Urbanization affects the microclimate and forms a unique urban climate environment. To deepen the understanding on the microclimate regulation function of an urban wetland, this study analyzed the influence of a suburb wetland's urbanization process on the local climate through contrast observations of the protected wetland area and the former wetland area in Xixi wetland. Results show that the urbanization of suburb wetlands has an impact on the local microclimate and decreases human comfort, and that wetlands can effectively regulate the microclimate. The fragmentation of urban wetlands caused by urban sprawl decreases their microclimate regulation function, a decrease that is particularly evident in summer. Additionally, wetlands stabilize the microclimate in all seasons. For every land cover type in wetlands, vegetation has a better stabilizing effect on temperature, whereas a water body has a better stabilizing effect on wind speed and humidity. Meteorological conditions also affect the microclimate regulation function of wetlands. Temperature, humidity, atmospheric pressure, and wind speed influence the cooling function of urban wetlands, while solar radiation modifies the humidifying function of urban wetlands.
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Κυριακή 4 Σεπτεμβρίου 2016
Sustainability, Vol. 8, Pages 885: Effect of the Urbanization of Wetlands on Microclimate: A Case Study of Xixi Wetland, Hangzhou, China
Nanomaterials, Vol. 6, Pages 162: The Effect of Viscous Air Damping on an Optically Actuated Multilayer MoS2 Nanomechanical Resonator Using Fabry-Perot Interference
We demonstrated a multilayer molybdenum disulfide (MoS2) nanomechanical resonator by using optical Fabry-Perot (F-P) interferometric excitation and detection. The thin circular MoS2 nanomembrane with an approximate 8-nm thickness was transferred onto the endface of a ferrule with an inner diameter of 125 μm, which created a low finesse F-P interferometer with a cavity length of 39.92 μm. The effects of temperature and viscous air damping on resonance behavior of the resonator were investigated in the range of −10–80 °C. Along with the optomechanical behavior of the resonator in air, the measured resonance frequencies ranged from 36 kHz to 73 kHz with an extremely low inflection point at 20 °C, which conformed reasonably to those solved by previously obtained thermal expansion coefficients of MoS2. Further, a maximum quality (Q) factor of 1.35 for the resonator was observed at 0 °C due to viscous dissipation, in relation to the lower Knudsen number of 0.0025~0.0034 in the tested temperature range. Moreover, measurements of Q factor revealed little dependence of Q on resonance frequency and temperature. These measurements shed light on the mechanisms behind viscous air damping in MoS2, graphene, and other 2D resonators.
http://ift.tt/2clPZIN
Effects of response delays and of unknown stimulus-response mappings on the oddball effect on P3
Abstract
P3b is a prominent component of human event-related EEG potentials. P3b has been related to consciousness, encoding into memory, and updating of strategic schemata, among others, yet evidence has also been provided for its close relationship with deciding how to respond to the presented stimuli. P3b is large with rarely occurring stimuli and small with frequent ones. Here, we investigate the extent to which this oddball effect depends on selecting and executing responses. Participants pressed one of two keys in response to one of two letters, one of which was presented rarely and one frequently. Information about letter-key mapping was provided by a second stimulus. In different blocks, this mapping stimulus was either constant across trials or varied randomly, and either preceded or followed the letter. The oddball effect was reduced when responses were delayed (by waiting for the constant mapping stimulus following the letter) and was further reduced when responses could not be assigned to the letters (because letters were followed by varying mapping stimuli). This evidence suggests that P3b is closely related to decision processes, possibly reflecting reactivation of stimulus-response links.
http://ift.tt/2bQUBsl
Child cortisol moderates the association between family routines and emotion regulation in low-income children
Abstract
Biological and social influences both shape emotion regulation. In 380 low-income children, we tested whether biological stress profile (cortisol) moderated the association among positive and negative home environment factors (routines; chaos) and emotion regulation (negative lability; positive regulation). Children (M age = 50.6, SD = 6.4 months) provided saliva samples to assess diurnal cortisol parameters across 3 days. Parents reported on home environment and child emotion regulation. Structural equation modeling was used to test whether cortisol parameters moderated associations between home environment and child emotion regulation. Results showed that home chaos was negatively associated with emotion regulation outcomes; cortisol did not moderate the association. Child cortisol level moderated the routines-emotion regulation association such that lack of routine was most strongly associated with poor emotion regulation among children with lower cortisol output. Findings suggest that underlying child stress biology may shape response to environmental influences.
http://ift.tt/2cAymcK
Identification of embryo-fetal cells in celomic fluid using morphological and short-tandem repeats analysis
Abstract
Objective
The main problem to wide acceptability of celocentesis as earlier prenatal diagnosis is contamination of the sample by maternal cells. The objective of this study was to investigate the cellular composition of celomic fluid for morphological discrimination between maternal and embryo-fetal cells.
Method
Celomic fluids were aspired by ultrasound-guided transcervical celocentesis at 7-9 weeks' gestation from singleton pregnancies before surgical termination for psychological reasons. DNA was extracted from celomic fluid cells showed the same morphology and quantitative fluorescentPCR assay was performed to evaluate their fetal or maternal origin.
Results
Six different types of non-hematological maternal and four different types of embryo-fetal cells were detected. The most common maternal cells were of epithelial origin. The majority of embryo-fetal cells were roundish with a nucleus located in an eccentric position near the wall. These cells were considered to be erythroblasts, probably derived from the yolk sac that serves as the initial site of erythropoiesis.
Conclusions
The combined use of morphology and DNA analysis make it possible to select and isolate embryo-fetal cells, even when maternal contamination is high. This development provides the opportunity for the use of celocentesis for early prenatal diagnosis of genetic diseases and application of array-CGH. This article is protected by copyright. All rights reserved.
http://ift.tt/2c0Zc8L
Discontinuities in arid zone rock art: Graphic indicators for changing social complexity across space and through time
Publication date: Available online 3 September 2016
Source:Journal of Anthropological Archaeology
Author(s): Jo McDonald
For several decades it been argued that episodic behavioral dynamism provides a better explanation for Australian arid zone social organization than earlier models founded on perceptions of long term, widespread cultural conservatism. This new understanding continues to develop with the consideration of rock art as a behavioral proxy. The development of a rock art style sequence in the Australian Western Desert has modelled for changing occupation indices and art production modes through time based on environmental changes and their likely effects on mobility patterns and territoriality (McDonald and Veth, 2013a). This model which sees rock art accompanying the first peopling of Australia's deserts and stands in stark contrast to that of Smith (2013) which sees rock art as a mid-Holocene addition to the adaptive social repertoires of arid-zone peoples. We have argued that rock art provides evidence for an early mapping onto arid landscapes and that there is a long, albeit syncopated, arid zone style chronology. Early pigment rock art dates from Sulawesi (Aubert el al., 2014) support the view that symbolic behaviour was part of the social repertoire of human groups colonizing Australia and its interior. This paper tests the arid-zone style sequence by quantifying the synchronic and diachronic stylistic discontinuities observable at Kaalpi and Katjarra – two style provinces in the Australian Western Desert. While stylistic variability in the recent past demonstrates the nature of synchronic discontinuity in arid zone symbolic behaviour, punctuated changes in style graphics and changes in the way that this art has been placed through time demonstrate deep-time stylistic discontinuities, providing support for the phased art sequence and evidence for earlier configurations of arid-zone social networks.
Graphical abstract
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Assaying Predatory Feeding Behaviors in Pristionchus and Other Nematodes
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Potentiodynamic Corrosion Testing
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A Push-pull Protocol to Reduce Colonization of Bird Nest Boxes by Honey Bees
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Data on combination effect of PEG-coated gold nanoparticles and non-thermal plasma inhibit growth of solid tumors
Publication date: Available online 4 September 2016
Source:Data in Brief
Author(s): Nagendra Kumar Kaushik, Neha Kaushik, Ki Chun Yoo, Nizam Uddin, Ju Sung Kim, Su Jae Lee, Eun Ha Choi
Highly resistant tumor cells are hard to treat at low doses of plasma. Therefore, researchers have gained more attention to development of enhancers for plasma therapy. Some enhancers could improve the efficacy of plasma towards selectivity of cancer cells damage. In this dataset, we report the application of low doses of PEG-coated gold nanoparticles with addition of plasma treatment. This data consists of the effect of PEG-coated GNP and cold plasma on two solid tumor cell lines T98G glioblastoma and A549 lung adenocarcinoma. Cell proliferation, frequency of cancer stem cell population studies by this co-treatment was reported. Finally, we included in this dataset the effect of co-treatment in vivo, using tumor xenograft nude mice models. The data supplied in this article supports the accompanying publication "Low doses of PEG-coated gold nanoparticles sensitize solid tumors to cold plasma by blocking the PI3K/AKT-driven signaling axis to suppress cellular transformation by inhibiting growth and EMT" [1].
http://ift.tt/2bPIuvE
Time Perspective and Well-Being: Swedish Survey Questionnaires and Data
Publication date: Available online 4 September 2016
Source:Data in Brief
Author(s): Danilo Garcia, Ali Al Nima, Erik Lindskär
The data pertains 448 Swedes' responses to questionnaires on time perspective (Zimbardo Time Perspective Inventory), temporal life satisfaction (Temporal Satisfaction with Life Scale), affect (Positive Affect and Negative Affect Schedule), and psychological well-being (Ryff's Scales of Psychological Well-Being—short version). The data was collected among university students and individuals at a training facility (see [1]). Since there were no differences in any of the other background variables, but exercise frequency, all subsequent analyses were conducted on the 448 participants as one single sample. In this article we include the Swedish versions of the questionnaires used to operationalize the time perspective and well-being variables. The data is available, SPSS file, as supplementary material in this article. We used the Expectation-Maximization Algorithm to input missing values. Little's Chi-Square test for Missing Completely at Random showed a χ2=67.25 (df=53, p=.09) for men and χ2=77.65 (df=72, p=.31) for women. These values suggested that the Expectation-Maximization Algorithm was suitable to use on this data for missing data imputation.
http://ift.tt/2bWNBrb
Morphological and optical data of AgNW embedded transparent conductive layer
Publication date: Available online 4 September 2016
Source:Data in Brief
Author(s): Hong-Sik Kim, Dipal B. Patel, Malkeshkumar Patel, Joondong Kim
In this data article, morphological and optical data of AgNW encapsulated between ITO layers are presented to get insights into our article (DOI:10.1016/j.solmat.2016.04.038) [1]. SEM images for the formation of AgNWs networks by number of spin coating are also presented. SEM photographs showing the surface morphologies before and after rapid thermal treatment of prepared samples have been presented. Apart from morphological data set, optical characteristics of this type of samples are given. The comparison plots of optical reflectance from AgNW encapsulated between ITO layers and bare ITO are given between the wavelength ranges from 300 to 1100nm. At the end, transmittance and reflectance curves of native glass substrates used in this study are presented.
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Application of Traditional Chinese Medical Herbs in Prevention and Treatment of Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) is a common viral pathogen of the lower respiratory tract, which, in the absence of effective management, causes millions of cases of severe illness per year. Many of these infections develop into fatal pneumonia. In a review of English and Chinese medical literature, recent traditional Chinese medical herb- (TCMH-) based progress in the area of prevention and treatment was identified, and the potential anti-RSV compounds, herbs, and formulas were explored. Traditional Chinese medical herbs have a positive effect on inhibiting viral attachment, inhibiting viral internalization, syncytial formation, alleviation of airway inflammation, and stimulation of interferon secretion and immune system; however, the anti-RSV mechanisms of TCMHs are complicated, which should be further investigated.
http://ift.tt/2cqtLc1
Acupuncture Decreases Blood Pressure Related to Hypothalamus Functional Connectivity with Frontal Lobe, Cerebellum, and Insula: A Study of Instantaneous and Short-Term Acupuncture Treatment in Essential Hypertension
The therapeutic effects of acupuncture in decreasing blood pressure are ambiguous and underlying acupuncture in hypertension treatment has not been investigated. Our objective was to observe the change of quality of life and compare the differences in brain functional connectivity by investigating instantaneous and short-term acupuncture treatment in essential hypertension patients. A total of 30 patients were randomly divided into the LR3 group and sham acupoint group. Subjects received resting-state fMRI among preacupuncture, postinstantaneous, and short-term acupuncture treatment in two groups. Hypothalamus was selected as the seed point to analyze the changes in connectivity. We found three kinds of results: (1) There was statistical difference in systolic blood pressure in LR3 group after the short-term treatment and before acupuncture. (2) Compared with sham acupoint, acupuncture at LR3 instantaneous effects in the functional connectivity with seed points was more concentrated in the frontal lobe. (3) Compared with instantaneous effects, acupuncture LR3 short-term effects in the functional connectivity with seed points had more regions in frontal lobe, cerebellum, and insula. These brain areas constituted a neural network structure with specific functions that could explain the mechanism of therapy in hypertension patients by LR3 acupoint.
http://ift.tt/2cf0AGz
Efficacy and Safety of LASIK Combined with Accelerated Corneal Collagen Cross-Linking for Myopia: Six-Month Study
This was a prospective controlled clinical trial. 48 myopia patients (96 eyes) were included in this study. After LASIK, accelerated corneal collagen cross-linking (ACXL) was used for myopia treatment. During 6-month follow-up, the results of LASIK-ACXL treatment were studied and compared to the LASIK-only procedure. The results showed that no statistically significant differences in UDVA, CDVA, MRSE, mean, pachymetry, or ECD were found between the two groups at the visit after 6 months of follow-up (all ). At 6 months postoperatively, 2 eyes lost one or more lines of visual acuity in the LASIK-ACXL group, whereas all LASIK-only treated eyes had a stable CDVA. In vivo confocal microscopy showed a decrease of keratocyte density and appearance of honeycomb-like structures in the anterior residual stroma bed; the changes were similar but more pronounced following LASIK-only. None of the cases in both groups developed signs of significant keratitis, regression, or ectasia during the 6-month follow-up. LASIK-ACXL can effectively correct refractive error in patients with myopia, with no significant complications during 6-month follow-up, indicating stability and morphologic change similar to those with LASIK-only treatment.
http://ift.tt/2bOcXgv
Aberrant LncRNA Expression Profile in a Contusion Spinal Cord Injury Mouse Model
Long noncoding RNAs (LncRNAs) play a crucial role in cell growth, development, and various diseases related to the central nervous system. However, LncRNA differential expression profiles in spinal cord injury are yet to be reported. In this study, we profiled the expression pattern of LncRNAs using a microarray method in a contusion spinal cord injury (SCI) mouse model. Compared with a spinal cord without injury, few changes in LncRNA expression levels were noted 1 day after injury. The differential changes in LncRNA expression peaked 1 week after SCI and subsequently declined until 3 weeks after injury. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the reliability of the microarray, demonstrating that the results were reliable. Gene ontology (GO) analysis indicated that differentially expressed mRNAs were involved in transport, cell adhesion, ion transport, and metabolic processes, among others. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the neuroactive ligand-receptor interaction, the PI3K-Akt signaling pathway, and focal adhesions were potentially implicated in SCI pathology. We constructed a dynamic LncRNA-mRNA network containing 264 LncRNAs and 949 mRNAs to elucidate the interactions between the LncRNAs and mRNAs. Overall, the results from this study indicate for the first time that LncRNAs are differentially expressed in a contusion SCI mouse model.
http://ift.tt/2c45u9R
Abdominal paracentesis drainage protects rats against severe acute pancreatitis-associated lung injury by reducing the mobilization of intestinal XDH/XOD
Publication date: October 2016
Source:Free Radical Biology and Medicine, Volume 99
Author(s): Jing Zhou, Zhu Huang, Ning Lin, Weihui Liu, Guan Yang, Dongye Wu, Heda Xiao, Hongyu Sun, Lijun tang
Our previous study showed that abdominal paracentesis drainage (APD) benefits patients with severe acute pancreatitis (SAP) by delaying or avoiding multiple organ failure. However, the role of APD treatment in SAP-associated lung injury (PALI) remains unclear. Therefore, we investigated the impact of APD on PALI in rats to explore the mechanisms underlying its potential treatment benefits. A drainage tube was inserted into the right lower quadrant of rats immediately after SAP induction via the retrograde infusion of 5% sodium taurocholate into the biliopancreatic duct. Mortality rates, histological scores, wet-to-dry weight (W/D) ratios, inflammatory infiltration and oxidative stress in lung tissues were then examined. Xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) activities in the sera, intestines and lungs were assessed, as was P-selectin expression. APD treatment significantly decreased pathological damage scores, oxidative stress and neutrophil infiltration in lung tissues, indicating that APD has protective effects against PALI in rats. Moreover, APD decreased the levels of serum α-amylase and trypsin and resulted in a significant decrease in XDH mobilization from the intestines, which suppressed P-selectin expression in lung tissues following SAP induction. APD treatment exerts a significant protective effect against lung injury secondary to SAP by reducing the mobilization of intestinal XDH or XOD (XDH/XOD) and the expression of P-selectin in the lungs. These findings provide novel insights into the mechanisms underlying the effectiveness of APD in patients with SAP.
Graphical abstract
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Nutrient overload, lipid peroxidation and pancreatic beta cell function
Source:Free Radical Biology and Medicine
Author(s): Shlomo Sasson
Since the landmark discovery of α,β-unsaturated 4-hydroxyalkenals by Esterbauer and colleagues most studies have addressed the consequences of the tendency of these lipid peroxidation products to form covalent adducts with macromolecules and modify cellular functions. Many studies describe detrimental and cytotoxic effects of 4-hydroxy-2E-nonenal (4-HNE) in myriad tissues and organs and numerous pathologies. Other studies similarly assigned unfavorable effects to 4-hydroxy-2E-hexenal (4-HHE) and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE). Nutrient overload (e.g., hyperglycemia, hyperlipidemia) modifies lipid metabolism in cells and promotes lipid peroxidation and the generation of α,β-unsaturated 4-hydroxyalkenals. Advances glycation- and lipoxidation end products (AGEs and ALEs) have been associated with the development of insulin resistance and pancreatic beta cell dysfunction and the etiology of type 2 diabetes and its peripheral complications. Less acknowledged are genuine signaling properties of 4-hydroxyalkenals in hormetic processes that provide defense against the consequences of nutrient overload. This review addresses recent findings on such lipohormetic mechanisms that are associated with lipid peroxidation in pancreatic beta cells.
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Effects of Betaine Aldehyde Dehydrogenase-Transgenic Soybean on Phosphatase Activities and Rhizospheric Bacterial Community of the Saline-Alkali Soil
The development of transgenic soybean has produced numerous economic benefits; however the potential impact of root exudates upon soil ecological systems and rhizospheric soil microbial diversity has also received intensive attention. In the present study, the influence of saline-alkali tolerant transgenic soybean of betaine aldehyde dehydrogenase on bacterial community structure and soil phosphatase during growth stages was investigated. The results showed that, compared with nontransgenic soybean as a control, the rhizospheric soil pH of transgenic soybean significantly decreased at the seedling stage. Compared to HN35, organic P content was 13.5% and 25.4% greater at the pod-filling stage and maturity, respectively. The acid phosphatase activity of SRTS was significantly better than HN35 by 12.74% at seedling, 14.03% at flowering, and 59.29% at podding, while alkaline phosphatase achieved maximum activity in the flowering stage and was markedly lower than HN35 by 13.25% at pod-filling. The 454 pyrosequencing technique was employed to investigate bacterial diversity, with a total of 25,499 operational taxonomic units (OTUs) obtained from the 10 samples. Notably, the effect of SRTS on microbial richness and diversity of rhizospheric soil was marked at the stage of podding and pod-filling. Proteobacteria, Acidobacteria, and Actinobacteria were the dominant phyla among all samples. Compared with HN35, the relative abundance of Proteobacteria was lower by 2.01%, 2.06%, and 5.28% at the stage of seedling, at pod-bearing, and at maturity. In genus level, the relative abundance of Gp6, Sphingomonas sp., and GP4 was significantly inhibited by SRTS at the stage of pod-bearing and pod-filling.
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Effectiveness of Fluticasone Furoate–Vilanterol for COPD in Clinical Practice
Guidelines on the management of chronic obstructive pulmonary disease (COPD) are based on numerous randomized, controlled trials of efficacy, which are usually generated for registration purposes. However, these trials have included patients who were selected with the use of strict criteria and…
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Potential impact of dengue vaccination: Insights from two large-scale phase III trials with a tetravalent dengue vaccine
Publication date: Available online 3 September 2016
Source:Vaccine
Author(s): Laurent Coudeville, Nicolas Baurin, Maïna L'Azou, Bruno Guy
BackgroundA tetravalent dengue vaccine demonstrated its protective efficacy in two phase III efficacy studies. Results from these studies were used to derive vaccination impact in the five Asian (Indonesia, Malaysia, Philippines, Thailand, Vietnam) and the five Latin American countries (Brazil, Colombia, Honduras, Mexico and Puerto Rico) participating in these trials.MethodsVaccination impact was investigated with an age-structured, host-vector, serotype-specific compartmental model. Parameters related to vaccine efficacy and levels of dengue transmission were estimated using data collected during the phase III efficacy studies. Several vaccination programs, including routine vaccination at different ages with and without large catch-up campaigns, were investigated.ResultsAll vaccination programs explored translated into significant reductions in dengue cases at the population level over the first 10years following vaccine introduction and beyond. The most efficient age for vaccination varied according to transmission intensity and 9years was close to the most efficient age across all settings. The combination of routine vaccination and large catch-up campaigns was found to enable a rapid reduction of dengue burden after vaccine introduction.ConclusionOur analysis suggests that dengue vaccination can significantly reduce the public health impact of dengue in countries where the disease is endemic.
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Simultaneous subcutaneous and conjunctival administration of the influenza viral vector based Brucella abortus vaccine to pregnant heifers provides better protection against B. abortus 544 infection than the commercial B. abortus S19 vaccine
Source:Vaccine
Author(s): Kaissar Tabynov, Mukhit Orynbayev, Gourapura J. Renukaradhya, Abylai Sansyzbay
In this study, we explored possibility of increasing the protective efficacy of our novel influenza viral vector based B. abortus vaccine (Flu-BA) in pregnant heifers by adapting an innovative method of vaccine delivery. We administered the vaccine concurrently via the conjunctival and subcutaneous routes to pregnant heifers, and these routes were previously tested individually. The Flu-BA vaccination of pregnant heifers (n=9) against a challenge B. abortus 544 infection provided protection from abortion, infection of heifers and fetuses/calves by 88.8%, 100% and 100%, respectively (alpha=0.004–0.0007 vs. negative control; n=7). Our candidate vaccine using this delivery method provided slightly better protection than the commercial B. abortus S19 vaccine in pregnant heifers (n=8), which provided protection from abortion, infection of heifers and fetuses/calves by 87.5%, 75% and 87.5%, respectively. This improved method of the Flu-BA vaccine administration is highly recommended for the recovery of farms which has high prevalence of brucellosis.
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Antibody titers to vaccination are not predictive of level of protection against a BVDV type 1b challenge in Bos indicus - Bos taurus steers
Publication date: Available online 3 September 2016
Source:Vaccine
Author(s): E.D. Downey-Slinker, J.F. Ridpath, J.E. Sawyer, L.C. Skow, A.D. Herring
Subclinical illness associated with infection is thought to reduce performance and increase production costs in feedlot cattle, but underlying components remain largely unidentified. Vaccination is frequently used in feedlot settings but producers lack metrics that evaluate the effectiveness of vaccination programs. The goal of this study was to determine if levels of serum neutralizing antibody titers were predictive of levels of vaccine protection in a commercial setting. During this four-year study, Angus-Nellore steers housed in a production feedlot setting were assigned to 1 of 3 vaccine treatments: killed vaccine (kV), modified live virus (MLV) vaccine, or no vaccine (control), and were challenged with a noncytopathic 1b field strain of bovine viral diarrhea virus. Rectal temperature and levels of circulating lymphocytes and platelets were monitored following challenge. While no animals were diagnosed as clinically ill with respiratory disease, indicators of disease (pyrexia, lymphopenia, and thrombocytopenia) were observed. The MLV treatment elicited higher antibody titers to the vaccination than the kV, and calves in the MLV treatment had higher mean titers at challenge. The year that elicited the highest antibody response to the vaccination and the year with the lowest frequency of phenotypic responses to the challenge were not concurrent. The MLV treatment had the highest proportion, 34.68%, of animals that were protected against the challenge regardless of the pre-challenge antibody titer and had the fewest number of lymphopenia cases in response to the challenge. Both vaccine treatments mitigated thrombocytopenia when compared to the control treatment, and the MLV treatment reduced lymphopenia; however, these symptoms were not completely eliminated in vaccinated animals. Pyrexia was present in 40.11% of the animals, but no difference in the frequency of cases between treatments was observed. Pre-challenge vaccination response was not indicative of the level of protection nor was anamnestic antibody response correlated with health status.
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Herb-Drug Interaction: Effects of Relinqing® Granule on the Pharmacokinetics of Ciprofloxacin, Sulfamethoxazole, and Trimethoprim in Rats
Relinqing granule (RLQ) is the best-selling Chinese patent drug for treatment of urinary system diseases. In this study, the effects of RLQ on the pharmacokinetics of ciprofloxacin, sulfamethoxazole, and trimethoprim in SD rats were investigated. Rats were randomly divided into control group 1, control group 2, RLQ group 1, and RLQ group 2. RLQ group 1 and RLQ group 2 were treated orally with RLQ for 7 days, and rats were treated with the same volume of water in control group 1 and control group 2. Then, RLQ group 1 and control group 1 were given intragastrically ciprofloxacin on day 8, while RLQ group 2 and control group 2 were given intragastrically sulfamethoxazole and trimethoprim on day 8. Blood samples were collected and determined. There was no significant influence of pharmacokinetic parameters of trimethoprim on two groups. But some pharmacokinetic parameters of ciprofloxacin and sulfamethoxazole in RLQ pretreated rats were evidently altered (P
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3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Wei-Kang Shi, Rui-Cheng Deng, Peng-Fei Wang, Qin-Qin Yue, Qi Liu, Kun-Ling Ding, Mei-Hui Yang, Hong-Yu Zhang, Si-Hua Gong, Min Deng, Wen-Run Liu, Qiu-Ju Feng, Zhu-Ping Xiao, Hai-Liang Zhu
Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori-caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5-chlorophenyl)-3-hydroxypropionylhydroxamic acid (d24) was the most active inhibitor with IC50 of 0.15±0.05μM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12μg·mL−1 for Ki and Ki′, respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins.
Graphical abstract
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6-Aryl-4-amino-pyrimido[4,5-b]indole 2′-deoxyribonucleoside triphosphates (benzo-fused 7-deaza-dATP analogues): Synthesis, fluorescent properties, enzymatic incorporation into DNA and DNA-protein binding study
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Andrea Bosáková, Pavla Perlíková, Michal Tichý, Radek Pohl, Michal Hocek
Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2′-deoxyribonucleoside triphosphates (dABXTPs) were prepared by glycosylation of 4,6-dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335–378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5-b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein.
Graphical abstract
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Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase)
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Amy J. Rice, Hao Lei, Bernard D. Santarsiero, Hyun Lee, Michael E. Johnson
Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (KD) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors.
Graphical abstract
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2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Georgia Antonopoulou, Victoria Magrioti, Maroula G. Kokotou, Aikaterini Nikolaou, Efrosini Barbayianni, Varnavas D. Mouchlis, Edward A. Dennis, George Kokotos
Cytosolic GIVA phospholipase A2 (GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048.
Graphical abstract
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The human tyrosine kinase Kit and its gatekeeper mutant T670I, show different kinetic properties: Implications for drug design
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Miroslava Kissova, Giovanni Maga, Emmanuele Crespan
The tyrosine kinase Kit, a receptor for Stem Cell Factor, is involved, among others, in processes associated to cell survival, proliferation and migration. Upon physiological conditions, the activity of Kit is tightly regulated. However, primary mutations that lead to its constitutive activation are the causal oncogenic driver of gastrointestinal stromal tumours (GISTs). GISTs are known to be refractory to conventional therapies but the introduction of Imatinib, a selective inhibitor of tyrosine kinases Abl and Kit, significantly ameliorated the treatment options of GISTs patients. However, the acquisition of secondary mutations renders Kit resistant towards all available drugs. Mutation involving gatekeeper residues (such as V654a and T670I) influence both the structure and the catalytic activity of the enzyme. Therefore, detailed knowledge of the enzymatic properties of the mutant forms, in comparison with the wild type enzyme, is an important pre-requisite for the rational development of specific inhibitors. In this paper we report a thorough kinetic analysis of the reaction catalyzed by the Kit kinase and its gatekeeper mutated form T670I. Our results revealed the different mechanisms of action of these two enzymes and may open a new avenue for the future design of specific Kit inhibitors.
Graphical abstract
http://ift.tt/2bOLmsH
Editorial board
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
http://ift.tt/2bOMPPz
Design, synthesis and biological evaluation of novel hamamelitannin analogues as potentiators for vancomycin in the treatment of biofilm related Staphylococcus aureus infections
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Arno Vermote, Gilles Brackman, Martijn D.P. Risseeuw, Tom Coenye, Serge Van Calenbergh
Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure–activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues.
Graphical abstract
http://ift.tt/2bVB8Uk
In vitro cytotoxicity of novel 2,5,7-tricarbo-substituted indoles derived from 2-amino-5-bromo-3-iodoacetophenone
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Malose J. Mphahlele, Tshepiso J. Makhafola, Mmakwena M. Mmonwa
A series of novel 2,5,7-tricarbo-substituted indoles were prepared via sequential Sonogashira and Suzuki–Miyaura cross-coupling of 2-amino-5-bromo-3-iodoacetophenone with terminal acetylenes and aryl/styrylboronic acids followed by palladium chloride-mediated heteroannulation of the incipient 5-aryl/styryl-substituted 2-amino-3-(arylalkynyl)acetophenones. These polycarbo-substituted indole derivatives were evaluated for potential in vitro antiproliferative activity against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines. Compounds 6f, 6i, 6k, 6m and 6n were found to exhibit significant cytotoxicity and selectivity against the HeLa cells. Compounds 6i and 6m were chosen as representative examples to evaluate their pro-apoptotic efficacy against the HeLa cell line. The compounds induced apoptosis through cell membrane alteration and DNA fragmentation caspase-dependent pathways.
Graphical abstract
http://ift.tt/2bVBcnb
Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Shaffali Singla, Poonam Piplani
A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a–i, 16a–d, 17a–b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC50=2.42μM) and antioxidant activity in comparison to donepezil (IC50=1.82μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme.
Graphical abstract
http://ift.tt/2bVAW7G
Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Rosania Yang, Maurício T. Tavares, Sarah F. Teixeira, Ricardo A. Azevedo, Diego C. Pietro, Thais B. Fernandes, Adilson K. Ferreira, Gustavo H.G. Trossini, José A.M. Barbuto, Roberto Parise-Filho
A series of novel chelerythrine analogues was designed and synthesized. Antitumor activity was evaluated against A549, NCI-H1299, NCI-H292, and NCI-H460 non-small-cell lung cancer (NSCLC) cell lines in vitro. The selectivity of the most active analogues and chelerythrine was also evaluated, and we compared their cytotoxicity in NSCLC cells and non-tumorigenic cell lines, including human umbilical vein endothelial cells (HUVECs) and LL24 human lung fibroblasts. In silico studies were performed to establish structure–activity relationships between chelerythrine and the analogues. The results showed that analogue compound 3f induced significant dose-dependent G0/G1 cell cycle arrest in A549 and NCI-H1299 cells. Theoretical studies indicated that the molecular arrangement and electron characteristics of compound 3f were closely related to the profile of chelerythrine, supporting its activity. The present study presents a new and simplified chelerythrinoid scaffold with enhanced selectivity against NSCLC tumor cells for further optimization.
Graphical abstract
http://ift.tt/2bVAw1b
Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Lei Fang, Minchang Feng, Feihong Chen, Xia Liu, Hong Shen, Jian Zhao, Shaohua Gou
By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase.
Graphical abstract
http://ift.tt/2bVARB1
2-(4-Fluorophenyl)-quinazolin-4(3H)-one as a novel tyrosinase inhibitor: Synthesis, inhibitory activity, and mechanism
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Rui Wang, Wei-Ming Chai, Qin Yang, Man-Kun Wei, Yiyuan Peng
2-(4-Fluorophenyl)-quinazolin-4(3H)-one (FQ) was synthesized, and its structure was identified with 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), fourier transform infrared spectroscopy (FTIR), and high resolution mass spectrometry (HRMS). From the enzyme analysis, the results showed that it could inhibit the diphenolase activity of tyrosinase (IC50=120±2μM). Furthermore, the results of kinetic studies showed that the compound was a reversible mixed-type inhibitor, and that the inhibition constants were determined to be 703.2 (KI) and 222.1μM (KIS). The results of fluorescence quenching experiment showed that the compound could interact with tyrosinase and the substrates (tyrosine and l-DOPA). Molecular docking analysis revealed that the mass transfer rate was affected by FQ blocking the enzyme catalytic center. In brief, current study identified a novel tyrosinase inhibitor which deserved further study for hyperpigmentation drugs.
Graphical abstract
http://ift.tt/2bVAx5c
Structure–activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Xiaoli Xu, Yue Wu, Mingyang Hu, Xiang Li, Congying Gu, Qidong You, Xiaojin Zhang
Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure–activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.
Graphical abstract
http://ift.tt/2bVzWjQ
Towards the PET radiotracer for p75 neurotrophin receptor: [11C]LM11A-24 shows biological activity in vitro, but unfavorable ex vivo and in vivo profile
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Julien Gibon, Min Su Kang, Arturo Aliaga, Behrang Sharif, Pedro Rosa-Neto, Philippe Séguéla, Philip A. Barker, Alexey Kostikov
Mature neurotrophins as well as their pro forms are critically involved in the regulation of neuronal functions. They are signaling through three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75NTR) and sortilin. Aberrant expression of p75NTR in the CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer's disease. The goal of this work was to evaluate one of the very few reported p75NTR small molecule ligands as a lead compound for development of novel PET radiotracers for in vivo p75NTR imaging. Here we report that previously described ligand LM11A-24 shows significant inhibition of carbachol-induced persistent firing (PF) of entorhinal cortex (EC) pyramidal neurons in wild-type mice via selective interaction with p75NTR. Based on this electrophysiological assay, the compound has very high potency with an EC50<10nM. We optimized the radiosynthesis of [11C]LM11A-24 as the first attempt to develop PET radioligand for in vivo imaging of p75NTR. Despite some weak interaction with CNS tissues, the radiolabeled compound showed unfavorable in vivo profile presumably due to high hydrophilicity.
Graphical abstract
http://ift.tt/2bVBaf3
New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Hamada H.H. Mohammed, Amer Ali Abd El-Hafeez, Samar H. Abbas, El-Shimaa M.N. Abdelhafez, Gamal El-Din A. Abuo-Rahma
New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC50=14.8, 24.8, 23.6 and 20.7μM, respectively) compared to the parent ciprofloxacin (IC50 >100μM) and doxorubicin as a positive control (IC50=1μM). The flow cytometric analysis for 2b showed dose dependent G2/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G2/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G2/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.
Graphical abstract
http://ift.tt/2bVB8UH
Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Ana L. Valenciano, Aaron C. Ramsey, Webster L. Santos, Zachary B. Mackey
Human African trypanosomiasis (HAT) is a lethal, vector-borne disease caused by the parasite Trypanosoma brucei. Therapeutic strategies for this neglected tropical disease suffer from disadvantages such as toxicity, high cost, and emerging resistance. Therefore, new drugs with novel modes of action are needed. We screened cultured T. brucei against a focused kinase inhibitor library to identify promising bioactive compounds. Among the ten hits identified from the phenotypic screen, AZ960 emerged as the most promising compound with potent antiparasitic activity (IC50=120nM) and was shown to be a selective inhibitor of an essential gene product, T. brucei extracellular signal-regulated kinase 8 (TbERK8). We report that AZ960 has a Ki of 1.25μM for TbERK8 and demonstrate its utility in establishing TbERK8 as a potentially druggable target in T. brucei.
Graphical abstract
http://ift.tt/2bVAbeZ
Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Xian-Hai Lv, Zi-Li Ren, Ben-Guo Zhou, Qing-Shan Li, Ming-Jie Chu, Dao-Hong Liu, Kai Mo, Li-Song Zhang, Xiao-Kang Yao, Hai-Qun Cao
Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.
Graphical abstract
http://ift.tt/2bVB6fa
Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Lauren E. Ragle, Dilip J. Palanisamy, Margaux J. Joe, Rachel S. Stein, Derek D. Norman, Gabor Tigyi, Daniel L. Baker, Abby L. Parrill
Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4μM) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA1–5 GPCR.
Graphical abstract
http://ift.tt/2bVB8DX
Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Michiyo Mochizuki, Masakuni Kori, Mitsunori Kono, Takahiko Yano, Yuu Sako, Maiko Tanaka, Naoyuki Kanzaki, Albert C. Gyorkos, Christopher P. Corrette, Kazuyoshi Aso
A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50=27nM, 56nM, respectively). This compound exhibited ex vivo 125I-Tyr0 (125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.
Graphical abstract
http://ift.tt/2bVAgz1
Design, synthesis, and biological evaluation of 1,9-diheteroarylnona-1,3,6,8-tetraen-5-ones as a new class of anti-prostate cancer agents
Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Xiaojie Zhang, Rubing Wang, German Ruiz Perez, Guanglin Chen, Qiang Zhang, Shilong Zheng, Guangdi Wang, Qiao-Hong Chen
In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner–Wadsworth–Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G0/G1 phase.
Graphical abstract
http://ift.tt/2bVA8Ql
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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