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Recent studies have indicated that pyroptosis may participate in the regulation of tumorigenesis and immune microenvironment. However, the role of pyroptosis-related genes (PRGs) in pancreatic adenocarcinoma (PAAD) remains unclear. Through multiple bioinformatics analysis, we constructed a prognostic gene model and competing endogenous RNA network. The correlation between PRGs and prognosis, immune infiltration, immune checkpoints, and tumor mutational burden was analyzed by Kaplan-Meier curve, univariate Cox, multivariate regression, and Spearman's analysis in PAAD patients. The qRT-PCR, Western blotting, CCK-8, Wound healing, and Transwell assay were applied to examine the role of CASP6 in PANC-1 cell. Thirty-one PRGs were upregulated in PAAD. Functional enrichment analysis revealed that the PRGs were mainly involved in pyroptosis, NOD-like receptor signaling pathway, and response to bacteria. We established a novel 4-gene signature related to PRGs for evaluating the prognosis of PAAD patients. Patients with PAAD in the low-risk group had a better prognosis than those in the high-risk group. The nomogram suggested that the 1-, 3-, and 5-years survival probability exhibited robust predictive performance. Significant correlation was observed between prognostic PRGs and immune infiltration, immune checkpoints, and tumor mutational burden. We first identified the potential competing endogenous RNA regulatory axis in PAAD: lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8. Moreover, knockdown of CASP6 dramatically inhibited the proliferation, migration, and invasion ability of PANC-1 cell in vitro. In conclusion, CASP6 could be a potential biomarker, promoting the occurrence and progression in PAAD. The lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8 regulatory axis plays an vital role in regulating the anti-tumor immune responses for PAAD.
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Adenocarcinoma , MicroRNAs , Neoplasias Pancreáticas , RNA Longo não Codificante , Humanos , Adenocarcinoma/genética , Prognóstico , Neoplasias Pancreáticas/genética , Piroptose/genética , RNA Longo não Codificante/genética , Apoptose , Tomada de Decisão Clínica , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMO
NRP1 is a transmembrane glycoprotein that is highly expressed in a variety of tumors. There is evidence that NRP1 can enhance the stem cell properties of tumor cells, which are thought to be resistant to radiotherapy. This study aims to elucidate the potential mechanism of NRP1 in radiation resistance. We transfected NRP1 siRNA and plasmid in breast cancer cells to detect the expression of cancer stem cell markers by western blot and qRT-PCR. The effect of NRP1 on radiotherapy resistance was assesses by immunofluorescence and flow cytometry. In vivo, we established xenograft tumor model treating with shRNA-NRP1 to assess radiotherapy sensitivity. We found that NRP1 could enhance the stem cell properties and confer radioresistance of breast cancer cells. Mechanistically, we proved that NRP1 reduced IR-induced apoptosis by downregulation of Bcl-2 via methyltransferase WTAP in m6A-depentent way. It is suggested that these molecules may be the therapeutic targets for improving the efficacy of radiotherapy for breast cancer.
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Neoplasias da Mama , Animais , Humanos , Feminino , Neoplasias da Mama/patologia , Metilação , Linhagem Celular Tumoral , RNA Mensageiro/metabolismo , Apoptose/efeitos da radiação , RNA Interferente Pequeno/genética , Modelos Animais de Doenças , Fatores de Processamento de RNA/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
The construction of type-II or S-scheme heterojunctions can effectively accelerate the directional migration of charge carriers and inhibit the recombination of electron-hole pairs to improve the catalytic performance of the composite catalyst; therefore, the construction and formation mechanism of a heterojunction are worth further investigation. Herein, Cu2O@Cu4(SO4)(OH)6·H2O core-shell polyhedral heterojunctions were fabricated via in situ etching Cu2O with octahedral, cuboctahedral, and cubic shapes by sodium thiosulfate (Na2S2O3). Cu2O@Cu4(SO4)(OH)6·H2O polyhedral heterojunctions demonstrated obviously enhanced sterilization and degradation performance than the corresponding single Cu2O polyhedra and Cu4(SO4)(OH)6·H2O. When Cu2O with a different morphology contacts with Cu4(SO4)(OH)6·H2O, a built-in electric field is established at the interface due to the difference in Fermi level (Ef); meanwhile, the direction of band bending and the band alignment are determined. These lead to the different migration pathways of electrons and holes, and thereby, a type-II or S-scheme heterojunction is constructed. The results showed that octahedral o-Cu2O@Cu4(SO4)(OH)6·H2O is an S-scheme heterojunction; however, cuboctahedral co-Cu2O@Cu4(SO4)(OH)6·H2O and cubic c-Cu2O@Cu4(SO4)(OH)6·H2O are type-II heterojunctions. By means of X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), diffuse reflectance spectra (DRS), and Mott-Schottky analyses, the band alignments, Fermi levels, and band offsets (ΔECB, ΔEVB) of Cu2O@Cu4(SO4)(OH)6·H2O polyhedral heterojunctions were estimated; the results indicated that the catalytic ability of the composite catalyst is determined by the type of heterojunction and the sizes of band offsets. Cubic c-Cu2O@Cu4(SO4)(OH)6·H2O has the strongest driving force (namely, biggest band offsets) to accelerate charge migration and effectively separate charge carriers, so it exhibits the strongest catalytic bactericidal and degrading abilities.
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A strong light-matter interaction is highly desirable from the viewpoint of both fundamental research and practical application. Here, we propose a dielectric-metal hybrid nanocavity composed of a silicon (Si) nanoparticle and a thin gold (Au) film and investigate numerically and experimentally the coupling between the plasmons supported by the nanocavity and the excitons in an embedded tungsten disulfide (WS2) monolayer. When a Si/WS2/Au nanocavity is excited by the surface plasmon polariton generated on the surface of the Au film, greatly enhanced plasmon-exciton coupling originating from the hybridization of the surface plasmon polariton, the mirror-image-induced magnetic dipole, and the exciton modes is clearly revealed in the angle- or size-resolved scattering spectra. A Rabi splitting as large as â¼240 meV is extracted by fitting the experimental data with a coupled harmonic oscillator model containing three oscillators. Our findings open new horizons for constructing nanoscale photonic devices by exploiting dielectric-metal hybrid nanocavities.
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BACKGROUND: Anillin (ANLN) is an actin-binding protein that is essential for cell division and contributes to cell growth and migration. Although previous studies have shown that ANLN is related to carcinogenesis, no pan-cancer analyses of ANLN have been reported. Accordingly, in this study, we evaluated the carcinogenic roles of ANLN in various cancer types using online databases. METHODS: We evaluated the potential carcinogenic roles of ANLN using TIMER2 and Gene Expression Omnibus databases with 33 types of cancers. We further investigated the associations of ANLN with patient prognosis, genetic alterations, phosphorylation levels, and immune infiltration in multiple cancers using GEPIA2, cBioPortal, UACLAN, and TIMER2 databases. Additionally, the potential functions of ANLN were explored using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Reverse transcription quantitative polymerase chain reaction and immunohistochemistry were used to determine ANLN mRNA and protein expression in colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC) cell lines. RESULTS: ANLN was overexpressed in various tumor tissues compared with corresponding normal tissues, and significant correlations between ANLN expression and patient prognosis, genetic alterations, phosphorylation levels, and immune infiltration were noted. Moreover, enrichment analysis suggested that ANLN functionally affected endocytosis, regulation of actin cytoskeleton, and oxytocin signaling pathways. Importantly, ANLN mRNA and protein expression levels were upregulated in gastrointestinal cancers, including CRC, GC, and HCC. CONCLUSIONS: Our findings suggested that ANLN participated in tumorigenesis and cancer progression and may have applications as a promising biomarker of immune infiltration and prognosis in various cancers.
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BACKGROUND: Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1 (TIMP1), an inflammatory cytokine, under serum-depleted conditions which leads to suppression of lung cancer cell metastasis has been reported. Starvation is also a stimulus of autophagic activity. Herein, we reveal that starvation activates Rab37 and induces autophagy. METHODS: We used an overexpression/knockdown system to determine the relationship between autophagy and Rab37 in vitro and in vivo. The autophagy activity was detected by immunoblotting, transmission electron microscope, autophagosome purification, and immunofluorescence under the confocal microscope. Lung-to-lung metastasis mouse model was used to clarify the role of autophagy and Rab37 in lung cancer. Clinical lung cancer patient specimens and an online big database were analyzed. RESULTS: Initially, we demonstrated that active-form Rab37 increased LC3-II protein level (the marker of autophagosome) and TIMP1 secretion. Accordingly, silencing of Rab37 gene expression alleviated Rab37 and LC3-II levels as well as TIMP1 secretion, and induction of autophagy could not increase TIMP1 exocytosis under such conditions. Moreover, silencing the Atg5 or Atg7 gene of lung cancer cells harboring active-mutant Rab37 (Q89L) led to decreased autophagy activity and TIMP1 secretion. In the lung-to-lung metastasis mouse model, increased TIMP1 expression accompanied by amiodarone-induced autophagy led to decreased tumor nodules and cancer cell metastasis. These phenomena were reversed by silencing the Atg5 or Atg7 gene. Notably, increasing autophagy activity alone showed no effect on TIMP1 secretion under either Rab37 or Sec22b silencing conditions. We further detected colocalization of LC3 with either Rab37 or TIMP1, identified Rab37 and Sec22b proteins in the purified autophagosomes of the lung cancer cells harboring the active-form Rab37 gene, and confirmed that these proteins are involved in the secretion of TIMP1. We reveal that autophagic activity was significantly lower in the tumors compared to the non-tumor parts and was associated with the overall lung cancer patient survival rate. CONCLUSIONS: We are the first to report that autophagy plays a promoting role in TIMP1 secretion and metastasis in a Rab37-dependent manner in lung cancer cells and the lung-to-lung mouse model.
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Neoplasias Pulmonares , Inibidor Tecidual de Metaloproteinase-1 , Proteínas rab de Ligação ao GTP , Animais , Camundongos , Autofagossomos , Autofagia/genética , Modelos Animais de Doenças , Exocitose , Neoplasias Pulmonares/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Proteínas rab de Ligação ao GTP/genéticaRESUMO
To detect the magnetic component of arbitrary unknown optical fields, a candidate probe must meet a list of demanding requirements, including a spatially isotropic magnetic response, suppressed electric effect, and wide operating bandwidth. Here, we show that a silicon nanoparticle satisfies all these requirements, and its optical magnetism driven multiphoton luminescence enables direct mapping of the magnetic field intensity distribution of a tightly focused femtosecond laser beam with varied polarization orientation and spatially overlapped electric and magnetic components. Our work establishes a powerful nonlinear optics paradigm for probing unknown optical magnetic fields of arbitrary electromagnetic structures, which is not only essential for realizing subwavelength-scale optical magnetometry but also facilitates nanophotonic research in the magnetic light-matter interaction regime.
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Silicon (Si) is generally considered as a poor photon emitter, and various scenarios have been proposed to improve the photon emission efficiency of Si. Here, we report the observation of a burst of the hot electron luminescence from Si nanoparticles with diameters of 150-250 nm, which is triggered by the exponential increase of the carrier density at high temperatures. We show that the stable white light emission above the threshold can be realized by resonantly exciting either the mirror-image-induced magnetic dipole resonance of a Si nanoparticle placed on a thin silver film or the surface lattice resonance of a regular array of Si nanopillars with femtosecond laser pulses of only a few picojoules, where significant enhancements in two- and three-photon-induced absorption can be achieved. Our findings indicate the possibility of realizing all-Si-based nanolasers with manipulated emission wavelength, which can be easily incorporated into future integrated optical circuits.
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Epidermal growth factor-like domain multiple 6 (EGFL6) is implicated in tumor growth, metastasis and angiogenesis, and its ectopic alteration has been detected in aggressive malignancies. However, the pathophysiologic roles and molecular mechanisms of EGFL6 in gastric cancer (GC) remain to be elucidated. In this study, we investigated EGFL6 expression in GC cell lines and tissues using western blotting and immunohistochemistry. We found that EGFL6 was elevated expression in GC cell lines and tissues. The high expression of EGFL6 significantly was correlated with histological grade, depth of invasion, lymph node involvement, distant metastasis and TNM stage in GC and predicted poorer prognosis, and it could act an independent prognostic factor for GC patients. EGFL6 enhanced the proliferation, migration and invasion of GC cells. In addition, we identified the possible molecular mechanisms of EGFL6-involved epithelial-mesenchymal transition (EMT). EGFL6 regulated EMT process and induced metastasis partly through FAK/PI3K/AKT/mTOR, Notch and MAPK signaling pathways. In conclusion, EGFL6 confers an oncogenic function in GC progression and may be proposed as a potential therapeutic target for GC.
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Proteínas de Ligação ao Cálcio/biossíntese , Moléculas de Adesão Celular/biossíntese , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais/fisiologiaRESUMO
As the key factor of the polarity protein complex, Par6 not only regulates polarization processes, but also plays important roles in tumor metastasis and progression in many epithelium malignancy tumors. Here, we showed that Par6 is an essential component in glioma tumorigenesis. Our results indicated the aberrant expression of Par6 in malignant glioma tissues and cell lines. We found that the regulation of Par6 expression induces cell proliferation and tumor growth in vivo and in vitro. Additionally, RNA-seq revealed the effects of Par6 were associated with cyclin D1-regulated cell cycle progression in glioma cells. Moreover, our results demonstrated that the regulation of Par6 can enhance the activation of Akt/PI3K signaling pathway, and subsequently upregulate the expression level of GSK-3ß protein, which then regulate cyclin D1-mediated cell cycle regulation. Furthermore, we found that TGF-ß-induced the upregulation of Par6 expression may be involved in this process. The pathological analysis confirmed the correlation between Par6 expression and the prognosis in human glioma tissues, suggesting the regulation of Par6 expression regulates glioma tumorigenesis and progression. Thus, our findings showed that Par6 might be a potential biomarker for the diagnosis and providing a therapeutic strategy for the treatment of malignant glioma.
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Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Biomarcadores Tumorais/biossíntese , Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Glioma/genética , Glioma/patologia , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. METHODS: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model. RESULTS: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3'-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of ß-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. CONCLUSIONS: PAK5 contributed to the sorafenib resistant characteristics of HCC via ß-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.
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Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Animais , Antineoplásicos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Through the incorporation of various halogen-substituted chiral organic cations, the effects of chiral molecules on the chiroptical properties of hybrid organic-inorganic perovskites (HOIPs) are investigated. Among them, the HOIP having a Cl-substituted chiral cation exhibits the highest circular dichroism (CD) and circular polarized luminescence (CPL) intensities, indicating the existence of the largest rotatory strength, whereas the F-substituted HIOP shows the weakest intensities. The observed modulation can be correlated to the varied magnetic transition dipole of HOIPs, which is sensitive to the d-spacing between inorganic layers and the halogen-halogen interaction between organic cations and the inorganic sheets. These counteracting effects meet the optimal CD and CPL intensity with chlorine substitution, rendering the rotatory strength of HOIPs arranged in the order of (ClMBA)2 PbI4 >(BrMBA)2 PbI4 >(IMBA)2 PbI4 >(MBA)2 PbI4 >(FMBA)2 PbI4 .
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BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is widely prevalent in Taiwan, and high metastatic spread of ESCC leads to poor survival rate. Fibronectin (FN) assembly on the cell membrane may induce ESCC mobility. MicroRNAs (MiRNAs) are abundant in and participate in tumorigenesis in many cancers. However, the role of MiRNA in FN assembly-related ESCC mobility remains unexplored. METHODS: We divided ESCC CE81T cells into high-FN assembly (CE81FN+) and low-FN assembly (CE81FN-) groups by flow cytometry. MiRNA microarray analysis identified miR-146a expression as the most down-regulated miRNA in comparison of CE81FN+ and CE81FN- cells. RESULTS: Cell proliferation and migration were decreased when CE81FN+ cells overexpressed transgenic miR-146a compared to the parental cells, indicating an inverse correlation between low miR-146a expression and high proliferation as well as motility of FN assembly ESCC cells. Furthermore, vimentin is the target gene of miR-146a involved in ESCC tumorigenesis. MiR-146a suppressed cell proliferation, migration and invasion of CE81FN+ cells through the inhibition of vimentin expression, as confirmed by real-time PCR, Western blotting and Transwell™ assay. Analysis of one hundred and thirty-six paired ESCC patient specimens revealed that low miR-146a and high vimentin levels were frequently detected in tumor, and that the former was associated with late tumor stages (III and IV). Notably, either low miR-146a expression or high vimentin level was significantly associated with poor overall survival rate among ESCC patients. CONCLUSIONS: This is the first report to link FN assembly in the cell membrane with miR-146a, vimentin and ESCC tumorigenesis both in vitro and in ESCC patients.
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Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Fibronectinas/genética , MicroRNAs/genética , Vimentina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Membrana Celular/fisiologia , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/etiologia , Carcinoma de Células Escamosas do Esôfago/etiologia , Feminino , Fibronectinas/metabolismo , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Vimentina/metabolismoRESUMO
Airway exposure to 1,3-ß-D-glucan (ß-glucan), an essential component of the cell wall of several pathogenic fungi, causes various adverse responses, such as pulmonary inflammation and airway hypersensitivity. The former response has been intensively investigated; however, the mechanism underlying ß-glucan-induced airway hypersensitivity is unknown. Capsaicin-sensitive lung vagal (CSLV) afferents are very chemosensitive and stimulated by various insults to the lungs. Activation of CSLV afferents triggers several airway reflexes, such as cough. Furthermore, the sensitization of these afferents is known to contribute to the airway hypersensitivity during pulmonary inflammation. This study was carried out to determine whether ß-glucan induces airway hypersensitivity and the role of the CSLV neurons in this hypersensitivity. Our results showed that the intratracheal instillation of ß-glucan caused not only a distinctly irregular pattern in baseline breathing, but also induced a marked enhancement in the pulmonary chemoreflex responses to capsaicin in anesthetized, spontaneously breathing rats. The potentiating effect of ß-glucan was found 45 min later and persisted at 90 min. However, ß-glucan no longer caused the irregular baseline breathing and the potentiating of pulmonary chemoreflex responses after treatment with perineural capsaicin treatment that blocked the conduction of CSLV fibers. Besides, the potentiating effect of ß-glucan on pulmonary chemoreflex responses was significantly attenuated by N-acetyl-L-cysteine (a ROS scavenger), HC-030031 (a TRPA1 antagonist), and Laminarin (a Dectin-1 antagonist). A combination of Laminarin and HC-030031 further reduced the ß-glucan-induced effect. Indeed, our fiber activity results showed that the baseline fiber activity and the sensitivity of CSLV afferents were markedly elevated by ß-glucan instillation, with a similar timeframe in anesthetized, artificially ventilated rats. Moreover, this effect was reduced by treatment with HC-030031. In isolated rat CSLV neurons, the ß-glucan perfusion caused a similar pattern of potentiating effects on capsaicin-induced Ca2+ transients, and ß-glucan-induced sensitization was abolished by Laminarin pretreatment. Furthermore, the immunofluorescence results showed that there was a co-localization of TRPV1 and Dectin-1 expression in the DiI-labeled lung vagal neurons. These results suggest that CSLV afferents play a vital role in the airway hypersensitivity elicited by airway exposure to ß-glucan. The TRPA1 and Dectin-1 receptors appear to be primarily responsible for generating ß-glucan-induced airway hypersensitivity.
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Acetilcisteína/farmacologia , Capsaicina/farmacologia , Pulmão/metabolismo , Hipersensibilidade Respiratória/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Canal de Cátion TRPA1/metabolismo , beta-Glucanas/farmacologia , Acetanilidas/farmacologia , Animais , Células Cultivadas , Glucanos/farmacologia , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/metabolismo , Pulmão/citologia , Pulmão/efeitos dos fármacos , Masculino , Neurônios Aferentes/efeitos dos fármacos , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Reflexo/efeitos dos fármacos , Respiração/efeitos dos fármacos , Canal de Cátion TRPA1/antagonistas & inibidores , Nervo Vago/efeitos dos fármacos , Nervo Vago/metabolismoRESUMO
Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)-224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy-selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K33-238 R) and phosphorylation site (T286A) mutants, lentivirus-mediated silencing autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy-selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. CONCLUSION: Taken together, our data demonstrate that autophagic degradation machinery and the cell-cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141-154).
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Autofagia , Carcinoma Hepatocelular/metabolismo , Ciclina D1/metabolismo , Neoplasias Hepáticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autofagossomos/metabolismo , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos SCID , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Ratos Sprague-Dawley , Proteína Sequestossoma-1/metabolismo , Taiwan/epidemiologia , UbiquitinaçãoRESUMO
Sharp electromagnetic resonances play an essential role in physics in general and optics in particular. The last decades have witnessed the successful developments of high-quality (Q) resonances in microcavities operating below the light line, which however is fundamentally challenging to access from free space. Alternatively, metasurface-based bound states in the continuum (BICs) offer a complementary solution of creating high-Q resonances in devices operating above the light line, yet the experimentally demonstrated Q factors under normal excitations are still limited. Here, we present the realizations of quasi-BIC under normal excitation with a record Q factor up to 18 511 by engineering the symmetry properties and the number of the unit cells in all-dielectric metasurface platforms. The high-Q quasi-BICs exhibit exceptionally high conversion efficiency for the third harmonic generation and even enable the second harmonic generation in Si metasurfaces. Such ultrasharp resonances achieved in this work may immediately boost the performances of BICs in a plethora of fundamental research and device applications, e.g., cavity QED, biosensing, nanolasing, and quantum light generations.
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Control and manipulation of radiation direction and directivity is highly desirable in future integrated optical circuits. Here, we investigate theoretically and numerically the scattering properties of a silicon nanosphere dimer illuminated by a focused radially polarized beam. As compared with single silicon nanospheres, a scattering peak with a significantly enhanced intensity and a dramatically reduced linewidth was observed in the scattering spectrum of the silicon nanosphere dimer. Relying on the multipole expansion method, it was revealed that the radiation at the scattering peak originates mainly from the total electric dipole and the magnetic quadrupole excited in the silicon nanosphere dimer. It was found that the radiation direction of the silicon dimer is parallel to its axis, implying a sharp (90°) bending of the radially polarized beam. In addition, the radiation directivity is significantly improved as compared with single silicon nanospheres because of the interference between the total electric dipole and magnetic quadrupole modes. For a homodimer composed of two identical silicon nanospheres, the scattering light is equally distributed in the two radiation directions. In comparison, the incident light is preferentially scattered to the small Si nanosphere for a heterodimer composed of two silicon nanospheres with different diameters. As a result, a unidirectional lateral scattering can be realized by using a single silicon nanosphere displaced appropriately from the focal point. Our findings are helpful for understanding the mode hybridization in silicon nanosphere dimers illuminated by a focused radially polarized beam and useful for designing photonic devices capable of manipulating the radiation direction and directivity of structured light.
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We propose an all-silicon-based nano-antenna that functions as not only a wavelength demultiplexer but also a polarization one. The nano-antenna is composed of two silicon cuboids with the same length and height but with different widths. The asymmetric structure of the nano-antenna with respect to the electric field of the incident light induced an electric dipole component in the propagation direction of the incident light. The interference between this electric dipole and the magnetic dipole induced by the magnetic field parallel to the long side of the cuboids is exploited to manipulate the radiation direction of the nano-antenna. The radiation direction of the nano-antenna at a certain wavelength depends strongly on the phase difference between the electric and magnetic dipoles interacting coherently, offering us the opportunity to realize wavelength demultiplexing. By varying the polarization of the incident light, the interference of the magnetic dipole induced by the asymmetry of the nano-antenna and the electric dipole induced by the electric field parallel to the long side of the cuboids can also be used to realize polarization demultiplexing in a certain wavelength range. More interestingly, the interference between the dipole and quadrupole modes of the nano-antenna can be utilized to shape the radiation directivity of the nano-antenna. We demonstrate numerically that radiation with adjustable direction and high directivity can be realized in such a nano-antenna which is compatible with the current fabrication technology of silicon chips.
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Significantly enhanced electric field in plasmonic hot spots can dramatically increase the linear and nonlinear absorption of light, leading to a high-temperature electron gas which radiates, through mainly intraband transition, a broadband luminescence quite similar to blackbody radiation. Here, we demonstrate that such hot-electron intraband luminescence (HEIL) can also be achieved by exploiting the significantly enhanced electric field at the magnetic dipole resonances of gallium arsenide (GaAs) nanospheres (NSs). We show that monocrystalline GaAs NSs with distinct electric and magnetic dipole (ED and MD) resonances can be obtained by using femtosecond laser ablation and annealing. Significantly enhanced second harmonic generation and broadband HEIL are observed when the MD resonances of such GaAs NSs are resonantly excited. The lifetime of the HEIL is found to be as short as â¼82 ps, indicating a significant enhancement in radiative intraband transition rate. We reveal that the slope extracted from the dependence of the HEIL intensity on the irradiance is linearly proportional to the energy of the emitted photon. The existence of distinct ED and MD resonances in combination with a direct bandgap makes GaAs NSs an attractive candidate for constructing novel all-dielectric metamaterials and active photonic devices.
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Three new polyynes, named choushenpilosulynes A-C (1-3), were isolated from an 85% aqueous EtOH extract of the roots of Codonopsis pilosula cultivated in Xundian County of Yunnan province, China. Their structures, including the absolute configuration of the glucose residue in 1 and 2, were determined by spectroscopic analysis and gas chromatography (GC). In addition, biological evaluation shows that all the compounds can inhibit the expression of the squalene monooxygenase (SQLE) gene in HepG2 cells, suggesting that these compounds may be involved in lipid metabolism.