12 research outputs found
Structural basis for the specialization of Nur, a nickel-specific Fur homolog, in metal sensing and DNA recognition
Get PDFNur, a member of the Fur family, is a nickel-responsive transcription factor that controls nickel homeostasis and anti-oxidative response in Streptomyces coelicolor. Here we report the 2.4-Å resolution crystal structure of Nur. It contains a unique nickel-specific metal site in addition to a nonspecific common metal site. The identification of the 6-5-6 motif of the Nur recognition box and a Nur/DNA complex model reveals that Nur mainly interacts with terminal bases of the palindrome on complex formation. This contrasts with more distributed contacts between Fur and the n-1-n type of the Fur-binding motif. The disparity between Nur and Fur in the conformation of the S1-S2 sheet in the DNA-binding domain can explain their different DNA-recognition patterns. Furthermore, the fact that the specificity of Nur in metal sensing and DNA recognition is conferred by the specific metal site suggests that its introduction drives the evolution of Nur orthologs in the Fur family
Air quality evaluation of London Paddington train station
Get PDFEnclosed railway stations hosting diesel trains are at risk of reduced air quality as a result of exhaust emissions that may endanger passengers and workers. Air quality measurements were conducted inside London Paddington Station, a semi-enclosed railway station where 70% of trains are powered by diesel engines. Particulate matter (PM2.5) mass was measured at five station locations. PM size, PM number, oxides of nitrogen (NOx), and sulfur dioxide (SO2) were measured at two station locations. Paddington Station’s hourly mean PM2.5 mass concentrations averaged 16 μg/m3 [min 2, max 68]. Paddington Station’s hourly mean NO2 concentrations averaged 73 ppb [49, 120] and SO2 concentrations averaged 25 ppb [15, 37]. While UK train stations are not required to comply with air quality standards, there were five instances where the hourly mean NO2 concentrations exceeded the EU hourly mean limits (106 ppb) for outdoor air quality. PM2.5, SO2, and NO2 concentrations were compared against Marylebone, a busy London roadside 1.5 km from the station. The comparisons indicated that train station air quality was more polluted than the nearby roadside. PM2.5 for at least one measurement location within Paddington Station was shown to be statistically higher (P-value < 0.05) than Marylebone on 3 out of 4 days. Measured NO2 within Paddington Station was statistically higher than Marylebone on 4 out of 5 days. Measured SO2 within Paddington Station was statistically higher than Marylebone on all 3 days.We thank the Engineering and Physical Sciences Research Council (EP/F034350/1) for funding the Energy Efficient Cities Initiative and the Schiff Foundation for doctoral studentship funding.This is the final version of the article. It first appeared from IOP via http://dx.doi.org/10.1088/1748-9326/10/9/09401
DPP-IV Inhibitory Potentials of Flavonol Glycosides Isolated from the Seeds of Lens culinaris: In Vitro and Molecular Docking Analyses
No full textDipeptidyl peptidase IV (DPP-IV), a new target for the treatment of type 2 diabetes mellitus, degrades incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide. DPP-IV inhibitors shorten the inactivation of GLP-1, permitting the incretin to stimulate insulin release, thereby combating hyperglycemia. In our ongoing search for new DPP-IV inhibitors from medicinal plants and foods, three flavonol glycosides (1–3) were isolated from the seeds of Lens culinaris Medikus (Fabaceae) and tested for their DPP-IV–inhibitory activity. We demonstrated for the first time, that compounds 1–3 inhibited DPP-IV activity in a concentration-dependent manner in our in vitro bioassay system. In addition, molecular docking experiments of compounds 1–3 within the binding pocket of DPP-IV were conducted. All investigated compounds readily fit within the active sites of DPP-IV, in low-energy conformations characterized by the flavone core structure having optimal electrostatic attractive interactions with the catalytic triad residues of DPP-IV
CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling
No full textGiven the proven importance of the CXCL12/CXCR4 axis in the stroma–acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 inhibitor, induced apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-β signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-β in stromal cells or TGF-β-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-β signaling
Phytochemical Composition and Antioxidant Activities of Two Different Color Chrysanthemum Flower Teas
No full textChrysanthemum morifolium Ramat is a perennial flowering plant widely cultivated for use in a tea infusion and as a popular beverage. To identify and evaluate the tea infusion made with a γ-irradiated mutant chrysanthemum cultivar with dark purple petals (cv. ARTI-Dark Chocolate), its phytochemical composition and antioxidant activity were tested and compared with those of the commercially available chrysanthemum cultivar with yellow petals (cv. Gamguk) by HPLC-DAD-ESIMS, as well as DPPH and ABTS radical scavenging assays. The purple chrysanthemum tea contained anthocyanins and linarin, which were not detected in the yellow chrysanthemum tea and the content of chlorogenic acid, acacetin-7-O-β-glucoside, and luteolin was higher compared with the yellow chrysanthemum tea. In contrast, the yellow chrysanthemum tea had higher luteolin-7-O-β-glucoside, 3,5-dicaffeoylquinic acid, apigenin-7-O-β-glucoside, and apigenin contents in comparison with the purple chrysanthemum tea. In addition, the content and antioxidant activity of the two chrysanthemum teas were investigated according to different water temperatures and infusing time. The yellow chrysanthemum tea did not show any significant differences according to infusing time and temperature, while the purple chrysanthemum tea was more influenced by the infusing time than water temperature, showing the highest total compound content in the infusing condition of 100 °C and 4 min. Moreover, the floral scent volatiles of the two chrysanthemum tea sources were analyzed using HS-SPME-GC-MS. In the DPPH radical scavenging assay, the purple chrysanthemum tea broadly showed greater antioxidant activity than did the yellow chrysanthemum tea, corresponding to the high content of anthocyanins known as the powerful antioxidant. Further, both chrysanthemum flower teas exhibited strong ABTS radical scavenging effects ranging from 76% to 61% under all infusing conditions. Therefore, the purple chrysanthemum cultivar, ARTI-Dark Chocolate, is worthy of breeding as a new tea cultivar
Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease
No full textThe motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation
Composition and Antioxidant Activities of Volatile Organic Compounds in Radiation-Bred Coreopsis Cultivars
No full textCoreopsis is a flowering plant belonging to the Asteraceae family. It is an ornamental plant native to the Americas, Asia and Oceania and its flower is used as a raw material for tea and food manufacture in China. In this study, new cultivars of C. rosea (“golden ring”) were developed via radiation-induced mutation of the original cultivar, “pumpkin pie”. The chemical composition and antioxidant activities of flowers belonging to three different Coreopsis cultivars were evaluated: “golden ring”, “pumpkin pie” and “snow chrysanthemum” (coreopsis tea; C. tinctoria). The volatile compounds were characterized via gas chromatography-mass spectrometry (GC-MS) and 50–59 oils representing 95.3–96.8% of the total volatile compounds in these flower materials were identified. ”Golden ring” contained a high amount of fatty acids (38.13%), while “pumpkin pie” and “snow chrysanthemum” teas were rich in aliphatic amides (43.01%) and esters (67.22%), respectively. The antioxidant activities of the volatile oils of these cultivars were evaluated using 1,1-diphenyl-2-picrylhydraxyl (DPPH) and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays. The volatile extract of “golden ring” showed higher antioxidant activities compared with the extracts of the other cultivars. Therefore, “golden ring” can be used for further development as a raw material for tea manufacture or as a dietary supplement
Comparison of Flavonoid Profiles in Sprouts of Radiation Breeding Wheat Lines (Triticum aestivum L.)
No full textWheat (Triticum aestivum Linn.; Poaceae), one of the most popular food crops worldwide, contains basic and essential nutrients and various health benefiting phytochemicals. Among them, flavonoids have attracted significant interest owing to their various health-promoting properties. In this study, 35 wheat mutant lines were developed via gamma-irradiated mutation breeding from the original cultivar. The effects of radiation breeding on the endogenous phytochemical production in the sprouts of these mutant lines were investigated using high performance liquid chromatography-diode array detector-electrospray ionization mass spectrometry (HPLC-DAD-ESIMS) with multivariate analysis for the first time in this study. Fourteen characteristic peaks, including eleven flavone C-glycosides, two flavone O-glycosides, and one flavone, were identified. In addition, the contents of three flavone C-glycosides, namely, isoschaftoside, isoorientin, and isoscoparin, in 37 wheat sprout samples from the original cultivar, certificated cultivar, and the mutant lines were determined. A heat map combined with hierarchical clustering showed variation in the relative content for the flavonoids between the 37 wheat sprout samples, clustering into three groups. On principal component analysis scores scatter and loading plots, significant differences in the levels of flavonoids were found between the samples and several markers responsible for group separation were detected. These results provide a scientific reference for the phytochemical variation in wheat mutant lines, thereby aiding in further mutation mechanism studies and for the quality control of the improved wheat cultivars
Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease
No full textComparative Analysis of Coumarin Profiles in Different Parts of Peucedanum japonicum and Their Aldo–Keto Reductase Inhibitory Activities
No full textPeucedanum japonicum (Umbelliferae) is widely distributed throughout Southeast Asian countries. The root of this plant is used in traditional medicine to treat colds and pain, whereas the young leaves are considered an edible vegetable. In this study, the differences in coumarin profiles for different parts of P. japonicum including the flowers, roots, leaves, and stems were compared using ultra-performance liquid chromatography time-of-flight mass spectrometry. Twenty-eight compounds were tentatively identified, including three compounds found in the genus Peucedanum for the first time. Principal component analysis using the data set of the measured mass values and intensities of the compounds exhibited distinct clustering of the flower, leaf, stem, and root samples. In addition, their anticancer activities were screened using an Aldo–keto reductase (AKR)1C1 assay on A549 human non-small-cell lung cancer cells and the flower extract inhibited AKR1C1 activity. Based on these results, seven compounds were selected as potential markers to distinguish between the flower part versus the root, stem, and leaf parts using an orthogonal partial least-squares discriminant analysis. This study is the first to provide information on the comparison of coumarin profiles from different parts of P. japonicum as well as their AKR1C1 inhibitory activities. Taken together, the flowers of P. japonicum offer a new use related to the efficacy of overcoming anticancer drug resistance, and may be a promising source for the isolation of active lead compounds
