RESUMEN
This Letter proposes a high-security and high-order signal transmission method that is based on delta-sigma modulation (DSM) and discrete memristive-enhanced chaos (DMEC). We employ the DMEC for the encryption of DSM signals to achieve a key space of 1098 in size. Moreover, we demonstrated a high-security transmission of 16384QAM signals using the DSM over a 25â km single-mode fiber in the intensity-modulated direct detection (IMDD) system. The experimental results show that the proposed ultrahigh-order transmission scheme based on DMEC and DSM guarantees high signal transmission performances with improved security and a key sensitivity level of 10-17.
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In this Letter, we propose a method for ultrahigh-order QAM secure transmission and key distribution based on delta-sigma modulation (DSM) and discrete memristive-enhanced chaos (DMEC). The disturbance vectors generated by the DMEC scramble the DSM signals in both frequency and time domains, resulting in highly secure DSM signals. Through the key modulation and power adjustment and then superimposing them on the encrypted signals, the method achieves simultaneous transmission of keys and signals without the need for additional spectral resources. This approach allows for secure communication with continuous key iteration and updates, offering an effective solution for implementing "one-time pad" encryption. In the experimental demonstration, we achieved a secure transmission and key distribution of a 16384QAM signal at a rate of 17.09â Gb/s over 25â km in an intensity-modulated direct detection (IMDD) system, based on DSM.
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In this paper, a dynamic updated key distribution encryption scheme based on syncretic W band-passive optical network (PON) is proposed. The 102â Gb/s encrypted data rate using 64QAM is successfully transmitted over the 50â m wireless distance under 15% soft-decision forward error correction (SD-FEC) for a pre-FEC bit error rate (BER) threshold of 1.56 × 10-2. The scheme can realize an error-free public key transmission and public key updates up to 1014 times. In the encryption transmission system, there is a small deviation of the private key, and the received BER is more than 0.45. As far as we know, this is the first time to complete a dynamic key distribution based on a syncretic W band-PON system.
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The objective of this study is to explore the pharmacokinetics, tissue distribution, and excretion patterns of GL-V9 and its glucuronide metabolite, 5-O-glucuronide GL-V9, following the administration of GL-V9 to Sprague-Dawley (SD) rats. In this research, we developed and validated rapid, sensitive, and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods for quantifying GL-V9 and 5-O-glucuronide GL-V9 in various biological samples, including SD rat plasma, tissue homogenate, bile, urine, and feces. Quantification of GL-V9 and 5-O-glucuronide GL-V9 in plasma, tissue homogenate, bile, urine, and feces was performed using the validated LC-MS/MS methods. The bioavailability of GL-V9 in SD rats ranged from 6.23% to 7.08%, and both GL-V9 and 5-O-glucuronide GL-V9 exhibited wide distribution and rapid elimination from tissues. The primary distribution tissues for GL-V9 and 5-O-glucuronide GL-V9 in rats were the duodenum, liver, and lung. GL-V9 was predominantly excreted in urine, while 5-O-glucuronide GL-V9 was primarily excreted in bile. GL-V9 exhibited easy absorption and rapid conversion to its glucuronide metabolite, 5-O-glucuronide GL-V9, following administration.
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Glucurónidos , Espectrometría de Masas en Tándem , Ratas , Animales , Ratas Sprague-Dawley , Glucurónidos/química , Cromatografía Liquida/métodos , Distribución Tisular , Espectrometría de Masas en Tándem/métodos , Heces/química , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Wogonin, a flavone from the root of Scutellaria baicalensis Georgi, has shown various biological activities. In our previous study, it was confirmed that wogonin could decrease the expression of hypoxia-inducible factor-1α (HIF-1α) by affecting its stability under hypoxia. However, it is still unknown whether wogonin could influence Wnt/ß-catenin pathway under hypoxia. In this study, we found that wogonin disrupted Wnt/ß-catenin signaling and reduced the secretion of vascular endothelial growth factor (VEGF, also known as vascular permeability factor, VPF), which increased vascular permeability in certain diseases. It was found that wogonin suppressed HUVECs hyperactivity and actin remodeling induced by hypoxia, inhibited transendothelial cell migration of the human breast carcinoma cell MDA-MB-231 and the extravasated Evans in vivo Miles vascular permeability assay. Wogonin-treated cells showed a decrease in the expression of Wnt protein and its co-receptors, as well as a parallel increase in the expression of Axin and GSK-3ß in degradation complex, leading to degradation of ß-catenin. In addition, wogonin promoted the binding between Axin and ß-catenin, increased ubiquitination of ß-catenin and promoted its degradation. Interestingly, wogonin decreased the expression of TCF-1, TCF-3, and LEF-1 and inhibited nuclear accumulation of ß-catenin as well as the binding of ß-catenin and TCF-1, TCF-3, or LEF-1. All of the above results showed that wogonin could inhibit the expression of VEGF, which is an important factor regulated by ß-catenin. Taken together, the results suggested that wogonin was a potent inhibitor of Wnt/ß-catenin and influenced vascular permeability, and this might provide new therapeutics in certain diseases.
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Permeabilidad Capilar/efectos de los fármacos , Flavanonas/farmacología , Scutellaria/química , Vía de Señalización Wnt/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Flavanonas/química , Flavanonas/aislamiento & purificación , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proteolisis/efectos de los fármacos , Migración Transendotelial y Transepitelial , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1α by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1α by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel-Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1α. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1α and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1α. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1α in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1α directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1α and provided a new insight into the mechanisms of wogonin against cancers.
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Inhibidores de la Angiogénesis , Antioxidantes/farmacología , Flavanonas/farmacología , Factor 1 Inducible por Hipoxia/metabolismo , Neovascularización Patológica/prevención & control , Animales , Antioxidantes/aislamiento & purificación , Aorta/citología , Aorta/efectos de los fármacos , Aorta/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , ADN de Neoplasias/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Flavanonas/aislamiento & purificación , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , ARN Interferente Pequeño/genética , Ratas , Scutellaria baicalensis/química , Translocación Genética/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
OBJECTIVE: Traditional Chinese medicine plays a significant role in the treatment of the pandemic of coronavirus disease 2019 (COVID-19). Tanreqing Capsule (TRQC) was used in the treatment of COVID-19 patients in the Shanghai Public Health Clinical Center. This study aimed to investigate the clinical efficacy of TRQC in the treatment of COVID-19. METHODS: A retrospective cohort study was conducted on 82 patients who had laboratory-confirmed mild and moderate COVID-19; patients were treated with TRQC in one designated hospital. The treatment and control groups consisted of 25 and 57 cases, respectively. The treatment group was given TRQC orally three times a day, three pills each time, in addition to conventional Western medicine treatments which were also administered to the control group. The clinical efficacy indicators, such as the negative conversion time of pharyngeal swab nucleic acid, the negative conversion time of fecal nucleic acid, the duration of negative conversion of pharyngeal-fecal nucleic acid, and the improvement in the level of immune indicators such as T-cell subsets (CD3, CD4 and CD45) were monitored. RESULTS: COVID-19 patients in the treatment group, compared to the control group, had a shorter negative conversion time of fecal nucleic acid (4 vs. 9 days, P = 0.047) and a shorter interval of negative conversion of pharyngeal-fecal nucleic acid (0 vs. 2 days, P = 0.042). The level of CD3+ T cells increased in the treatment group compared to the control group ([317.09 ± 274.39] vs. [175.02 ± 239.95] counts/µL, P = 0.030). No statistically significant differences were detected in the median improvement in levels of CD4+ T cells (173 vs. 107 counts/µL, P = 0.208) and CD45+ T cells (366 vs. 141 counts/µL, P = 0.117) between the treatment and control groups. CONCLUSION: Significant reductions in the negative conversion time of fecal nucleic acid and the duration of negative conversion of pharyngeal-fecal nucleic acid were identified in the treatment group as compared to the control group, illustrating the potential therapeutic benefits of using TRQC as a complement to conventional medicine in patients with mild and moderate COVID-19. The underlying mechanism may be related to the improved levels of the immune indicator CD3+ T cells.
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Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , ADN Viral/análisis , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China/métodos , SARS-CoV-2/genética , Adulto , COVID-19/patología , Cápsulas , Heces/virología , Femenino , Humanos , Tiempo de Internación , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To observe the early interventions of traditional Chinese Medicine (TCM) on the conversion time of nucleic acid in patients with coronavirus disease 2019 (COVID-19), and find possible underlying mechanisms of action. METHODS: A retrospective cohort study was conducted on 300 confirmed COVID-19 patients who were treated with TCM, at a designated hospital in China. The patients were categorized into three groups: TCM1, TCM2 and TCM3, who respectively received TCM interventions within 7, 8-14, and greater than 15 days of hospitalization. Different indicators such as the conversion time of pharyngeal swab nucleic acid, the conversion time of fecal nucleic acid, length of hospital stay, and inflammatory markers (leukocyte count, and lymphocyte count and percentage) were analyzed to observe the impact of early TCM interventions on these groups. RESULTS: The median conversion times of pharyngeal swab nucleic acid in the three groups were 5.5, 7 and 16 d (P < 0.001), with TCM1 and TCM2 being statistically different from TCM3 (P < 0.01). TCM1 (P < 0.05) and TCM3 (P < 0.01) were statistically different from TCM2. The median conversion times of fecal nucleic acid in the three groups were 7, 9 and 17 d (P < 0.001). Conversion times of fecal nucleic acid in TCM1 were statistically different from TCM3 and TCM2 (P < 0.01). The median lengths of hospital stay in the three groups were 13, 16 and 21 d (P < 0.001). TCM1 and TCM2 were statistically different from TCM3 (P < 0.01); TCM1 and TCM3 were statistically different from TCM2 (P < 0.01). Both leucocyte and lymphocyte counts increased gradually with an increase in the length of hospital stay in TCM1 group patients, with a statistically significant difference observed at each time point in the group (P < 0.001). Statistically significant differences in lymphocyte count and percentage in TCM2 (P < 0.001), and in leucocyte count (P = 0.043) and lymphocyte count (P = 0.038) in TCM3 were observed. The comparison among the three groups showed a statistically significant difference in lymphocyte percentage on the third day of admission (P = 0.044). CONCLUSION: In this study, it was observed that in COVID-19 patients treated with a combination of Chinese and Western medicines, TCM intervention earlier in the hospital stay correlated with faster conversion time of pharyngeal swab and fecal nucleic acid, as well as shorter length of hospital stay, thus helping promote faster recovery of the patient. The underlying mechanism of action may be related to improving inflammation in patients with COVID-19.
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Tratamiento Farmacológico de COVID-19 , Medicina Tradicional China , SARS-CoV-2 , Adulto , Anciano , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Tumor cells recruit vascular endothelial cells and circulating endothelial progenitor cells to form new vessels to support their own growth and metastasis. VEGF, PDGF-BB and FGF-2 are three major pro-angiogenic factors and applied to promote angiogenesis. In this research, we demonstrated that anlotinib, a potent multi-tyrosine kinases inhibitor (TKI), showed a significant inhibitory effect on VEGF/PDGF-BB/FGF-2-induced angiogenesis in vitro and in vivo. Wound healing assay, chamber directional migration assay and tube formation assay indicated that anlotinib inhibited VEGF/PDGF-BB/FGF-2-induced cell migration and formation of capillary-like tubes in endothelial cells. Furthermore, anlotinib suppressed blood vessels sprout and microvessel density in rat aortic ring assay and chicken chorioallantoic membrane (CAM) assay. Importantly, according to our study, the anti-angiogenic effect of anlotinib is superior to sunitinib, sorafenib and nintedanib, which are three main anti-angiogenesis drugs in clinic. Mechanistically, anlotinib inhibits the activation of VEGFR2, PDGFRß and FGFR1 as well their common downstream ERK signaling. Therefore, anlotinib is a potential agent to inhibit angiogenesis and be applied to tumor therapy.
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Indoles/farmacología , Neovascularización Patológica , Quinolinas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Aorta/patología , Aorta Torácica/patología , Línea Celular , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Pollos , Membrana Corioalantoides/metabolismo , Humanos , Masculino , Microcirculación , Fosforilación , Ratas , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
The epithelial-to-mesenchymal transition (EMT) contributes to the disruption of cell-cell junctions and imbues cancer cells with invasive and migratory properties. In this study, we investigated the effect of gambogic acid, a xanthone extracted from the resin of Garciania hanburyi, on transforming growth factor ß1 (TGFß1)-induced EMT. Gambogic acid inhibited the invasion and migration of TGFß1-induced A549 cells in vitro. Gambogic acid also increased the mRNA and protein expression of E-cadherin, but repressed the mRNA and protein expression of N-cadherin, vimentin, and transcription factor TWIST1. Further examination of the mechanism revealed that the nuclear factor κB (NF-κB) pathway is involved in this regulation of EMT-related biomarkers. Gambogic acid inhibited NF-κB p65 nuclear translocation and the phosphorylation of the inhibitor of NF-κB (IκBα) and IκBα kinase (IKKα). Gambogic acid also suppressed the EMT induced by TGFß1 and tumor necrosis factor α by inhibiting the NF-κB pathway. Our data also indicate that gambogic acid inhibited the primary lesion and lung metastasis of orthotopic model of A549 cells in vivo. We propose that gambogic acid might be developed as a candidate drug with therapeutic potential for the treatment of cancer invasion and migration.
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Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/farmacología , Xantonas/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/genética , Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , FN-kappa B/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Wogonin, a naturally occurring monoflavonoid extracted from the root of Scutellaria baicalensis Georgi, has been shown to have anti-inflammatory and anti-tumor activities and inhibits oxidant stress-induced vascular permeability. However, the influence of wogonin on vascular hyperpermeability induced by overabounded inflammatory factors often appears in inflammatory diseases and tumor is not well known. In this study, we evaluate the effects of wogonin on LPS induced vascular permeability in human umbilical vein endothelial cells (HUVECs) and investigate the underlying mechanisms. We find that wogonin suppresses the LPS-stimulated hyperactivity and cytoskeleton remodeling of HUVECs, promotes the expression of junctional proteins including VE-Cadherin, Claudin-5 and ZO-1, as well as inhibits the invasion of MDA-MB-231 across EC monolayer. Miles vascular permeability assay proves that wogonin can restrain the extravasated Evans in vivo. The mechanism studies reveal that the expressions of TLR4, p-PLC, p-MLCK and p-MLC are decreased by wogonin without changing the total steady state protein levels of PLC, MLCK and MLC. Moreover, wogonin can also inhibit KCl-activated MLCK/MLC pathway, and further affect vascular permeability. Significantly, compared with wortmannin, the inhibitor of MLCK/MLC pathway, wogonin exhibits similar inhibition effects on the expression of p-MLCK, p-MLC and LPS-induced vascular hyperpermeability. Taken together, wogonin can inhibit LPS-induced vascular permeability by suppressing the MLCK/MLC pathway, suggesting a therapeutic potential for the diseases associated with the development of both inflammatory and tumor.
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Permeabilidad Capilar/efectos de los fármacos , Flavanonas/farmacología , Lipopolisacáridos/farmacología , Cadenas Ligeras de Miosina/metabolismo , Quinasa de Cadena Ligera de Miosina/metabolismo , Transducción de Señal/efectos de los fármacos , Antígenos CD/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Células Cultivadas , Claudina-5/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Scutellaria baicalensis/química , Receptor Toll-Like 4/metabolismo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Wogonin, a natural monoflavonoid extracted from Scutellariae radix, has been reported for its ability of inhibiting tumor angiogenesis. In this study, we assessed the effect of wogonin on angiogenesis induced by low level of H2O2 (10 µM) in human umbilical vein endothelial cells (HUVECs). Wogonin suppressed H2O2-induced migration and tube formation of HUVECs as well as microvessel sprouting from rat aortic rings in vitro. Meanwhile, wogonin suppressed vessel growth in chicken chorioallantoic membrane (CAM) model in vivo. Mechanistic studies showed that wogonin suppressed H2O2-activated PI3K/Akt pathway and reduced the expression of vascular endothelial growth factor (VEGF) up-regulated by H2O2 in both protein and mRNA levels. In addition, wogonin also inhibited nuclear translocation of NF-κB, and decreased the binding ability of NF-κB with exogenous consensus DNA oligonucleotide. Then we further investigated the effect of wogonin on over-activated PI3K/Akt pathway by insulin-like growth factor-1 (IGF-1) and H2O2. We found that wogonin suppressed phosphorylation of Akt, up-regulation of VEGF and angiogenesis in vitro which was further induced by IGF-1 and H2O2. Moreover, in NF-κB overexpressed HUVECs, wogonin could also reduce the expression of VEGF and inhibited the migration and tube formation. Taken together, these results suggested that wogonin was potential in inhibiting H2O2-induced angiogenesis in vitro and in vivo via suppressing PI3K/Akt pathway and NF-κB signaling.
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Inductores de la Angiogénesis , Flavanonas/farmacología , Peróxido de Hidrógeno/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Inductores de la Angiogénesis/toxicidad , Animales , Embrión de Pollo , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno/toxicidad , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Scutellaria baicalensis , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Wogonin has been shown to have anti-angiogenesis and anti-tumor effects. However, whether wogonin inhibits LPS-induced tumor angiogenesis is not well known. In this study, we investigated the effect of wogonin on inhibiting LPS-induced tumor angiogenesis and further probed the underlying mechanisms. ELISA results revealed that wogonin could suppress LPS-induced VEGF secretion from tumor cells. Transwell assay, tube formation assay, rat aortic ring assay and CAM model were used to evaluate the effect of wogonin on angiogenesis induced by MCF-7 cell (treated with LPS) in vitro and in vivo. The inhibitory effect of wogonin on angiogenesis in LPS-treated MCF-7 cells was then confirmed by the above in vitro and in vivo assays. The study of the molecular mechanism showed that wogonin could suppress PI3K/Akt signaling activation. Moreover, wogonin inhibited nuclear translocation of NF-κB and its binding to DNA. The result of real-time PCR and luciferase reporter assay suggested that VEGF expression was down-regulated by wogonin primarily at the transcriptional level. IGF-1 and p65 expression plasmid were used to activate PI3K/Akt and NF-κB pathways, and to observe the effect of wogonin on the simualtion of PI3K/Akt/NF-κB signaling. Taken together, the result suggested that wogonin was a potent inhibitor of tumor angiogenesis and provided a new insight into the mechanisms of wogonin against cancer.
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Antineoplásicos/farmacología , Flavanonas/farmacología , Lipopolisacáridos/efectos adversos , Neoplasias/irrigación sanguínea , Neovascularización Patológica/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Flavanonas/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Receptor Toll-Like 4/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Previous studies have demonstrated that wogonoside, a bioactive flavonoid extracted from the root of Scutellaria baicalensis Gerogi, has anti-inflammatory and anti-angiogenic activities. In this study, we evaluated wogonoside-induced autophagy on human breast MDA-MB-231 cells. We report that wogonoside triggered the formation of microtubule-associated protein-light chain 3 (MAP-LC3) positive autophagosomes and the accumulation of acidic vesicular and autolysosomes in MDA-MB-231 cells. In addition, cells treated by wogonoside developed autophagosome-like characteristics, including single and double membrane vacuoles containing intact and degraded cellular debris. The results showed that wogonoside promotes the expression of LC3-II and Beclin-1. Furthermore, wogonoside inhibited cell growth of MDA-MB-231 cells in a concentration- and time-dependent manner, which was associated with wogonoside-induced autophagy. Wogonoside also suppressed the activation of mammalian target of rapamycin (mTOR) and p70-S6 kinase (p70S6K) by regulating the expression of the extracellular signal-regulated kinase (ERK1/2) and p38 involved mitogen-activated protein kinase (MAPK) signaling pathway. Taken together, these results suggest that wogonoside partially inhibits MDA-MB-231 cell growth by inducing autophagy through the MAPK-mTOR pathway and may be a promising anti-tumor agent.
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Autofagia/efectos de los fármacos , Flavanonas/farmacología , Glucósidos/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Antineoplásicos Fitogénicos/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lisosomas/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Vacuolas/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Wogonin, a naturally occurring monoflavonoid extracted from the root of Scutellaria baicalensis Georgi, has been reported for its anti-oxidant activity. However, it is still unclear whether wogonin can inhibit oxidant-induced vascular permeability. In this study, we evaluated the effects of wogonin on H2O2-induced vascular permeability in human umbilical vein endothelial cells (HUVECs). We found that wogonin can suppress the H2O2-stimulated actin remodeling and albumin uptake of HUVECs, as well as transendothelial cell migration of the human breast carcinoma cell MDA-MB-231. The mechanism revealed that wogonin inhibited H2O2-induced phosphorylation of caveolin-1 (cav-1) associating with the suppression of stabilization of VE-cadherin and ß-catenin. Moreover, wogonin repressed anisomycin-induced phosphorylation of p38, cav-1 and vascular permeability. These results suggested that wogonin could inhibit H2O2-induced vascular permeability by downregulating the phosphorylation of cav-1, and that it might have a therapeutic potential for the diseases associated with the development of both oxidant and vascular permeability.
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Permeabilidad Capilar/efectos de los fármacos , Caveolina 1/metabolismo , Flavanonas/farmacología , Depuradores de Radicales Libres/farmacología , Peróxido de Hidrógeno/antagonistas & inhibidores , Actinas/metabolismo , Albúminas/metabolismo , Western Blotting , Movimiento Celular , Células Cultivadas , Endocitosis/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/farmacología , Inmunoprecipitación , Microscopía Confocal , Fosforilación , Migración Transendotelial y Transepitelial/efectos de los fármacos , beta Catenina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: There is an obvious relationship among angiogenesis and inflammation. From previous study, we learn that oroxylin A possesses anti-angiogenic activity in vitro and in ovo. It also has an inhibitory effect on inflammation. But whether oroxylin A suppresses the inflammation-induced angiogenesis is still unknown. Our present study focuses on the role of oroxylin A in targeting LPS-induced angiogenesis, inflammatory and related pathways. METHODS: The effects of oroxylin A on angiogenesis were investigated by transwell assay, tube formation assay, rat aortic ring assay and chorioallantoic membrane (CAM) model. Western blotting analysis was used to detect the expression of certain proteins. RESULTS: We found that oroxylin A inhibited LPS-induced migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as microvessel sprouting from rat aotric ring in vitro and the angiogenesis of chicken chorioallantoic membrane (CAM) model in ovo. The results also indicated that oroxylin A could inhibit the expression of LPS acceptor toll-like receptor 4 (TLR4) and the activities of its downstream mitogen-activated protein kinases (MAPKs), including reducing expressions of the phosphorylation of JNK, p38, and ERK. Moreover, oroxylin A prevented NF-κB dimers from translocating to the nucleus. CONCLUSIONS: Taken together, oroxylin A can suppress the angiogenesis induced by LPS and it may affect the LPS/TLR4 signaling pathway.