-09-induced FaDu cell death may involve LKB1-AMPK-p38MAPK-p63-survivin signaling cascade. HDACs inhibition and disruption of microtubule assembly may also contribute to WMJ-J-09's actions in FaDu cells. This study suggests that WMJ-J-09 may be a potential lead compound and warrant the clinical development in the treatment of HNSCC.
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BACKGROUND AND PURPOSE: Histone deacetylase (HDAC) inhibitors have been demonstrate to have broad-spectrum anti-tumour properties and have attracted lots of attention in the field of drug discovery. However, the underlying anti-tumour mechanisms of HDAC inhibitors remain incompletely understood. In this study, we aimed to characterize the underlying mechanisms through which the novel hydroxamate-based HDAC inhibitor, WMJ-8-B, induces the death of MDA-MB-231 breast cancer cells. EXPERIMENTAL APPROACH: Effects of WMJ-8-B on cell viability, cell cycle distribution, apoptosis and signalling molecules were analysed by the MTT assay, flowcytometric analysis, immunoblotting, reporter assay, chromatin immunoprecipitation analysis and use of siRNAs. A xenograft model was used to determine anti-tumour effects of WMJ-8-B in vivo. KEY RESULTS: WMJ-8-B induced survivin reduction, G2/M cell cycle arrest and apoptosis in MDA-MB-231 cells. STAT3 phosphorylation, transactivity and its binding to the survivin promoter region were reduced in WMJ-8-B-treated cells. WMJ-8-B activated the protein phosphatase SHP-1 and when SHP-1 signalling was blocked, the effects of WMJ-8-B on STAT3 phosphorylation and survivin levels were abolished. However, WMJ-8-B increased the transcription factor Sp1 binding to the p21 promoter region and enhanced p21 levels. Moreover, WMJ-8-B induced α-tubulin acetylation and disrupted microtubule assembly. Inhibition of HDACs was shown to contribute to WMJ-8-B's actions. Furthermore, WMJ-8-B suppressed the growth of MDA-MB-231 xenografts in mammary fat pads in vivo. CONCLUSIONS AND IMPLICATIONS: The SHP-1-STAT3-survivin and Sp1-p21 cascades are involved in WMJ-8-B-induced MDA-MB-231 breast cancer cell death. These results also indicate the potential of WMJ-8-B as a lead compound for treatment of breast cancer and warrant its clinical development.
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Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Compuestos Policíclicos/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ácidos Hidroxámicos/química , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones Desnudos , Compuestos Policíclicos/química , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , SurvivinRESUMEN
This corrects the article DOI: 10.1038/srep15796.
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Cancer stem cells (CSCs), or cancer cells with stem cell-like properties, generally exhibit drug resistance and have highly potent cancer inducing capabilities. Genome-wide expression data collected at public repositories over the last few years provide excellent material for studies that can lead to insights concerning the molecular and functional characteristics of CSCs. Here, we conducted functional genomic studies of CSC based on fourteen PCA-screened high quality public CSC whole genome gene expression datasets and, as control, four high quality non-stem-like cancer cell and non-cancerous stem cell datasets from the Gene Expression Omnibus database. A total of 6,002 molecular signatures were taken from the Molecular Signatures Database and used to characterize the datasets, which, under two-way hierarchical clustering, formed three genotypes. Type 1, consisting of mainly glia CSCs, had significantly enhanced proliferation, and significantly suppressed epithelial-mesenchymal transition (EMT), related functions. Type 2, mainly breast CSCs, had significantly enhanced EMT, but not proliferation, related functions. Type 3, composed of ovarian, prostate, and colon CSCs, had significantly suppressed proliferation related functions and mixed expressions on EMT related functions.
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Transición Epitelial-Mesenquimal/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proliferación Celular , Análisis por Conglomerados , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Genotipo , Humanos , Análisis de Componente PrincipalRESUMEN
Elevated serum interleukin-6 (IL-6) levels correlates with tumor grade and poor prognosis in cancer patients. IL-6 has been shown to promote tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. We recently showed that IL-6 also induced VEGF-C expression in lymphatic endothelial cells (LECs). However, the signaling mechanisms involved in IL-6-induces VEGF-C induction in LECs remain incompletely understood. In this study, we explored the causal role of focal adhesion kinase (FAK) in inducing VEGF-C expression in IL-6-stimulated murine LECs (SV-LECs). FAK signaling blockade by NSC 667249 (a FAK inhibitor) attenuated IL-6-induced VEGF-C expression and VEGF-C promoter-luciferase activities. IL-6's enhancing effects of increasing FAK, ERK1/2, p38MAPK, C/EBPß, p65 and STAT3 phosphorylation as well as C/EBPß-, κB- and STAT3-luciferase activities were reduced in the presence of NSC 667249. STAT3 knockdown by STAT3 siRNA abrogated IL-6's actions in elevating VEGF-C mRNA and protein levels. Moreover, Src-FAK signaling blockade reduced IL-6's enhancing effects of increasing STAT3 binding to the VEGF-C promoter region, cell migration and endothelial tube formation of SV-LECs. Together these results suggest that IL-6 increases VEGF-C induction and lymphangiogenesis may involve, at least in part, Src-FAK-STAT3 cascade in LECs.
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Células Endoteliales/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Interleucina-6/farmacología , Factor de Transcripción STAT3/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Familia-src Quinasas/metabolismo , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Células Endoteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica/efectos de los fármacos , Immunoblotting , Linfangiogénesis/efectos de los fármacos , Ratones , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor C de Crecimiento Endotelial Vascular/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Statins are used widely to lower serum cholesterol and the incidence of cardiovascular diseases. Growing evidence shows that statins also exhibit beneficial effects against cancers. In this study, we investigated the molecular mechanisms involved in lovastatin-induced cell death in Fadu hypopharyngeal carcinoma cells. Lovastatin caused cell cycle arrest and apoptosis in FaDu cells. Lovastatin increased p21(cip/Waf1) level while the survivin level was decreased in the presence of lovastatin. Survivin siRNA reduced cell viability and induced cell apoptosis in FaDu cells. Lovastatin induced phosphorylation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK) and transcription factor p63. Lovastatin also caused p63 acetylation and increased p63 binding to survivin promoter region in FaDu cells. AMPK-p38MAPK signaling blockade abrogated lovastatin-induced p63 phosphorylation. Lovastatin's enhancing effect on p63 acetylation was reduced in HDAC3- or HDAC4- transfected cells. Moreover, transfection of cells with AMPK dominant negative mutant (AMPK-DN), HDAC3, HDAC4 or p63 siRNA significantly reduced lovastatin's effects on p21(cip/Waf1) and survivin. Furthermore, lovastatin inhibited subcutaneous FaDu xenografts growth in vivo. Taken together, lovastatin may activate AMPK-p38MAPK-p63-survivin cascade to cause FaDu cell death. This study establishes, at least in part, the signaling cascade by which lovastatin induces hypopharyngeal carcinoma cell death.
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Antineoplásicos/farmacología , Muerte Celular , Células Epiteliales/efectos de los fármacos , Lovastatina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Línea Celular Tumoral , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Transducción de Señal , Survivin , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Hydroxamate derivatives have attracted considerable attention due to their broad pharmacological properties and have been extensively investigated. We recently demonstrated that WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory and anti-angiogenic activities. In this study, we explored the underlying mechanisms by which WMJ-S-001 induces HCT116 colorectal cancer cell death. WMJ-S-001 inhibited cell proliferation and induced cell apoptosis in HCT116 cells. These actions were associated with AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) activation, p53 phosphorylation and acetylation, as well as the modulation of p21(cip/Waf1), cyclin D1, survivin and Bax. AMPK-p38MAPK signaling blockade reduced WMJ-S-001-induced p53 phosphorylation. Transfection with AMPK dominant negative mutant (DN) reduced WMJ-S-001's effects on p53 and Sp1 binding to the survivn promoter region. Transfection with HDAC3-Flag or HDAC4-Flag also abrogated WMJ-S-001's enhancing effect on p53 acetylation. WMJ-S-001's actions on p21(cip/Waf1), cyclin D1, survivin, Bax were reduced in p53-null HCT116 cells. Furthermore, WMJ-S-001 was shown to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. In summary, the death of HCT116 colorectal cancer cells exposed to WMJ-S-001 may involve AMPK-p38MAPK-p53-survivin cascade. These results support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Ácidos Hidroxámicos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Naftalenos/farmacología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Humanos , Sistema de Señalización de MAP Quinasas/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The Josephson effect is especially appealing to physicists because it reveals macroscopically the quantum order and phase. In excitonic bilayers the effect is even subtler due to the counterflow of supercurrent as well as the tunneling between layers (interlayer tunneling). Here we study, in a quantum Hall bilayer, the excitonic Josephson junction: a conjunct of two exciton condensates with a relative phase Ï0 applied. The system is mapped into a pseudospin ferromagnet then described numerically by the Landau-Lifshitz-Gilbert equation. In the presence of interlayer tunneling, we identify a family of fractional sine-Gordon solitons which resemble the static fractional Josephson vortices in the extended superconducting Josephson junctions. Each fractional soliton carries a topological charge Q that is not necessarily a half/full integer but can vary continuously. The calculated current-phase relation (CPR) shows that solitons with Q = Ï0/2π is the lowest energy state starting from zero Ï0 - until Ï0 > π - then the alternative group of solitons with Q = Ï0/2π - 1 takes place and switches the polarity of CPR.
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The lymphatic endothelium plays an important role in the maintenance of tissue fluid homeostasis. It also participates in the pathogenesis of several inflammatory diseases. However, little is known about the underlying mechanisms by which lymphatic endothelial cell responds to inflammatory stimuli. In this study, we explored the mechanisms by which lipopolysaccharide (LPS) induces cyclooxygenase (COX)-2 expression in murine lymphatic endothelial cells (SV-LECs). LPS caused increases in cox-2 mRNA and protein levels, as well as in COX-2 promoter luciferase activity in SV-LECs. These actions were associated with protein phosphatase 2A (PP2A), apoptosis signal-regulating kinase 1 (ASK1), JNK1/2 and p38MAPK activation, and NF-κB subunit p65 and C/EBPß phosphorylation. PP2A-ASK1 signaling blockade reduced LPS-induced JNK1/2, p38MAPK, p65 and C/EBPß phosphorylation. Transfection with PP2A siRNA reduced LPS's effects on p65 and C/EBPß binding to the COX-2 promoter region. Transfected with the NF-κB or C/EBPß site deletion of COX-2 reporter construct also abrogated LPS's enhancing effect on COX-2 promoter luciferase activity in SV-LECs. Taken together, the induction of COX-2 in SV-LECs exposed to LPS may involve PP2A-ASK1-JNK and/or p38MAPK-NF-κB and/or C/EBPß cascade.