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Migraine is a neurological disorder characterized by severe headaches, visual aversions, auditory, and olfactory disorders, accompanied by nausea and vomiting. Zolmitriptan (ZMT®) is a potent 5HT1B/1D serotonin receptor agonist frequently used for the treatment of migraine. It has erratic absorption from the gastrointestinal tract (GIT), but its oral bioavailability is low (40-45%) due to the hepatic metabolism. This makes it an ideal candidate for oral fast dissolving formulations. Hence, the current study was undertaken to design and develop oral fast-dissolving films (OFDFs) containing ZMT for migraine treatment. The OFDFs were formulated by the solvent casting method (SCM) using Pullulan (PU) and maltodextrin (MDX) as film-forming agents and propylene glycol (PG) as a plasticizer. The strategy was designed using Box-Behnken experimental design considering the proportion of PU:MDX and percentage of PG as independent variables. The effectiveness of the OFDF's was measured based on the following responses: drug release at five min, disintegration time (D-time), and tensile strength (TS). The influence of formulation factors, including percent elongation (%E), thickness, water content, moisture absorption, and folding endurance on ZMT-OFDFs, were also studied. The results showed a successful fabrication of stable ZMT-OFDFs, with surface uniformity and amorphous shape of ZMT in fabricated films. The optimized formulation showed a remarkable rapid dissolution, over 90% within the first 5 min, a fast D-time of 18 s, and excellent mechanical characteristics. Improved maximum plasma concentration (C max) and area under the curve (AUC 0-t) in animals (rats) treated with ZMT-OFDFs compared to those treated with an intra-gastric (i-g) suspension of ZMT were also observed. Copolymer OFDFs with ZMT is an exciting proposition with great potential for the treatment of migraine headache. This study offers a promising strategy for developing ZMT-OFDFs using SCM. ZMT-OFDFs showed remarkable rapid dissolution and fast D-time, which might endeavor ZMT-OFDFs as an auspicious alternative approach to improve patient compliance and shorten the onset time of ZMT in migraine treatment.

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Multiple high-performance liquid chromatographic (HPLC) approaches have been briefly defined for the assessment of zolmitriptan (ZMT). These methods are either cumbersome or require a plentiful volume of organic solvents, thus offering extortionate procedures. The objective of this study was to establish and validate a new rapid, eco- friendly and cost-effective HPLC method for the analysis of ZMT. The calibration curve for ZMT was established using simulated salivary fluid (SSF) and rat plasma for in-vitro and in-vivo analysis, respectively. Chromatogram separation was performed using a CST column (250mm × 4.6mm, 5µm) as a stationary phase and maintained at a temperature of 40°C. The methods were authenticated for linearity, system suitability, accuracy, precision, reproducibility, limit of detection (LOD) and limit of quantification (LOQ). The results of the validation variables and stability studies indicated that the methods were established in accordance with the guidelines of ICH and the USFDA. The established technique was time-saving, precise, eco- friendly and economical compared with the reported technique. In addition, the developed method was sufficiently repeatable for in vitro and in vivo analysis of ZMT.

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Oxazolidinonas , Ratas , Animales , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Límite de Detección

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The pathogenesis of COVID-19 emerges as complex, with multiple factors leading to injury of different organs. Several studies on underlying cellular processes have produced contradictory claims, e.g. on SARS-CoV-2 cell entry or innate immune responses. However, clarity in these matters is imperative for therapy development. We therefore performed a meta-study with a diverse set of transcriptomes under infections with SARS-CoV-2, SARS-CoV and MERS-CoV, including data from different cells and COVID-19 patients. Using these data, we investigated viral entry routes and innate immune responses. First, our analyses support the existence of cell entry mechanisms for SARS and SARS-CoV-2 other than the ACE2 route with evidence of inefficient infection of cells without expression of ACE2; expression of TMPRSS2/TPMRSS4 is unnecessary for efficient SARS-CoV-2 infection with evidence of efficient infection of A549 cells transduced with a vector expressing human ACE2. Second, we find that innate immune responses in terms of interferons and interferon simulated genes are strong in relevant cells, for example Calu3 cells, but vary markedly with cell type, virus dose, and virus type.

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Objective · To demonstrate the effect of TRIM59 on gliomagenesis and the molecular mechanism.Methods · TRIM59 protein expression in glioma specimens was analyzed by immunohistochemical staining,and in several glioma cell lines by Western blotting and quantative PCR.After TRIM59 was knocked down by shRNAs,cell proliferation,migration,colony formation,and orthotopic xenograft brain tumor development were detected.The signaling pathway of TRIM59 in gliomas was also explored by RNA-Seq and KEGG PATHWAY analyses.Results· The levels of TRIM59 protein expression in clinical glioma specimens were positively correlated with glioma malignancy.TRIM59 was highly expressed in LN229 and U87 glioma cells compared with normal human astrocytes.Knockdown of TRIM59 in these two cell lines with lentivirus-mediated shRNAs inhibited their proliferation,migration,and colony formation.Compared with the control xenograft models,knockdown of TRIM59 significantly inhibited glioma tumor growth.RNASeq and KEGG PATHWAY analyses identified that TRIM59 knockdown down-regulated 306 genes,among which PI3K/AKT signal pathway-related genes were the most.Moreover,TRIM59 knockdown suppressed AKT phosphorylation,whereas overexpression of a constitutively actived AKT (Myr-AKT)rescued TRIM59 knockdown-inhibited cell proliferation.Conclusion· TRIM59 is a new glioma oncogene,which may take effect through activating PI3K/AKT signaling pathway.

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BACKGROUND: Chemoresistance remains a significant challenge in chronic myelogenous leukemia (CML) management, which is one of the most critical prognostic factors. Elucidation the molecular mechanisms underlying the resistance to chemoresistance may lead to better clinical outcomes. RESULTS: In order to identify potential protein targets involved in the drug-resistant phenotype of leukemia, especially the chronic myelogenous leukemia (CML), we used a high-resolution "ultra-zoom" 2DE-based proteomics approach to characterize global protein expression patterns in doxorubicin-resistant myelogenous leukemia cells compared with parental control cells. Ultra-high resolution of 2DE was achieved by using a series of slightly overlapping narrow-range IPG strips during isoelectric focusing (IEF) separation. A total number of 44 proteins with altered abundances were detected and identified by MALDI-TOF or LC-MS/MS. Among these proteins, enolase, aldolase, HSP70 and sorcin were up-regulated in doxorubicin-resistant myelogenous leukemia cell line, whereas HSP27 was down-regulated. Some of the results have been validated by Western blotting. Both enolase and aldolase were first reported to be involved in chemoresistance, suggesting that process of glycolysis in doxorubicin-resistant myelogenous leukemia cells was accelerated to some extent to provide more energy to survive chemical stress. Possible roles of most of the identified proteins in development of chemoresistance in myelogenous leukemia cells were fully discussed. The results presented here could provide clues to further study for elucidating the mechanisms underlying drug resistance in leukemia. CONCLUSIONS: As a whole, under the chemical stress, the doxorubicin-resistant myelogenous leukemia cells may employ various protective strategies to survive. These include: (i) pumping the cytotoxic drug out of the cells by P-glycoprotein, (ii) increased storage of fermentable fuel, (iii) sophisticated cellular protection by molecular chaperones, (iv) improved handling of intracellular calcium, (v) increased glucose utilization via increased rates of glycolysis. In the present study, proteomic analysis of leukemia cells and their drug resistant variants revealed multiple alterations in protein expression. Our results indicate that the development of drug resistance in doxorubicin-resistant myelogenous leukemia cells is a complex phenomenon undergoing several mechanisms.

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To study the effects of surfactants on wettability of excipients, the contact angles of six types of surfactants on the surface of two common excipients and mixture of three surfactants with excipients were measured using hypsometry method. The results demonstrated that contact angle of water on the surface of excipients was associated with hydrophilcity of excipients. Contact angle was lowered with increase in hydrophilic groups of excipient molecules. The sequence of contact angle from small to large was starch < sodium benzoate < polyvinylpyrrolidone < sodium carboxymethylcellulose < sodium alginate < chitosan < hydroxypropyl methyl cellulose

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Objective To study the distribution characteristics of radon progeny at different air quality index (AQI) and evaluate health risks for the exposed population.Methods EQF3120 Monitor was used to monitor the concentration of radon and its daughters.The relevant air quality data was provided by the environmental monitoring station at Suzhou Industrial Park.SPSS 16.0 software was used for statistical description,principal component analysis and simple correlation analysis.Environmental radon exposure-caused effective dose to lung region was estimated by using the radon dose formulas.Results Radon progeny in fog haze weather in winter of Suzhou Industrial Park had relationships with NO2,SO2,O3,PM10 and PM2.5.The correlation coefficient of 214Bi were 0.741,0.681,-0.431,0.597 and 0.675.The correlation coefficient of radon progeny with PM2.5 was greater than that with PM10.When AQI ＞ 200,the effective dose to residents outdoor from radon and its short-lived progeny was 0.63 mSv/a.Conclusions Higher AQI results in higher concentration of attached radon progeny.There is little variation in concentration of unattached radon progeny.Fog and haze can increase exposure of the population to inhalated radon.

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CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146(EC-KO)) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146(EC-KO) mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) of CD146(EC-KO) mice. Mechanistic studies further confirmed that VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-κB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146(EC-KO) mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.

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Animales , Femenino , Masculino , Ratones , Antígeno CD146 , Genética , Metabolismo , Células Cultivadas , Células Endoteliales , Biología Celular , Metabolismo , Fibrosarcoma , Metabolismo , Patología , Melanoma Experimental , Metabolismo , Patología , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B , Metabolismo , Neovascularización Fisiológica , Fosforilación , Proteínas Proto-Oncogénicas c-akt , Metabolismo , Vena Retiniana , Patología , Transducción de Señal , Trasplante Homólogo , Factor A de Crecimiento Endotelial Vascular , Farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Metabolismo

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FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na(+)/K(+)-ATPase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma (HCC) and enhances the migration and proliferation of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na(+)/K(+)-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

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Animales , Femenino , Humanos , Anticuerpos Monoclonales , Farmacología , Antineoplásicos , Farmacología , Carcinoma Hepatocelular , Quimioterapia , Metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Células HEK293 , Canales Iónicos , Metabolismo , Neoplasias Hepáticas , Quimioterapia , Metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , ATPasa Intercambiadora de Sodio-Potasio , Metabolismo , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto

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Objective To study the chemical constituents of Epimedium sutchuenense.Methods The compounds were repeatedly separated and purified on column chromatography of silica gel,polyamide,Sephadex LH-20,and ODS.The structures were identified on the basis of spectral methods.Results Ten compounds were isolated from 70% ethanol extract of E.sutchuenense and were identified as sutchuenoside A(Ⅰ),sutchuenoside B(Ⅱ),daidzein(Ⅲ),baohuoside-Ⅰ(Ⅳ),kaempferide 3-rhamnoside(Ⅴ),icariin(Ⅵ),anhydroicaritin-3-O-?-L-rhamnopyranosyl(1→2)-?-L-rhamnopyranoside(Ⅶ),p-hydroxybenzoic acid(Ⅷ),daucosterol(Ⅸ),and ?-sitosterol(Ⅹ),respectively.Conclusion Compounds Ⅰ and Ⅱ are novel ones named as sutchuentins A and B respectively.Compounds Ⅲ,Ⅴ,Ⅶ,and Ⅷ-Ⅹ are isolated from this plant for the first time.

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Objective To investigate the effect of the peptide APP17 on regulating the expression of Bcl\|2,Bax,cAMP response element binding Protein(CREB),Ser\|Thr kinase B/protein kinase B(Akt/PKB),apoptosis inducing factor(AIF) in neurons of the hippocampus from the D\|gal mouse. Methods D\|gal mouse models were established by injection of D\|gal.In experimental group,these models were injected with APP17 petide subcutaneously and their brain sections were taken after 3 months of survival.The immunohistochemical staining of these sections was then performed with Bcl\|2,Bax,CREB,Akt,AIF antibody. Results Bax,AIF positive neurons were widely distributed in the hippocampus of the D\|gal mice,and the cytoplasm was darkly stained.In contrast,positive cells in the hippocampus were poorly stained in those normal mice and the APP17 peptide\|treated D\|gal mice.But Bcl\|2,CREB,AKt positive neurons were widely distributed in the hippocampus of those normal mice and the APP17 peptide\|treated D\|gal mice,and the cytoplasm was darkly stained.In contrast,positive cells in the hippocampaus were poorly stained in the D\|gal mice.Conclusion\ The expression of Bax and AIF could be increased in the hippocampus of D\|gal mice.But the expression of Bcl\|2,CREB,AKt decreased in the hippocampus of D\|gal mice.The APP17 can regulate the distribution of Bcl\|2,Bax,CREB,Akt,AIF in the brain of D\|gal mice and return them to normal situation.\;[