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BACKGROUND: The efficacy of adjuvant sublingual immunotherapy (SLIT) in correcting structural problems in patients with allergic rhinitis (AR) caused by mite who have undergone septomeatoplasty (SMP) has not been studied. METHODS: This non-randomized controlled study recruited patients with AR (caused by mite) and concurrent septal deviation and inferior turbinate hypertrophy, at a tertiary hospital in Taiwan. SMP was performed on all patients as a surgical intervention. The patients were then divided into two groups: the control group, which underwent surgery only, and the experimental group, which received SLIT as an adjuvant treatment. Demographic data and rhinitis control assessment test (RCAT) results were analyzed. RESULTS: A total of 96 patients were enrolled in the study (SMP + SLIT group, n = 52; SMP only group, n = 44). No significant differences were observed in any of the variables between the two groups before and one month after surgery. However, during evaluations at the third and sixth month, the SMP + SLIT group showed significant improvement in the total RCAT scores compared to the SMP only group (28.6 ± 1.56 vs. 24.5 ± 3.66, p < 0.001; 27.1 ± 2.87 vs. 19.9 ± 5.56, p < 0.001). In addition, significantly better control of all RCAT sub-categories was observed in the SMP + SLIT group at the third and sixth month evaluations. CONCLUSIONS: SLIT may serve as an ideal adjuvant therapy after SMP in patients with AR. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3073-3079, 2024.
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Rinitis Alérgica , Inmunoterapia Sublingual , Humanos , Masculino , Inmunoterapia Sublingual/métodos , Femenino , Adulto , Resultado del Tratamiento , Rinitis Alérgica/terapia , Tabique Nasal/cirugía , Persona de Mediana Edad , Adulto Joven , Taiwán , Animales , Cornetes Nasales/cirugía , Terapia Combinada , HipertrofiaRESUMEN
This study investigated why object-gap relative clauses (RCs) are dominant in early child Mandarin. We discuss how restrictive-RCs differ from pseudo-RCs syntactically and pragmatically, and examine how these two types of RCs are distributed in the RC utterances of ten children and their caregivers. The results showed that (a) Mandarin-speaking children produce many more pseudo-RCs than restrictive-RCs, (b) restrictive-RCs exhibit a subject-gap advantage and are dominantly headed, and (c) pseudo-RCs exhibit an object-gap advantage and are dominantly headless. We propose that the development of restrictive-RCs is mainly influenced by the structural factor, and that the extensive use of pseudo-RCs is attributed to the communicative needs of young children. Our findings also suggest that young children's pseudo-RCs tend to have a subject-focus reading, and the object-gap dominance observed in the pseudo-RCs of child Mandarin is related to the head-final RCs and the special structural features of the cleft construction in Mandarin.
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Desarrollo del Lenguaje , Lenguaje , Humanos , Niño , Preescolar , Comunicación , LecturaRESUMEN
Fluorescent gold nanoclusters conjugated with α-lipoic acid (FANC) is a promising biocompatible fluorescent nanomaterial with a high potential for drug development. However, there is still no FANC-related research on toxicology, which is very important for future research and the development of healthy food supplements or drugs. This study uses oral administration of FANC to determine the most appropriate dose range in ICR mice for further evaluation. The in vivo acute and subacute toxicity study was conducted by oral administration of FANC to male and female ICR mice. Animal survival, body weight, daily food consumption, hematological profile, organ coefficient, serum biochemistry profile, and histopathological changes were analyzed. FANC did not show any form of morbidity or mortality at acute and subacute toxicity in both male and female ICR mice. Animal behavior, daily food consumption, hematological profile, organ coefficient, and histopathology showed no treatment-related malignant changes at single and repeated doses. Furthermore, serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and creatinine (CRE) levels showed no significant malignant changes, which indicated that FANC does not cause liver and renal damage. The only change observed in this study was the change in body weight. The body weight of the FANC-treated group was slightly decreased in female mice but increased in male mice; however, the body weight decreases were below the threshold of concern, and there was no dose-response effect. In conclusion, no observed adverse effect level (NOAEL) in repeated doses was considered in 20 µM/100 µL/25 g male and female ICR mice.
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Trastornos del Olfato , Senos Paranasales , Rinitis , Enfermedad Crónica , Endoscopía , Humanos , Senos Paranasales/cirugía , Rinitis/cirugía , Olfato , Suturas , Cornetes Nasales/cirugíaRESUMEN
BACKGROUND: Successful surgery outcomes are limited to moderate to severe obstructive sleep apnea (OSA) syndrome. Multilevel collapse at retropalatal and retroglossal areas is often found during the drug-induced sleep endoscopy (DISE). Therefore, multilevel surgery is considered for these patients. The aim of our study was to survey surgical outcomes by modified uvulopalatoplasty (UPPP) plus transoral robotic surgery tongue base reduction (TORSTBR) versus barbed repositioning pharyngoplasty (BRP) plus TORSTBR. METHODS: The retrospective cohort study was performed at a tertiary referral center. We collected moderate to severe OSA patients who were not tolerant to positive pressure assistant PAP from September 2016 to September 2019; pre-operative-operative Muller tests all showed retropalatal and retroglossal collapse; pre-operative Friedman Tongue Position (FTP) > III, with the tonsils grade at grade II minimum, with simultaneous velum (V > 1) and tongue base (T > 1), collapsed by drug-induced sleep endoscopy (DISE) under the VOTE grading system. The UPPP plus TORSTBR (n = 31) and BRP plus TORSTBR (n = 31) techniques were offered. We compare the outcomes using an Epworth sleepiness scale (ESS) questionnaire, and measure the patients' apnea-hypopnea index (AHI), lowest O2 saturation, cumulative time spent below 90% (CT90), and arousal index (AI) by polysomnography six months after surgery; we also measure their length of hospital stay and complications between these two groups. RESULTS: Comparing BRP plus TORSTBR with UPPP plus TORSTBR, the surgical success rate is 67.74% and 38.71%, respectively. The significantly higher surgical success rate in the BRP plus TORSTBR group was noted. The surgical time is shorter in the BRP plus TORSTBR group. The complication rate is not significant in pain, bleeding, dysgeusia, dysphagia, globus sensation, and prolonged suture stay, even though the BRP plus TORSTBR rendered a higher percentage of globus sensation during swallowing and a more prevalent requirement of suture removal one month after surgery. The length of hospital stay is not significantly different between the two groups. CONCLUSION: In conclusion, BRP plus TORSTBR is a considerable therapy for moderate to severe OSA patients with DISE showing a multi-level collapse in velum and tongue base area. The BRP technique might offer a better anterior-posterior suspension vector for palate level obstruction.
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BACKGROUND: Antrodia cinnamomea is an indigenous medicinal mushroom in Taiwan, commonly used for the treatment of cancers and inflammatory disorders. 4-acetylantroquinonol B (4AAQB) is one of the active component isolated from the mycelium of A. cinnamomea. However, whether 4AAQB exhibits anti-inflammatory effect is not clear. METHODS: The anti-inflammatory activity of 4AAQB was examined by ELISA to measure the pro-inflammatory cytokines production in lipopolysaccharide (LPS)-simulated RAW264.7 cells, peritoneal macrophages and in mice. The effect of 4AAQB for MAPK kinase molecules phosphorylation in LPS-stimulated RAW264.7 macrophage including ERK, JNK and p38 were evaluated. The in vivo efficacy of 4AAQB was also demonstrated. RESULTS: In the present study, we found that 4AAQB exhibits anti-inflammatory effects inhibit tumor necrosis factor-α (TNF-α)/interleukin-6 (IL-6) releasing and LPS-stimulated phagocytes migration without affect cell growth. In addition, the MAPK kinase molecules phosphorylation in LPS-stimulated RAW264.7 macrophage including ERK, JNK and p38 was inhibited by 4AAQB. The phosphorylation of NFκB subunit p65 and IkBα were also decreased after 4AAQB treatment. Furthermore, 4AAQB attenuates the cytokine production in LPS-induced and CLP-induced septic mice. CONCLUSION: These results showed that 4AAQB exhibited anti-inflammatory property both in vitro and in vivo, suggesting that 4AAQB may be a therapeutic candidate which used in inflammatory disorders treatment.
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4-Butirolactona/análogos & derivados , Ciclohexanonas/farmacología , Lipopolisacáridos/efectos adversos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Sepsis/metabolismo , 4-Butirolactona/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Células RAW 264.7RESUMEN
OBJECTIVE: Currently prescribed antiplatelet drugs have 1 common side effect-an increased risk of hemorrhage and thrombocytopenia. On the contrary, bleeding defects associated with glycoprotein VI (GPVI) expression deficiency are usually slightly prolonged bleeding times. However, GPVI antagonists are lacking in clinic. APPROACH AND RESULTS: Using reverse-phase high-performance liquid chromatography and sequencing, we revealed the partial sequence of trowaglerix α subunit, a potent specific GPVI-targeting snaclec (snake venom C-type lectin protein). Hexapeptide (Troα6 [trowaglerix a chain hexapeptide, CKWMNV]) and decapeptide (Troα10) derived from trowaglerix specifically inhibited collagen-induced platelet aggregation through blocking platelet GPVI receptor. Computational peptide design helped to design a series of Troα6/Troα10 peptides. Protein docking studies on these decapeptides and GPVI suggest that Troα10 was bound at the lower surface of D1 domain and outer surface of D2 domain, which was at the different place of the collagen-binding site and the scFv (single-chain variable fragment) D2-binding site. The newly discovered site was confirmed by inhibitory effects of polyclonal antibodies on collagen-induced platelet aggregation. This indicates that D2 domain of GPVI is a novel and important binding epitope on GPVI-mediated platelet aggregation. Troα6/Troα10 displayed prominent inhibitory effect of thrombus formation in fluorescein sodium-induced platelet thrombus formation of mesenteric venules and ferric chloride-induced carotid artery injury thrombosis model without prolonging the in vivo bleeding time. CONCLUSIONS: We develop a novel antithrombotic peptides derived from trowaglerix that acts through GPVI antagonism with greater safety-no severe bleeding. The binding epitope of polypeptides on GPVI is novel and important. These hexa/decapeptides have therapeutic potential for developing ideal small-mass GPVI antagonists for arterial thrombogenic diseases.
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Plaquetas/efectos de los fármacos , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Venenos de Crotálidos/farmacología , Fibrinolíticos/farmacología , Fragmentos de Péptidos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Trombosis/prevención & control , Animales , Sitios de Unión , Plaquetas/metabolismo , Traumatismos de las Arterias Carótidas/sangre , Traumatismos de las Arterias Carótidas/inducido químicamente , Cloruros , Diseño Asistido por Computadora , Venenos de Crotálidos/metabolismo , Venenos de Crotálidos/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Compuestos Férricos , Fibrinolíticos/metabolismo , Fibrinolíticos/toxicidad , Fluoresceína , Hemorragia/inducido químicamente , Humanos , Lectinas Tipo C/metabolismo , Masculino , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Inhibidores de Agregación Plaquetaria/metabolismo , Inhibidores de Agregación Plaquetaria/toxicidad , Glicoproteínas de Membrana Plaquetaria/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal/efectos de los fármacos , Trombosis/sangre , Trombosis/inducido químicamenteRESUMEN
VEGF and VEGFR antibodies have been used as a therapeutic strategy to inhibit angiogenesis in many diseases; however, frequent and repeated administration of these antibodies to patients induces immunogenicity. In previous studies, we demonstrated that aggretin, a heterodimeric snake venom C-type lectin, exhibits pro-angiogenic activities via integrin α2ß1 ligation. We hypothesised that small-mass aggretin fragments may bind integrin α2ß1 and act as antagonists of angiogenesis. In this study, the anti-angiogenic efficacy of a synthesised aggretin α-chain C-terminus (AACT, residue 106-136) was evaluated in both in vitro and in vivo angiogenesis models. The AACT demonstrated inhibitory effects on collagen-induced platelet aggregation and HUVEC adhesion to immobilised collagen. These results indicated that AACT may block integrin α2ß1-collagen interaction. AACT also inhibited HUVEC migration and tube formation. Aortic ring sprouting and Matrigel implant models demonstrated that AACT markedly inhibited VEGF-induced neovascularisation. In addition, induction of FAK/PI3K/ERK1/2 tyrosine phosphorylation and talin 1/2 associated with integrin ß1 which are induced by VEGF were blocked by AACT. Similarly, tyrosine phosphorylation of VEFGR2 and ERK1/2 induced by VEGF was diminished in integrin α2-silenced endothelial cells. Our results demonstrate that AACT is a potential therapeutic candidate for angiogenesis related-diseases via integrin α2ß1 blockade.
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Inhibidores de la Angiogénesis/farmacología , Integrina alfa2beta1/antagonistas & inhibidores , Péptidos/farmacología , Venenos de Serpiente/farmacología , Inhibidores de la Angiogénesis/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colágeno/metabolismo , Combinación de Medicamentos , Quinasa 1 de Adhesión Focal/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Laminina , Lectinas Tipo C , Neovascularización Fisiológica/efectos de los fármacos , Péptidos/química , Fosfatidilinositol 3-Quinasas/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Unión Proteica , Proteoglicanos , Transducción de Señal/efectos de los fármacos , Venenos de Serpiente/química , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Snake venoms affect blood coagulation and platelet function in a complex manner. However, two classes of venom proteins, snaclecs and disintegrins have been shown to specifically target receptors including GPIb, α2ß1, GPVI, CLEC-2 and integrins αIIbß3, αvß3, α5ß1 expressed on platelets, endothelial cells, phagocytes, tumor cells, thus affecting cell-matrices and cell-cell interactions. Here, we focus on disintegrins, a class of low molecular mass Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing, cysteine-rich polypeptide derived from various viper snake venoms. This review describes the potential applications of disintegrins in field of integrin-related diseases, especially arterial thrombosis, angiogenesis, tumor progression and septic inflammation. In addition, a novel RGD-containing disintegrin TMV-7 is being developed as a safer antithrombotic agent with minimal side effects, such as thrombocytopenia and bleeding.
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INTRODUCTION: The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. EXPERIMENTAL APPROACH: We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. RESULTS: Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2µg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06µg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. CONCLUSIONS: PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.
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Hemorragia/inducido químicamente , Péptidos/efectos adversos , Péptidos/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Trombosis/tratamiento farmacológico , Animales , Plaquetas/efectos de los fármacos , Desintegrinas/efectos adversos , Desintegrinas/química , Desintegrinas/farmacocinética , Desintegrinas/uso terapéutico , Estabilidad de Medicamentos , Semivida , Hemorragia/sangre , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Péptidos/química , Péptidos/farmacocinética , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Polietilenglicoles/química , Estabilidad Proteica , Trombosis/sangreRESUMEN
In addition to antiplatelet activity, disintegrin, a small-mass RGD-containing polypeptide, has been shown to exert anti-inflammatory effects but the mechanism involved remains unclear. In this study, we report that trimucrin, a disintegrin from the venom of Trimeresurus mucrosquamatus, inhibits lipopolysaccharide (LPS)-induced stimulation of THP-1 and RAW 264.7 cells. We also investigate the underlying mechanism. Trimucrin decreased the release of proinflammatory cytokines including tumor necrosis factor α (TNFα), interleukin-6 (IL-6), nitric oxide, and reactive oxygen species (ROS), and inhibited the adhesion and migration of LPS-activated phagocytes. Trimucrin significantly blocked the expression of nuclear factor kappaB (NF-κB)-related downstream inducible enzymes such as inducible nitric oxide synthase (iNOS) and COX-2. In addition, its anti-inflammatory effect was associated with the decreased mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, trimucrin concentration dependently inhibited LPS-induced phosphorylation of focal adhesion kinase (FAK), PI3K, and Akt. Trimucrin also reversed the DNA-binding activity of NF-κB by suppressing the LPS-induced nuclear translocation of p65 and the cytosolic IκB release. Flow cytometric analyses showed that trimucrin bound to cells in a concentration-dependent manner. The anti-αVß3 mAb also specifically decreased the binding of fluorescein isothiocyanate (FITC)-conjugated trimucrin. Binding assays demonstrated that integrin αVß3 was the binding site for trimucrin on THP-1 and RAW 264.7 cells. In conclusion, we showed that trimucrin decreases the inflammatory reaction through the attenuation of iNOS expression and nitric oxide (NO) production by blocking MAP kinase and the NF-κB activation in LPS-stimulated THP-1 and RAW 264.7 cells.
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Antiinflamatorios/farmacología , Venenos de Crotálidos/química , Desintegrinas/farmacología , Lipopolisacáridos/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Péptidos/farmacología , Fagocitos/efectos de los fármacos , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/metabolismo , Sitios de Unión , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Quimiotaxis/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Desintegrinas/aislamiento & purificación , Desintegrinas/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Humanos , Mediadores de Inflamación/metabolismo , Integrina alfaVbeta3/metabolismo , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Péptidos/aislamiento & purificación , Péptidos/metabolismo , Fagocitos/enzimología , Fosforilación , Unión Proteica , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
Bacterial infection-induced sepsis is the leading cause of septic inflammatory disease. Rhodostomin (Rn), a snake venom disintegrin, was previously reported to interact with the αVß3 integrin and the TLR4 on phagocyte in attenuating LPS-induced endotoxemia. In this report, we further evaluated the effects of Rn on TLR2-activated monocytes and its in vivo efficacy. Rn effectively suppressed the adhesion, migration, and cytokine release of Pam3CSK4-activated THP-1 cells. Rn specifically bound to integrin αVß3 of TLR2-activated THP-1. Integrin αV and Akt siRNA transfection both restrained Pam3CSK4-elicited cytokine release. Rn decreased the Pam3CSK4-induced phosporylation of MAPKs, degradation of IκB and activation of FAK, Akt, c-Src and Syk. The Pam3CSK4-induced translocation of MyD88, a central adaptor of TLR2, to the cell membrane was also inhibited by Rn treatment. In the polymicrobial inflammatory caecal ligation and puncture model, Rn significantly reduced pro-inflammatory cytokine and chemokine release, alleviated tissue injury and elevated survival rate in vivo. Taken together, in addition to inhibiting the activation of TLR4, Rn exhibits anti-inflammatory activity through antagonizing the activation of phagocytes and interrupting the crosstalk between αVß3 and TLR2-dependent signaling pathways.
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Integrina alfaVbeta3/metabolismo , Monocitos/efectos de los fármacos , Péptidos/administración & dosificación , Sepsis/tratamiento farmacológico , Receptor Toll-Like 2/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Monocitos/citología , Péptidos/farmacología , Sepsis/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Recent advances in microscale flow propulsion through bioinspired artificial cilia provide a promising alternative for lab-on-a-chip applications. However, the ability of actuating artificial cilia to achieve a time-dependent local flow control with high accuracy together with the elegance of full integration into the biocompatible microfluidic platforms remains remote. Driven by this motive, the current work has constructed a series of artificial cilia inside a microchannel to facilitate the time-dependent flow propulsion through artificial cilia actuation with high-speed (>40 Hz) circular beating behavior. The generated flow was quantified using micro-particle image velocimetry and particle tracking with instantaneous net flow velocity of up to 10(1 ) µm/s. Induced flow patterns caused by the tilted conical motion of artificial cilia constitutes efficient fluid propulsion at microscale. This flow phenomenon was further measured and illustrated by examining the induced flow behavior across the depth of the microchannel to provide a global view of the underlying flow propulsion mechanism. The presented analytic paradigms and substantial flow evidence present novel insights into the area of flow manipulation at microscale.
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Hepatocellular carcinoma (HCC) has become one of most common malignancies and a leading cause of cancer mortality worldwide. Previous study has shown that 4-acetylantroquinonol B (4AAQB) isolated from Antrodia cinnamomea (or niu-chang-chih) was observed to inhibit HepG2 cell proliferation via affecting cell cycle. However, the in vivo effects and antimetastatic activity of 4AAQB have not yet been addressed. This study found that 4AAQB inhibited HepG2 and HuH-7 hepatoma cell growth in both in vitro and in vivo models and exhibited pronounced inhibitory effects on HuH-7 tumor growth in xenograft and orthotopic models. 4AAQB efficiently inhibited the phosphorylation of mTOR and its upstream kinases and the downstream effectors and decreased the production of VEGF and activity of Rho GTPases in HuH-7 cells. Furthermore, 4AAQB inhibited in vitro HuH-7 cell migration and in vivo pulmonary metastasis. The results suggested that 4AAQB is a potential candidate for HCC therapy.
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4-Butirolactona/análogos & derivados , Antineoplásicos/administración & dosificación , Antrodia/química , Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Ciclohexanonas/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , 4-Butirolactona/administración & dosificación , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/fisiopatología , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/fisiopatología , Masculino , Huesos Metatarsianos , Ratones Desnudos , Ratones SCID , Fosforilación/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
The classifier system categorizes nouns on a semantic basis. By inserting an object-gap relative clause (RC) between a classifier and its associate noun, we examined how temporary classifier-noun semantic incongruity and long-distance classifier-noun dependency are processed. Instead of a typical N400 effect, a midline anterior negativity was elicited by the temporary semantic incongruity, suggesting that the anticipation of coming words influences semantic processing and that metacognitive processes are involved in resolving the conflict. The lack of reduced P600 effects at the RC marker suggests that classifier-noun mismatch may not be effective in RC prediction. The N400 observed at the head noun suggests that the parser retains the temporary incongruity in the memory and computes the classifier-noun semantic agreement over a long distance. In addition, both successful and unsuccessful long-distance integration elicited P600 effects, supporting the view that P600 indexes more than just syntactic processing. Detailed discussion and implications are provided.
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Pueblo Asiatico , Potenciales Evocados/fisiología , Lenguaje , Adolescente , Adulto , Análisis de Varianza , Comprensión , Electroencefalografía , Femenino , Humanos , Masculino , Semántica , Adulto JovenRESUMEN
Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47(phox) and p67(phox) to the cell membrane. Yuwen02f1 also reverses IκBα degradation and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes.
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Artritis Experimental/inducido químicamente , Endotoxemia/inducido químicamente , Furanos/farmacología , Lipoproteínas/toxicidad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Pirazoles/farmacología , Animales , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Endotoxemia/tratamiento farmacológico , Furanos/química , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Macrófagos , Masculino , Ratones , Ratones Endogámicos ICR , Proteínas Quinasas Activadas por Mitógenos/genética , Estructura Molecular , Monocitos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pirazoles/química , Especies Reactivas de OxígenoRESUMEN
The development of restenosis involves migration and hyperproliferation of vascular smooth muscle cells (VSMCs). Platelet-derived growth factor (PDGF) is one of the major factors. Butein modulates inflammatory pathways and affects the proliferation and invasion of the tumor. We investigated the hypothesis that butein might prevent the restenosis process via a similar pathway. Our results demonstrated that butein inhibited PDGF-induced VSMC proliferation and migration as determined by BrdU proliferation and two-dimensional migration scratch assay. Butein also concentration-dependently repressed PDGF-induced phosphorylation of PDGF-receptor ß, mitogen-activated protein kinases, phosphoinositide 3-kinase/Akt, and phopholipase Cγ/c-Src in VSMCs. In addition, in vivo results showed that butein attenuated neointima formation in balloon-injured rat carotid arteries. These results indicate that butein may inhibit PDGF-induced VSMC proliferation and migration, resulting in attenuation of neointima formation after percutaneous transluminal coronary angioplasty. Our study demonstrates for the first time that systemic administration of butein is able to reduce neointima formation after vascular injury.
Asunto(s)
Chalconas/farmacología , Reestenosis Coronaria/tratamiento farmacológico , Neointima/tratamiento farmacológico , Animales , Movimiento Celular , Proliferación Celular , Células Cultivadas , Reestenosis Coronaria/genética , Reestenosis Coronaria/metabolismo , Reestenosis Coronaria/fisiopatología , Humanos , Masculino , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Neointima/genética , Neointima/metabolismo , Neointima/fisiopatología , Fosforilación , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: 1,4-Naphthoquinones exhibit antiplatelet activity both in vivo and in vitro. In the present study, we investigated the antiplatelet effect of a novel naphthoquinone derivative NP-313, 2-acetylamino-3-chloro-1,4-naphthoquinone and its mechanism of action. EXPERIMENTAL APPROACH: We measured platelet aggregation, Ca(2+) mobilization, thromboxane B2 formation and P-selectin expression and examined several enzymatic activities. Furthermore, we used the irradiated mesenteric venules in fluorescein sodium-treated mice to monitor the antithrombotic effect of NP-313 in vivo. KEY RESULTS: NP-313 concentration-dependently inhibited human platelet aggregation induced by collagen, arachidonic acid, thapsigargin, thrombin and A23187. NP-313 also inhibited P-selectin expression, thromboxane B(2) formation and [Ca(2+) ](i) elevation in platelets stimulated by thrombin and collagen. NP-313 at 10 µM inhibited cyclooxygenase, thromboxane A(2) synthase, and protein kinase Cα, whereas it did not affect phospholipase A(2) or phospholipase C activity. In the presence of indomethacin and an adenosine 5-diphosphate scavenger, NP-313 concentration-dependently inhibited thrombin- and A23187-induced [Ca(2+)](i) increase through its inhibitory effects on Ca(2+) influx, rather than blocking Ca(2+) release from intracellular stores. NP-313 also inhibited thapsigargin-mediated Ca(2+) influx through store-operated calcium channel but had no effect on Ca(2+) influx through store-independent calcium channel evoked by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol. Nevertheless, it had little effect on cyclic AMP and cyclic GMP levels. Also, intravenously administered NP-313 dose-dependently inhibited the thrombus occlusion of the irradiated mesenteric vessels of fluorescein-pretreated mice. CONCLUSIONS AND IMPLICATIONS: Taken together, these results indicate that NP-313 exerts its antithrombotic activity through dual inhibition of thromboxane A(2) synthesis and Ca(2+) influx through SOCC.
Asunto(s)
Fibrinolíticos/farmacología , Naftoquinonas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Animales , Calcio/metabolismo , Canales de Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Fibrinolíticos/administración & dosificación , Masculino , Ratones , Ratones Endogámicos ICR , Naftoquinonas/administración & dosificación , Selectina-P/genética , Inhibidores de Agregación Plaquetaria/administración & dosificación , Tromboxano A2/biosíntesis , Tromboxano B2/biosíntesisRESUMEN
This study examines the effect of familiarity, context, and linguistic convention on idiom comprehension in Mandarin speaking children. Two experiments (a comprehension task followed by a comprehension task coupled with a metapragmatic task) were administered to test participants in three age groups (6 and 9-year-olds, and an adult control group). Laval (Journal of Pragmatics 35(2):723-739, 2003) showed that familiarity had an effect on idiom comprehension for French 9-year-olds. However, our finding showed that familiarity was important for 6-year-old Chinese children when a context was not given. Abkarian et al. (Journal of Speech and Hearing Research 35:580-587, 1992) claimed that context has little or no effect on comprehension for children under 6. Our results show that context has an effect on 6-year-old children's understanding of idioms in a different way. Overall, our major research findings are: (1) Familiarity first appeared in responses at age 6. (2) Context played an important role in idiom comprehension and had different effects on different age groups. (3) Linguistic convention starts from age 6 on, and a significant effect took place at the age of 9. (4) Metapragmatic knowledge showed at the age of 6 and could surface even younger. As context and linguistic convention have a substantial effect on the comprehension of idioms, it is necessary to take them into account to explain language functioning and communicative situations.