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Cistanche deserticola is a precious Chinese medicinal material with extremely high health care and medicinal value. In recent years, the frequent occurrence of stem rot has led to reduced or even no harvests of C. deserticola. The unstandardized use of farm chemicals in the prevention and control processes has resulted in excessive chemical residues, threatening the fragile desert ecological environment. Therefore, it is urgent to explore safe and efficient prevention and control technologies. Biocontrol agents, with the advantages of safety and environment-friendliness, would be an important idea. The isolation, screening and identification of pathogens and antagonistic endophytic bacteria are always the primary basis. In this study, three novel pathogens causing C. deserticola stem rot were isolated, identified and pathogenicity tested, namely Fusarium solani CPF1, F. proliferatum CPF2, and F. oxysporum CPF3. For the first time, the endophytic bacteria in C. deserticola were isolated and identified, of which 37 strains were obtained. Through dual culture assay, evaluation experiment and tissue culture verification, a biocontrol candidate strain Bacillus atrophaeus CE6 with outstanding control effect on the stem rot was screened out. In the tissue culture system, CE6 showed excellent control effect against F. solani and F. oxysporum, with the control efficacies reaching 97.2% and 95.8%, respectively, indicating its great potential for application in the production. This study is of great significance for the biocontrol of plant stem rot and improvement of the yield and quality of C. deserticola.
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Cistanche , Bacterias/genética , Ambiente , Granjas , Tallos de la PlantaRESUMEN
Infrared ship target detection is crucial technology in marine scenarios. Ship targets vary in scale throughout navigation because the distance between the ship and the infrared camera is constantly changing. Furthermore, complex backgrounds, such as sea clutter, can cause significant interference during detection tasks. In this paper, multiscale morphological reconstruction-based saliency mapping, combined with a two-branch compensation strategy (MMRSM-TBC) algorithm, is proposed for the detection of ship targets of various sizes and against complex backgrounds. First, a multiscale morphological reconstruction method is proposed to enhance the ship targets in the infrared image and suppress any irrelevant background. Then, by introducing a structure tensor with two feature-based filter templates, we utilize the contour information of the ship targets and further improve their intensities in the saliency map. After that, a two-branch compensation strategy is proposed, due to the uneven distribution of image grayscale. Finally, the target is extracted using an adaptive threshold. The experimental results fully show that our proposed algorithm achieves strong performance in the detection of different-sized ship targets and has a higher accuracy than other existing methods.
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The XELOX chemotherapy protocol that includes capecitabine and oxaliplatin is the routine treatment for colorectal cancer (CRC), but it can cause chemotherapy-related adverse events such as thrombocytopenia (TCP). To identify predictive biomarkers and clarify the mechanism of TCP susceptibility, we conducted integrative analysis using normal colorectal tissue (CRT), plasma, and urine samples collected before CRC patients received adjuvant XELOX chemotherapy. RNA-sequencing and DNA methylation arrays were performed on CRT samples, while liquid chromatography-mass spectrometry was performed on CRT, plasma, and urine samples. Differentially expressed features (DEFs) from each uni-omics analysis were then subjected to integrative analysis using Multi-Omics Factor Analysis (MOFA). Choline-deficiency in plasma and CRT was found as the most critical TCP-related feature. Based on bioinformatic analysis and literature research, we further concluded that choline-deficiency was the possible reason for most of the other TCP-related multi-omics DEFs, including metabolites representing reduced sphingolipid de novo synthesis and elevated solute carrier-mediated transmembrane transportation in CRT and plasma, DNA hypermethylation and elevated expression of genes involved in neuronal system genes. In terms of thrombocytopoiesis, these TCP-related DEFs may cause atypical maintenance and differentiation of megakaryocyte, resulting a suppressed ability of thrombocytopoiesis, making patients more susceptible to chemotherapy-induced TCP. At last, prediction models were developed and validated with reasonably good discrimination. The area under curves (AUCs) of training sets were all > 0.9, while validation sets had AUCs between 0.778 and 0.926. In conclusion, our results produced reliable marker systems for predicting TCP and promising target for developing precision treatment to prevent TCP.
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Antineoplásicos , Deficiencia de Colina , Neoplasias Colorrectales , Leucopenia , Trombocitopenia , Antineoplásicos/efectos adversos , Colina , Deficiencia de Colina/inducido químicamente , Deficiencia de Colina/tratamiento farmacológico , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo/uso terapéutico , Humanos , Leucopenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
Low-light image enhancement can effectively assist high-level vision tasks that often fail in poor illumination conditions. Most previous data-driven methods, however, implemented enhancement directly from severely degraded low-light images that may provide undesirable enhancement results, including blurred detail, intensive noise, and distorted color. In this paper, inspired by a coarse-to-fine strategy, we propose an end-to-end image-level alignment with pixel-wise perceptual information enhancement pipeline for low-light image enhancement. A coarse adaptive global photometric alignment sub-network is constructed to reduce style differences, which facilitates improving illumination and revealing under-exposure area information. After the learned aligned image, a hierarchy pyramid enhancement sub-network is used to optimize image quality, which helps to remove amplified noise and enhance the local detail of low-light images. We also propose a multi-residual cascade attention block (MRCAB) that involves channel split and concatenation strategy, polarized self-attention mechanism, which leads to high-resolution reconstruction images in perceptual quality. Extensive experiments have demonstrated the effectiveness of our method on various datasets and significantly outperformed other state-of-the-art methods in detail and color reproduction.
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Systematic regulation of hydrophilic regions plays a key role in optimizing the heterogeneous hydrophilic-hydrophobic surface for promoting condensate transfer ability (CTA) under subcooling or high-humidity conditions. In this work, we develop an operable method to fabricate wettability-controllable coatings by regulating the mass ratio of superamphiphobic and superamphiphilic powder (MRP). By investigating the synergic relationship between CTA and MRP, we display an interesting competition between condensation and detachment of condensates. The initial dewing rate associated with reflecting phase change heat transfer capacity could be continuously strengthened by promoting MRP, while the detachment capacity with respect to improving the long-term condensing rate can be limited by the excessive superamphiphilic microregions. Based on this, we have optimized the threshold of MRP for promoting the condensation heat transfer ability and the water harvesting efficiency with the values of 10:0-8:2 and 10:0-4:6, respectively. This work provides important guidance in designing and optimizing heterogeneous hydrophilic-hydrophobic surfaces for multiple industrial applications including heat management, water harvesting, and desalination.
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Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)-one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.
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Resistencia a Antineoplásicos/genética , Sustancias Intercalantes/administración & dosificación , Leucemia Promielocítica Aguda/tratamiento farmacológico , Fenantridinas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Trióxido de Arsénico/administración & dosificación , Trióxido de Arsénico/química , Caspasas/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Sustancias Intercalantes/química , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Ratones , Simulación del Acoplamiento Molecular , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Fenantridinas/química , Proteína de la Leucemia Promielocítica/genética , Proteolisis/efectos de los fármacos , Receptor alfa de Ácido Retinoico/genética , Tretinoina/administración & dosificación , Tretinoina/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To investigate pepsinogen secretion from the neonatal stage to childhood and its diagnostic value for peptic ulcer (PU) in children. METHODS: In this study, 2114 'healthy' children and 51 children with PUs undergoing a medical examination by gastroscopy were selected as subjects. The serum content of pepsinogen I (PGI) and serum pepsinogen II (PGII) was tested for each of the subjects using time-resolved fluorescence immunoassay, which is characterised by high sensitivity and a wide measuring range. RESULTS: The serum PGI and PGII levels were found to increase with age, becoming stable and similar to those of adults at the age of 16. In 51 children with PUs, PGI was 201.03 ± 30.74 ng/mL before treatment and 187.92 ± 19.86 ng/mL after treatment (P > 0.05); PGII was 17.36 ± 1.47 ng/mL before treatment and 17.20 ± 3.98 ng/mL after treatment (P > 0.05). CONCLUSIONS: It is difficult to establish the normal range of PG in children owing to its variance by age. However, if the normal reference range for individual age groups is known, it may still serve as a useful diagnosis system as well as a detecting indicator during the course of PU treatment. There are significant differences in PGI expression in children with PU before and after PU is cured, whereas other indicators show no differences before and after treatment.
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Biomarcadores , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Úlcera Péptica/tratamiento farmacológico , Adolescente , Niño , Preescolar , Humanos , Lactante , Resultado del Tratamiento , Adulto JovenRESUMEN
Pulmonary torsion is a rare but serious condition. Without prompt treatment it progresses to lobar ischaemia, pulmonary infarction and finally fatal gangrene. We present a case of this rare complication in a 61-year-old woman following thoracic operation without involving any lung resection. Careful post-operative clinical observation, chest X-ray and CT scans are crucial for precise diagnosis of lobar torsion. The bedside radiograph provided initial evidence of torsion. Computed tomography scans revealed the presumptive diagnosis of right upper lobe torsion. On exploration, a 70° rotation of the right upper lobe in a clockwise direction was found. The lobar torsion was carefully relieved, and lobar fixation was performed as a prophylaxis against recurrence of this complication. The post-operative period was uneventful. Early recognition and prompt intervention is imperative in order to save the affected lung. Patients with well-developed interlobar fissures may benefit from pulmonary lobe fixation.
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Enfermedades Pulmonares , Pulmón/diagnóstico por imagen , Complicaciones Posoperatorias/diagnóstico por imagen , Toracotomía/efectos adversos , Anomalía Torsional , Femenino , Humanos , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/etiología , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Anomalía Torsional/diagnóstico por imagen , Anomalía Torsional/etiologíaRESUMEN
Asperchalasineâ A (1), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasinesâ B-D (2-4), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single-crystal X-ray diffraction techniques. Compound 1, which possesses an unprecedented 13-oxatetracyclo[7.2.1.1(2,5).0(1,6)]tridec-8,12-dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1-4 were described starting from the co-isolated compounds 5 and 6. More importantly, 1 induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells.
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Aspergillus/química , Citocalasinas/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular , Citocalasinas/química , Citocalasinas/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Efficient purification of gamma-cyclodextrin (γ-CD) is always challenging due to its structural similarity to other CDs and low crystallinity in water. In addressing this issue, an approach was proposed based on the formation mechanism of cyclodextrin metal-organic frameworks (CD-MOFs). This method involved the selective coordination of CDs mixture with potassium ions in water, facilitated by ethanol-induced crystallization, leading to the purification of γ-CD. The results showed that potassium ions enhanced γ-CD crystallization, and ethanol was crucial to selectively coordinating potassium ions with γ-CD. The characterizations revealed that the resulting CD-MOFs exhibited a small particle size, high surface area, and high thermal stability, and was identical to γ-CD-MOF, further indicating the final γ-CD with high purity. The separation factors of γ-CD/α-CD and γ-CD/ß-CD were 309 and 260, respectively. Moreover, this method was validated through its application to the industrial enzymatic CDs mixture. The purification of γ-CD could achieve 99.99 ± 0.01 % after four crystallization cycles. Therefore, selectively coordinating with potassium ions to form MOFs provided a valuable reference for the purification of γ-CD and even the direct synthesis of γ-CD-MOF from CDs mixture. This advancement will also benefit the future production and application of γ-CD.
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Investigation into the chemical diversity of Solanum lyratum led to the discovery of one new sesquiterpenoid, solyraterpenoid A (1), and two known compounds (2 and 3). The structure incorporating absolute configuration of 1 was determined via spectroscopic data, mainly including HRESIMS and NMR, and single-crystal X-ray diffraction analysis. Compound 1 showed significant antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae with MIC values of 8, 8, and 4 µg/mL, respectively.
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Sesquiterpenos , Solanum , Solanum/química , Estructura Molecular , Sesquiterpenos/farmacología , Sesquiterpenos/química , Antibacterianos/farmacología , Antibacterianos/química , Pseudomonas aeruginosaRESUMEN
Colorectal cancer (CRC) is becoming increasingly prevalent worldwide. Fluoropyrimidine drugs are the primary chemotherapy regimens in routine clinical practice of CRC. However, the survival rate of patients on fluoropyrimidine-based chemotherapy varies significantly among individuals. Biomarkers of fluoropyrimidine drugs'' efficacy are needed to implement personalized medicine. This review summarized fluoropyrimidine drug-related microRNA (miRNA) by affecting metabolic enzymes or showing the relevance of drug efficacy. We first outlined 42 miRNAs that may affect the metabolism of fluoropyrimidine drugs. Subsequently, we filtered another 41 miRNAs related to the efficacy of fluoropyrimidine drugs based on clinical trials. Bioinformatics analysis showed that most well-established miRNA biomarkers were significantly enriched in the cancer pathways instead of the fluoropyrimidine drug metabolism pathways. The result also suggests that the miRNAs screened from metastasis patients have a more critical role in cancer development than those from non-metastasis patients. There are five miRNAs shared between these two lists. The miR-21, miR-215, and miR-218 can suppress fluoropyrimidine drugs'' catabolism. The miR-326 and miR-328 can reduce the efflux of fluoropyrimidine drugs. These five miRNAs could jointly act by increasing intracellular levels of fluoropyrimidine drugs'' cytotoxic metabolites, leading to better chemotherapy responses. In conclusion, we demonstrated that the dynamic changes in the transcriptional regulation via miRNAs might play significant roles in the efficacy and toxicity of the fluoropyrimidine drug. The reported miRNA biomarkers would help evaluate the efficacy of fluoropyrimidine drug-based chemotherapy and improve the prognosis of colorectal cancer patients.
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Antineoplásicos , Neoplasias Colorrectales , MicroARNs , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , PronósticoRESUMEN
BACKGROUND: Chemotherapy-induced adverse effects (CIAEs) remain a challenging problem due to their high incidences and negative impacts on treatment in Chinese colorectal cancer (CRC) patients. We aimed to identify risk factors and predictive markers for CIAEs using food/nutrition data in CRC patients receiving post-operative capecitabine-based chemotherapy. METHODS: Food/nutrition data from 130 Chinese CRC patients were analyzed. Univariate and multivariate analyses were used to identify CIAE-related food/nutrition factors. Prediction models were constructed based on the combination of these factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the discrimination ability of models. RESULTS: A total of 20 food/nutrition factors associated with CIAEs were identified in the univariate analysis after adjustments for total energy and potential confounding factors. Based on multivariate analysis, we found that, among these factors, dessert, eggs, poultry, and milk were associated with several CIAEs. Most importantly, poultry was an overall protective factor; milk and egg were risk factors for hand-foot syndrome (HFS) and bone marrow suppression (BMS), respectively. Developed multivariate models in predicting grade 1 to 3 CIAEs and grade 2/3 CIAEs both had good discrimination (AUROC values from 0.671 to 0.778, 0.750 to 0.946 respectively), which had potential clinical application value in the early prediction of CIAEs, especially for more severe CIAEs. CONCLUSIONS: Our findings suggest that patients with high milk and egg intakes should be clinically instructed to control their corresponding dietary intake to reduce the likelihood of developing HFS and BMS during capecitabine-based chemotherapy, respectively. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03030508.
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Antimetabolitos Antineoplásicos , Capecitabina , Neoplasias Colorrectales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Animales , Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina/efectos adversos , China/epidemiología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Huevos , Fluorouracilo/efectos adversos , Síndrome Mano-Pie/tratamiento farmacológico , Síndrome Mano-Pie/etiología , Humanos , Leche , Factores de RiesgoRESUMEN
BACKGROUND: Currently, although Inula nervosa Wall is substantially investigated, little is understood about blossoms of Inula nervosa Wall (BINW). OBJECTIVE: In this work, we systematically investigated the antioxidant activity of the extract from BINW by various standard assays including 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical ability, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) di-ammonium salt radical cation (ABTS), and ferric reducing antioxidant potential (FRAP). METHODS: Chemical compounds were tentatively identified through an UHPLC-QTOF-MS system. Furthermore, the contents of nine compounds were detected with UHPLC method coupled with photodiode array (PDA) detector. By carefully analyzing the quantitative data via clusters analysis and principal component analysis (PCA). RESULTS: Forty-six compounds were tentatively identified, and our results showed that nine compound samples in 21 batches of BINW collected from different areas could be differentiated and analyzed by a heatmap visualization. In addition, the contents of nine compounds (flavonoids, phenolic acids) exhibited a total of higher amounts and better antioxidant activities from Yunnan than those from the other three origins. CONCLUSIONS: Our study not only developed a powerful platform to explain the difference between traditional Chinese medicines species that are closely related through the chemometric and chemical profiling, but also presented a useful method to establish quality criteria of BINW with multiple origins. HIGHLIGHTS: To characterize the BINW in detail, we not only performed DPPH, FRAP, and ABTS assays to investigate its antioxidant activity, but also established UHPLC-QTOF-MS/MS- and UHPLC-PDA-based methods to comprehensively identify and qualitatively analyze its components.
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Inula , Antioxidantes , China , Flores , Extractos Vegetales , Espectrometría de Masas en TándemRESUMEN
Hand-foot syndrome (HFS) is a common capecitabine-based chemotherapy-related adverse event (CRAE) in patients with colorectal cancer (CRC). It is of great significance to comprehensively identify susceptible factors for HFS, and further to elucidate the biomolecular mechanism of HFS susceptibility. We performed an untargeted multi-omics analysis integrating DNA methylation, transcriptome, and metabolome data of 63 Chinese CRC patients who had complete CRAE records during capecitabine-based chemotherapy. We found that the metabolome changes for each of matched plasma, urine, and normal colorectal tissue (CRT) in relation to HFS were characterized by chronic tissue damage, which was indicated by reduced nucleotide salvage, elevated spermine level, and increased production of endogenous cytotoxic metabolites. HFS-related transcriptome changes of CRT showed an overall suppressed inflammation profile but increased M2 macrophage polarization. HFS-related DNA methylation of CRT presented gene-specific hypermethylation on genes mainly for collagen formation. The hypermethylation was accumulated in the opensea and shore regions, which elicited a positive effect on gene expression. Additionally, we developed and validated models combining relevant biomarkers showing reasonably good discrimination performance with the area under the receiver operating characteristic curve values from 0.833 to 0.955. Our results demonstrated that the multi-omics variations associated with a profibrotic phenotype were closely related to HFS susceptibility. HFS-related biomolecular variations in CRT contributed more to the relevant biomolecular mechanism of HFS than in plasma and urine. Spermine-related DNA hypermethylation and elevated expression of genes for collagen formation were closely associated with HFS susceptibility. These findings provided new insights into the susceptible factors for chemotherapy-induced HFS, which can promote the implementation of individualized treatment against HFS.
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The article "Three new ent-abietane diterpenoids from the roots of Euphorbia fischeriana and their cytotoxicity in human tumor cell lines", written by Minghui Li, Fang He, Yuan Zhou, Meigui Wang, Pingde Tao, Qingmei Tu, Guanghui Lv, Xintao Chen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17 April 2019 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 4 September 2020 to © The Pharmaceutical Society of Korea 2020 and the article is forthwith distributed under the terms of copyright. The original article has been corrected.
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Three new ent-abietane diterpenoids, termed fischerianoids A-C (1-3), were isolated and identified from the ethyl acetate extracts of roots of the medicinally valuable plant Euphorbia fischeriana. The planar and relative structures of 1-3 were established via high-resolution electrospray ionisation mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopic analyses, and the absolute configuration of 1 was further established via X-ray crystallography experiment. Compounds 1-3 showed selective inhibitory potency against certain human tumor cell lines with IC50 values ranging from 8.50 ± 0.13 to 35.52 ± 0.08 µM.
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Abietanos/farmacología , Antineoplásicos Fitogénicos/farmacología , Euphorbia/química , Abietanos/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Raíces de Plantas/químicaRESUMEN
Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum ß-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 µg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1-8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1-8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens.
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Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Hongos/química , Pironas/farmacología , Sitios de Unión , Cromonas/química , Cromonas/aislamiento & purificación , Cromonas/farmacología , Enoil-ACP Reductasa (NADH)/química , Enoil-ACP Reductasa (NADH)/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Acido Graso Sintasa Tipo II/química , Acido Graso Sintasa Tipo II/metabolismo , Hongos/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Pseudomonas aeruginosa/efectos de los fármacos , Pironas/química , Pironas/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacosRESUMEN
Two new phenone derivatives penicophenones A (1) and B (2), a new cyclic tetrapeptide penicopeptide A (3), and five known compounds were isolated from the culture broth of Penicillium commune, an endophytic fungus derived from Vitis vinifera. Compounds 1-3 were elucidated by extensive spectroscopic analyses including 1D and 2D NMR and HRESIMS. The absolute configurations of 1 and 3 were determined by comparing its ECD with related molecules and modified Marfey's analysis, respectively. Penicophenone A (1) possesses a rare benzannulated 6,6-spiroketal moiety, which is a new member of the unusual structural class with peniphenone A as the representative. Compound 3 exhibited significant inhibition activities against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in vitro and showed strong binding affinity to 11ß-HSD1. Moreover, compound 3 treatments decreased the lipid droplet accumulation associate with the inhibition of 11ß-HSD1 expression in differentiate-induced 3T3-L1 preadipocytes. Furthermore, the molecular docking demonstrated that compound 3 coordinated in the active site of 11ß-HSD1 is essential for the ability of diminishing the enzyme activity.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteínas Fúngicas/farmacología , Oligopéptidos/farmacología , Penicillium/crecimiento & desarrollo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Células 3T3-L1 , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Dominio Catalítico/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Proteínas Fúngicas/química , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Oligopéptidos/química , Penicillium/metabolismo , Vitis/microbiologíaRESUMEN
Helicobacter pyloriinitiated chronic gastritis is characterized by the cytotoxinassociated gene (Cag) pathogenicity islanddependent upregulation of proinflammatory cytokines in gastric epithelial cells, which is largely mediated by the activation of nuclear factor (NF)κB as a transcription factor. However, the precise regulation of NFκB activation, particularly posttranslational modifications in the CagAinduced inflammatory response, has remained elusive. The present study showed that Helicobacter pylori CagA, an important virulence factor, induced the expression of P300/CBPassociated factor (PCAF) in gastric epithelial cells. Further study revealed that PCAF was able to physically associate with the NFκB p65 subunit and enhance its acetylation. More importantly, PCAFinduced p65 acetylation was shown to contribute to p65 phosphorylation and further upregulation of tumor necrosis factor (TNF)α and interleukin (IL)6 in gastric adenocarcinoma cells. In conclusion, the results of the present study indicated that Helicobacter pylori CagA enhanced TNFα and IL6 in gastric adenocarcinoma cells through PCAFmediated NFκB p65 subunit acetylation.