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The relationship between clinical outcomes and various factors influencing pregnancy was analyzed to provide reference data for patients and clinicians when selecting embryo transfer protocols. This was a retrospective study of 1309 transfer cycles between June 1, 2018, and May 1, 2023, in the Reproductive Medicine Center. Univariate analysis was performed on various factors that may have affected pregnancy outcomes, and further regression analysis was performed on those factors found by univariate analysis to correlate positively with clinical pregnancy outcomes. Finally, the embryo transfer schemes were compared based on the analysis results. The results showed that the stage of embryonic development significantly affected pregnancy outcomes after transplantation (Pâ <â .01, 95% confidence interval: 2.554 [1.958-3.332]). There was no significant difference in the pregnancy rate between 1 high-quality blastocyst transfer and 2 cleavage-stage embryos or blastocyst transfer (64.22% vs 70.11%, Pâ =â .439); however, the rate of multiple pregnancies after 1 high-quality blastocyst transfer was close to the rate of natural conception. These data show that the transfer of single high-quality blastocysts can significantly reduce the multiple pregnancy rate while ensuring an ideal pregnancy rate, which can be used as a reference for planning the first transplantation in patients with good prognoses.
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Transferencia de Embrión , Fertilización In Vitro , Resultado del Embarazo , Índice de Embarazo , Humanos , Femenino , Embarazo , Estudios Retrospectivos , Transferencia de Embrión/métodos , Transferencia de Embrión/estadística & datos numéricos , Adulto , Fertilización In Vitro/métodos , Criopreservación/métodos , Embarazo Múltiple/estadística & datos numéricosRESUMEN
Background: Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase inhibitor for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. However, drug resistance is commonly occurred after a long period of medication. This study aimed to investigate the characterization of induced resistance to CHI and explore the potential cross-resistance to chemotherapeutic agents. Methods: CHI with gradually increasing concentrations was added to breast cancer MCF7 cells to establish a CHI-resistant MCF7 (MCF7-CHI-R) cell line. Cell counting kit-8 (CCK-8) assays were performed to detect half-maximal inhibitory concentration (IC50) of CHI. Colony formation was used to determine the proliferation inhibition rate. Western blot analysis was conducted to detect expressions of protein related with cell cycle, apoptosis, ferroptosis, and histone deacetylase (HDAC). Flow cytometry was used to analyze apoptosis and cell cycle. Results: The IC50 value of CHI of MCF7-CHI-R cells was increased in comparison with MCF7 cells. And CHI led to cell cycle arrest and ferroptosis, which were not exhibited in MCF7-CHI-R cells. Moreover, HDAC activity decreased in MCF7-CHI-R cells in comparison with MCF7 cells, and HDAC1 and HDAC10 might be involved in the resistance to CHI. In addition, MCF7-CHI-R cells were resistant to gemcitabine (GEM), doxorubicin (ADM), docetaxel (DXT), albumin-bound paclitaxel (nab-PTX) and paclitaxel (PTX). Conclusions: The MCF7-CHI-R was established and the anti-ferroptosis pathway activation was involved in the resistance of MCF-CHI-R cells. Also, MCF7-CHI-R cells were resistant to GEM, ADM, DXT, nab-PTX and PTX.
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Background: Esophageal squamous cell carcinoma (ESCC) is a common pathological esophageal cancer with poor prognosis. Vitamin D deficiency reportedly occurs in ESCC patients, and this is related to single nucleotide polymorphism of vitamin D receptor (VDR). Objective: We investigated the effect of VDR on ESCC proliferation, invasion, and metastasis and its potential mechanism. Methods: ESCC and normal tissues were collected from 20 ESCC patients. The ESCC tissue microarray contained 116 pairs of ESCC and normal tissues and 73 single ESCC tissues. VDR expression and its clinicopathological role were determined by real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry staining. sh-VDR and VDR overexpression were used to validate the effect of VDR on ESCC cell phenotype, and tandem mass tag-based quantitative proteomics and bioinformatics methods identified differential VDR-related proteins. The downstream pathway and regulatory effect were analyzed using ingenuity pathway analysis (IPA). Differentially expressed proteins were verified through parallel reaction monitoring and Western blot. In vivo imaging visualized subcutaneous tumor growth following tail vein injection of VDR-deficient ESCC cells. Results: High VDR expression was observed in ESCC tissues and cells. Gender, T stage, and TNM stage were related to VDR expression, which was the independent prognostic factor related to ESCC. VDR downregulation repressed ESCC cell proliferation, invasion, and migration in vitro and subcutaneous tumor growth and lung metastases in vivo. The cell phenotype changes were reversed upon VDR upregulation, and differential proteins were mainly enriched in the p53 signaling pathway. TP53 cooperated with ABCG2, APOE, FTH1, GCLM, GPX1, HMOX1, JUN, PRDX5, and SOD2 and may activate apoptosis and inhibit oxidative stress, cell metastasis, and proliferation. TP53 was upregulated after VDR knockdown, and TP53 downregulation reversed VDR knockdown-induced cell phenotype changes. Conclusions: VDR may inhibit p53 signaling pathway activation and induce ESCC proliferation, invasion, and metastasis by activating oxidative stress.
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BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC), which has a complex pathogenesis and poor prognosis, is one of the most common malignancies worldwide. Hepatitis virus B infection is the most common cause of HCC in Asian patients. Autophagy is the process of digestion and degradation, and studies have shown that autophagy-associated effects are closely related to the development of HCC. In this study, we aimed to construct a prognostic model based on autophagy-related genes (ARGs) for the Asian HCC population to provide new ideas for the clinical management of HCC in the Asian population. METHODS: The clinical information and transcriptome data of Asian patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) database, and 206 ARGs were downloaded from the human autophagy database (HADB). We performed differential and Cox regression analyses to construct a risk score model. The accuracy of the model was validated by using the Kaplan-Meier (K-M) survival curve, receiver operating characteristic (ROC) curve, and univariate and multivariate Cox independent prognostic analyses. The results Thirteen ARGs that were significantly associated with prognosis were finally identified by univariate and multivariate Cox regression analyses. The K-M survival curves showed that the survival rate of the low-risk group was significantly higher than that of the high-risk group (p < 0.001), and the multi-indicator ROC curves further demonstrated the predictive ability of the model (AUC = 0.877). CONCLUSION: The risk score model based on ARGs was effective in predicting the prognosis of Asian patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Asiático , Autofagia/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , PronósticoRESUMEN
Luminescent N-heterocyclic carbene chloride copper (I) complexes incorporating pyrene chromophore (1-Pyrenyl-NHC-R)-Cu-Cl, (3, 4) have been prepared and fully characterized. Two complexes were prepared with R = methyl (3) and R = naphthyl groups (4) at the nitrogen center of the carbene unit to tune their electronic properties. The molecular structures of 3 and 4 have been elucidated by X-ray diffraction and confirm the formation of the target compounds. Preliminary results reveal that all compounds including the imidazole-pyrenyl ligand 1 are emissive in the blue region at room temperature in solution and in solid-state. All complexes display quantum yields comparable or higher when compared to the parent pyrene molecule. Interestingly replacement of the methyl by naphthyl group increases the quantum yield by almost two-folds. These compounds might show promise for applications as optical displays.
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OBJECTIVES: Non-small cell lung cancer (NSCLC) is a leading type of lung cancer with a high mortality rate worldwide. Although many procedures for the diagnosis and prognosis assessment of lung cancer exist, they are often laborious, expensive, and invasive. This study aimed to develop an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based analysis method for the plasma biomarkers of NSCLC with the potential to indicate the stages and progression of this malignancy conveniently and reliably. METHODS: A total of 53 patients with NSCLC in early stages (I-III) and advanced stage (IV) were classified into the early and advanced groups based on the tumor node metastasis staging system. A comprehensive metabolomic analysis of plasma from patients with NSCLC was performed via UPLC-MS/MS. Principal component analysis and partial least squares-discriminant analysis were conducted for statistical analysis. Potential biomarkers were evaluated and screened through receiver operating characteristic analyses and correlation analysis. Main differential metabolic pathways were also identified by utilizing metaboanalyst. RESULTS: A total of 129 differential metabolites were detected in accordance with the criteria of VIP ≥ 1 and a P-value of ≤ 0.05. The receiver operating characteristic curves indicated that 11 of these metabolites have the potential to be promising markers of disease progression. Apparent correlated metabolites were also filtered out. Furthermore, the 11 most predominant metabolic pathways with alterations involved in NSCLC were identified. CONCLUSION: Our study focused on the plasma metabolomic changes in patients with NSCLC. These changes may be used for the prediction of the stage and progression of NSCLC. Moreover, we discussed the metabolic pathways wherein the altered metabolites were mainly enriched.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/diagnóstico , Cromatografía Liquida , Espectrometría de Masas en Tándem , BiomarcadoresRESUMEN
The inefficient tumor penetration of therapeutic antibodies has hampered their effective use in treating solid tumors. Here, we report the identification of a fully human single-domain antibody (UdAb), designated as n501, targeting the oncofetal antigen 5T4. The high-resolution crystal structure indicates that n501 adopts a compact structure very similar to that of camelid nanobodies, and binds tightly to all eight leucine-rich repeats of 5T4. Furthermore, the UdAb n501 exhibits exceptionally high stability, with no apparent activity changes over 4 weeks of storage at various temperatures. Importantly, the UdAb-based antibody-drug conjugate (n501-SN38) showed much deeper tumor penetration, significantly higher tumor uptake, and faster accumulation at tumor sites than conventional IgG1-based antibody-drug conjugate (m603-SN38), resulting in improved tumor inhibition. These results highlight the potential of UdAb-based antibody-drug conjugates as a potential class of antitumor therapeutics with characteristics of high stability and strong tumor penetration for the effective treatment of solid tumors.
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Antineoplásicos , Inmunoconjugados , Anticuerpos de Dominio Único , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Anticuerpos de Dominio Único/farmacología , Anticuerpos de Dominio Único/uso terapéuticoRESUMEN
A series of chiral cyclometalated iridium complexes of the type [Ir(C^N)2(C^C:)], {(C^N) = ppy (2); dfppy (3)} featuring a naphthalimide N-heterocyclic carbene ligand (C^C:) = (Naphthalimide-NHC) are described and fully characterized. The racemic complexes rac-2 and rac-3 were resolved via chiral column chromatography techniques into their corresponding enantiopure species Δ-2, Λ-2, Δ-3, Λ-3 as confirmed by their CD curves. This unique class of molecules containing organic and inorganic chromophores might be used as a platform to probe the stereochemical effect on the photophysical properties. Vibrational circular dichroism (VCD) was used as an important tool to assign successfully the stereochemistry of the enantiomers. TD-DFT calculations are also advanced to support the experimental studies and to rationalize the observed results.
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The effective approaches to eliminate impacts of ethanol on the biodegradation of benzene, toluene, ethylbenzene, and xylene (BTEX) are concerned in the bioremediation of groundwater contaminated with ethanol-blended gasoline. In situ chemical oxidation (ISCO) is a common technique widely used for the remediation of contaminated groundwater. However, the selectivity of ISCO for BTEX and ethanol removal is poorly understood. Therefore, a batch experiment was performed with different aquifer materials, including calcareous soil, basalt soil, granite soil, dolomite, and sand. Gasoline was used to provide dissolved BTEX and ethanol reagent was used as additive to improve the quality of gasoline and to reduce the possibility of air pollution caused by gasoline. Persulfate (PS) was used as a chemical oxidant to oxidize organic contaminants. The target concentrations of BTEX and ethanol were 20 mg/L and 1000 mg/L, respectively. The results showed that ethanol could be preferentially degraded in the absence of PS and inhibit BTEX biodegradation. However, BTEX could be preferentially removed prior to ethanol in all aquifer materials used at ambient temperature, when PS was added at a PS/BTEX molar ratio of 150. Over 94% BTEX in sand, dolomite, and granite soil was preferentially removed with the first-order decay rate constants of 0.890-2.703 day-1 within the first ~ 10 days, followed by calcareous and basalt soil at the constants of 0.123-0.371 day-1. Ethanol could compete with BTEX for sulfate radical at the first-order decay rate constants of 0.005-0.060 day-1 for the first 25 days, which was slower than that of BTEX. The pH quickly decreased to < 2.5 in dolomite, sand, and granite soil, but maintained > 6.2 in calcareous soil. Rich organic matter in calcareous and basalt soil had an inhibition effect on BTEX oxidation by PS. The pH buffer in calcareous soil may imply the potential of PS oxidation combined with bioremediation in carbonate rock regions.
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Agua Subterránea , Xilenos , Benceno/metabolismo , Derivados del Benceno/metabolismo , Biodegradación Ambiental , Etanol/farmacología , Tolueno/metabolismo , Xilenos/metabolismoRESUMEN
In this study, Prussian blue@Carbon-dot (PB@C-dot) hybrids have been developed by one-step hydrothermal method. The incorporation of C-dots into Prussian blue thin film as a way of improving its electrochromic performance was investigated. The structure of the PB@C-dot hybrid was characterized through X-ray diffraction, Raman spectroscopy and scanning electron microscopy. The electrochromic properties showed that incorporation of 10 mL C-dots into the film showed higher optical contrast of 1.6 and superior coloration/bleaching response of 10 and 3 s. It is proposed that the C-dots component used in the construction of the PB@C-dot hybrid plays a key role to achieve superior electrochromic performance.
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Fluorination using chiral catalytic methods could result in a direct access to asymmetric fluorine chemistry. However, challenges in catalytic asymmetric fluorinations, especially the longstanding stereochemical challenges existed in BF3·Et2O-based fluorinations, have not yet been addressed. Here we report the catalytic asymmetric nucleophilic fluorination using BF3·Et2O as the fluorine reagent in the presence of chiral iodine catalyst. Various chiral fluorinated oxazine products were obtained with good to excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >20:1 dr). Control experiments (the desired fluoro-oxazines could not be obtained when Py·HF or Et3N·3HF were employed as the fluorine source) indicated that BF3·Et2O acted not only as a fluorine reagent but also as the activating reagent for activation of iodosylbenzene.
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Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intracellular selection method to generate covalent inhibitory antibody against human rhinovirus 14 (HRV14) 3C protease through unnatural amino acid mutagenesis along the heavy chain complementarity-determining region 3 (CDR-H3). A library of antibody mutants was thus constructed and screened in vivo through co-expression with the target protease. Using this screening strategy, six covalent antibodies with proximity-enabled bioactivity were identified, which were shown to covalently target HRV14-3C protease with high inhibitory potency and exquisite selectivity. Compared to structure-based rational design, this library-based screening method provides a simple and efficient way for the discovery and engineering of covalent antibody for enzyme inhibition.
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Proteasas Virales 3C/antagonistas & inhibidores , Anticuerpos/farmacología , Regiones Determinantes de Complementariedad/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Rhinovirus/enzimología , Proteasas Virales 3C/metabolismo , Anticuerpos/química , Inhibidores de Cisteína Proteinasa/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
An efficient nickel-catalyzed stereoselective asymmetric intramolecular reductive coupling of N-1,6-alkynones is reported. A P-chiral monophosphine ligand AntPhos was found to be a privileged catalyst for constructing versatile functionalized chiral pyrrolidine rings using triethylsilane as the reducing reagent. Concise synthesis of pyrrolidines with chiral tertiary allylic alcohols was achieved in high yields (99%), excellent stereoselectivity (>99:1 E/Z), and enantioselectivity (>99:1 er) with very broad substrate scope. Totally, thirty-five N-1,6-alkynones were synthesized and applied in this reaction successfully. This reaction can be scaled up to gram scale without loss of its enantioselectivity. Ligand effects and reaction mechanism are investigated in detail. While the developed asymmetric synthesis of pyrrolidine with chiral tertiary allylic alcohols is anticipated to find wider applications in organic synthesis and chemical biology, the discovered new reactions of N-1,6-alkynone with AntPhos using different catalyst systems would further expanded its new research fields and attract more detailed explorations in the future.
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Níquel , Catálisis , Ligandos , EstereoisomerismoRESUMEN
A palladium-catalyzed cross-coupling reaction with aryl halide functionalities has recently emerged as a valuable tool for protein modification. Herein, a new fluorogenic modification methodology for proteins, with genetically encoded fluorosulfate-l-tyrosine, which exhibits high efficiency and biocompatibility in bacterial cells as well as in aqueous medium, is described. Furthermore, the cross-coupling of 4-cyanophenylboronic acid on green fluorescent protein was shown to possess a unique fluorogenic property, which could open up the possibility of a responsive "off/on" switch with great potential to enable spectroscopic imaging of proteins with minimal background noise. Taken together, a convenient and efficient catalytic system has been developed that may provide broad utilities in protein visualization and live-cell imaging.
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Colorantes Fluorescentes , Proteínas Fluorescentes Verdes , Ácidos Borónicos/química , Catálisis , Colorantes Fluorescentes/química , Proteínas Fluorescentes Verdes/química , Paladio/química , Sulfatos/química , Agua/químicaRESUMEN
The combination of persulfate (PS) oxidation with enhanced bioremediation (EBR) is a potential trend in remediating organic-contaminated groundwater. However, the impacts of PS on EBR presented in the transition zone between PS oxidation zone and EBR zone need further study. To better characterize the impacts and provide available indicators, PS oxidation and EBR with nitrate amended were performed through the microcosm experiments to remove dissolved benzene, toluene, ethylbenzene and xylene (denoted as BTEX) in gasoline-saturated groundwater. The results indicated that PS oxidation combined with EBR almost completely removed BTEX with the ratio of > 93% over the experiments, which is better than PS oxidation (54-97%) but still worse than EBR (100%). The removal velocities of BTEX in EBR, PS oxidation, and PS oxidation combined with EBR were 0.94, 0.1-0.16, and 0.1-0.54 mg/L/d, respectively. High concentration of PS, along with high-strength activation, made the pH decrease to 3.3-4.4 and the Eh increase to 141-203 mV, thus greatly inhibited microbial activities as well. In such circumstances, oxygen and nitrate could not be significantly used as electron acceptors by microbials. To reduce the impacts of PS oxidation on EBR, the PS/BTEX molar ratio of < 6 and the PS/Fe2+ molar ratio of > 1 may be appropriate in transition zone. The hydro-chemical indicators, including pH, Eh, and availability of electron acceptors such as oxygen and nitrate, could reflect the impacts of PS oxidation on bioprocesses. During in-situ chemical oxidation (ISCO), PS injection and PS activation by Fe2+ should be managed for decreasing the impacts on EBR, based on the PS/BTEX and PS/Fe2+ molar ratios.
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Agua Subterránea , Contaminantes Químicos del Agua , Benceno , Derivados del Benceno , Biodegradación Ambiental , Gasolina , Sulfatos , Tolueno , XilenosAsunto(s)
Infecciones por Coronavirus/epidemiología , Brotes de Enfermedades/estadística & datos numéricos , Transmisión de Enfermedad Infecciosa/prevención & control , Endoscopía Gastrointestinal/métodos , Control de Infecciones/métodos , Neumonía Viral/epidemiología , Administración de la Seguridad/métodos , Betacoronavirus , COVID-19 , China , Infecciones por Coronavirus/prevención & control , Endoscopía Gastrointestinal/tendencias , Femenino , Humanos , Masculino , Salud Laboral , Pandemias/prevención & control , Seguridad del Paciente , Neumonía Viral/prevención & control , Medición de Riesgo , SARS-CoV-2 , Grabación en VideoRESUMEN
An anti-EGFR nanobody was labeled at the C-terminus with a lysosome-sorting NPGY (Asn-Pro-Gly-Tyr) motif via sortase-mediated ligation to enhance the engagement of the clathrin-mediated endocytosis. The synergistic effects of NPGY motif and nona-arginine peptide were found to induce robust internalization and lysosomal trafficking, which in turn improved anti-tumor activity of an antibody-drug conjugate.
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Anticuerpos/química , Antineoplásicos/química , Inmunoconjugados/química , Lisosomas/metabolismo , Péptidos/química , Secuencia de Aminoácidos , Anticuerpos/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Clatrina/metabolismo , Endocitosis/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Inmunoconjugados/farmacología , Conformación Molecular , Terapia Molecular Dirigida , Imagen Óptica , Péptidos/metabolismo , Unión Proteica , Transporte de Proteínas/efectos de los fármacosRESUMEN
Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[γ-butyrolactone-pyrrolidin-4,4'-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons α-imino γ-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.
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Lactonas/química , Pirazolonas/química , Cristalografía por Rayos X , Reacción de Cicloadición , EstereoisomerismoRESUMEN
Artemisia capillaris (A. capillaris) is a common herbal drug used for thousands years in ancient China. A. capillaris has been empirically used to manage hand-foot-mouth disease (HFMD), which is commonly caused by enterovirus 71 (EV71). EV71 can cause meningoencephalitis with mortality and neurologic sequelae without effective management. It is presently unknown whether A. capillaris is effective against EV71 infection. To test the hypothesis that it could protect cells from EV71-induced injury, a hot water extract of A. capillaris was tested in human foreskin fibroblast cells (CCFS-1/KMC) and human rhabdomyosarcoma cells (RD cells) by plaque reduction assay and flow cytometry. Inhibition of viral replication was examined by reverse quantitative RT-PCR (qRT-PCR). Its effect on translations of viral proteins (VP0, VP1, VP2, protease 2B and 3AB), and apoptotic proteins were examined by western blot. A. capillaris was dose-dependently effective against EV71 infection in both CCFS-1/KMC cells and RD cells by inhibiting viral internalization. However, A. capillaris was minimally effective on viral attachment, VP2 translation, and inhibition of virus-induced apoptosis. Further isolation of effective molecules is needed. In conclusion, A. capillaris has anti-EV71 activity mainly by inhibiting viral internalization. A. capillaris would be better to manage EV71 infection in combination with other agents.