Search

The present study was conducted to determine the effects of dietary phosphorus (P) levels on growth performance, body composition, liver histology and enzymatic activity, and expression of lipid metabolism-related genes in spotted seabass (Lateolabrax maculatus). Seven diets were prepared to contain available P levels of 0.48% (the control group), 0.69%, 0.89%, 1.10%, 1.28%, 1.51% and 1.77% and feed fish (4.26 ± 0.03 g) to satiety twice daily for 10 weeks. Significantly higher weight gain and specific growth rate were recorded at P levels of 0.69%-1.51% compared to the control group. Feed conversion ratio decreased with increasing P levels up to 0.89% and increased thereafter. The lowest liver lipid content, viscerosomatic index and lipid content of whole-body were obtained in the 0.89%-P group among dietary treatments. P and calcium (Ca) contents in whole body were increased, while liver triglyceride and cholesterol contents were decreased with increasing dietary P levels from 0.48% to 1.77%. The highest activity of hepatic lipase was recorded in the 1.10%-P group among dietary treatments. Compared to the control group, 1.10% P enhanced the proportion of HUFA and reduced the proportion of SFA and MUFA. The histological observations showed that P deficiency (0.48%) led to the vacuolization of hepatocytes and increased number of lipid droplets. Meanwhile, overall liver tissue structure was improved when P level increased to 1.28%. Compared to the control group, expression of lipid metabolismrelated genes such as FAS, ACC-2 and SREBP-1 was decreased at 0.89%-1.10% P group while an opposite trend was observed in the expression of PPARa2 and CPT-1 genes. The current study showed that 0.89% dietary P levels could promote growth performance of spotted seabass and reduce lipid accumulation in the liver. A broken-line regression analysis based on weight gain showed that the optimum dietary P level (available P) for juvenile spotted seabass reared in freshwater was 0.72%. [ABSTRACT FROM AUTHOR]

Although effects of paternal deprivation on offspring have been previously studied, the factors initiating and maintaining paternal care are not very clear. Using socially monogamous mandarin voles, we investigated whether cues from dams affect paternal behaviours. The sires were separated from their pups individually or placed with dams immediately prior to paternal behaviour testing. The results showed that sires kept with dams displayed more huddling behaviour and shorter latency of retrieving than sires isolated individually. Sires placed with dams in a closed box also exhibited less huddling behaviour and longer latency of retrieving than sires placed with dams in an open box. In addition, anosmia, deafness or combination of these two treatments all significantly reduced huddling and licking behaviour compared with sham-operated group respectively. These results suggest that communication between sires and dams especially via olfactory and auditory signals plays an important role in strengthening paternal behaviours. [ABSTRACT FROM AUTHOR]

Currently, Chemoinformatic methods are used to perform the prediction for FBPase inhibitory activity. A genetic algorithm-random forest coupled method (GA-RF) was proposed to predict fructose 1,6-bisphosphatase (FBPase) inhibitors to treat type 2 diabetes mellitus using the Mold molecular descriptors. A data set of 126 oxazole and thiazole analogs was used to derive the GA-RF model, yielding the significant non-cross-validated correlation coefficient r² ncv and cross-validated r² cv values of 0.96 and 0.67 for the training set, respectively. The statistically significant model was validated by a test set of 64 compounds, producing the prediction correlation coefficient r² pred of 0.90. More importantly, the building GA-RF model also passed through various criteria suggested by Tropsha and Roy with r² o and r² m values of 0.90 and 0.83, respectively. In order to compare with the GA-RF model, a pure RF model developed based on the full descriptors was performed as well for the same data set. The resulting GA-RF model with significantly internal and external prediction capacities is beneficial to the prediction of potential oxazole and thiazole series of FBPase inhibitors prior to chemical synthesis in drug discovery programs. [ABSTRACT FROM AUTHOR]

Relative deprivation (RD) refers to the fact that individuals may feel deprived of some desirable thing in social comparison relative to a reference group. Occupational group is widely recognized as the essential reference group and generally used to compare differences in earnings and social position. Four waves' data from the Social Attitudes Survey of Urban-Rural Residents (China) (SAS-C; 2005/2007/2008/2009) were used to compute to Stewart's new measure of RD for different occupational groups and its relationship to life satisfaction (a cognitive component of subjective well-being). Results showed that both economic RD (defined as individuals' RD of material benefits, such as income, wealth etc.) and social status RD (defined as individuals' RD on their evaluation of social status) consistently predicted Chinese life satisfaction for a period of time from 2005 to 2009; meanwhile, individual economic RD was moderately correlated to social status RD. The effects of RD and some demographic variables on life satisfaction are discussed and possible improvements for future research are suggested. [ABSTRACT FROM AUTHOR]

This study examined spatial variations in the concentration, grain size and heavy mineral assemblages on Cedar Beach (Lake Erie, Canada). Magnetic studies of heavy mineral-enriched, dark-reddish sands present on the beach showed that magnetite (~150 μm) is the dominant magnetic mineral. Surficial magnetic susceptibility values defined three zones: a lakeward region close to the water line (Zone 1), the upper swash zone (Zone 2) and the region landwards of the upper swash zone (Zone 3). Zone 2 showed the highest bulk and mass susceptibility (κ, χ) and the highest mass percentage of smaller grain-size (<250 μm) fractions in the bulk sand sample. Susceptibility (i.e. κ and χ) values decreased and grain size coarsened from Zone 2 lakewards (into Zone 1) and landwards (into Zone 3), and correlated with the distribution of the heavy mineral assemblage, most probably reflecting preferential separation of large, less dense particles by waves and currents both along and across the beach. The eroded western section of Cedar Beach showed much higher concentrations of heavy minerals including magnetite, and finer sand grain sizes than the accreting eastern section, suggesting that magnetic techniques could be used as a rapid, cost-effective way of examining erosion along sensitive coastline areas. [ABSTRACT FROM AUTHOR]

Precartilaginous stem cells (PCSC) are adult stem cells that control limb growth of animals and can differentiate directionally. In a previous study, PCSC was reported to begin differentiating at the fifth passage; therefore, sufficient uni-phenotype PCSC cannot be harvested from primary cell culture. The purpose of this study was to examine whether simian virus 40 large T antigen gene (SV40Tag) could induce rat PCSC to immortalize. Immunomagnetic separation was used to isolate PCSC labeled with fibroblast growth factor receptor-3 (FGFR-3). Plasmid pCMVSV40T/PUR containing SV40Tag was transfected into PCSC by liposome transfection method. One anti-puromycin cell clone was obtained, which was confirmed as FGFR-3 positive, and expanded to immortalized cell strain. Results from RT-PCR and immunocytochemistry demonstrated that SV40Tag was highly expressed at both mRNA and protein levels after stable transfection. The cells transfected with SV40Tag were expanded to immortalized cell strain, which could maintain its characteristics for 30 passages, named immortalized precartilaginous stem cells (IPCSC). IPCSC were short fusiform or triangular cells with two or three short axons. Immunocytochemistry results of FGFR-3 and Collagen II demonstrated that IPCSC retained the characteristics of PCSC and the high proliferation capability of IPCSC was confirmed by methyl thiazolyl tetrazolium assay. Therefore, we concluded that rat precartilaginous stem cells were purified and immortalized precartilaginous stem cell strain was established. It may provide a stable cell resource for basic research and cell transplantation therapies. [ABSTRACT FROM AUTHOR]

( R)-5,5'-Dibromo-6,6'-dibutyl-2,2'-binaphthol, ( R)-5,5'-dibromo-6,6'-di(4-methylphenyl)-2,2'-binaphthol, ( R)-5,5'-dibromo-6,6'-di(3,5-dimethylphenyl)-2,2'-binaphthol, and ( R)-5,5'-dibromo-6,6'-di(4-trifluoromethylphenyl)-2,2'-binaphthol were synthesized from ( R)-1,1'-bi-2-naphthol by a five-step reaction in excellent yields under mild conditions. [ABSTRACT FROM AUTHOR]

Chiral conjugated polymers P-1and P-2were synthesized by the polymerization of (S)-6,6‘-di(4-methylphenyl)-3,3‘-diiodo-2,2‘-bisoctoxy-1,1‘-binaphthyl (S-M-2) and (S)-6,6‘-dibromo-3,3‘-di(4-methylphenyl)-2,2‘-bisoctoxy-1,1‘-binaphthyl (S-M-3) with 5,5‘-divinyl-2,2‘- bipyridine (M-1) under Heck cross-coupling reaction, respectively. The chiral polymers P-1and P-2can show strong blue-green fluorescence. The responsive properties of chiral polymers on transition metal ions and Hwere investigated by fluorescent spectra. Cu2and Ni2lead to nearly complete fluorescent quenching of two polymers, and Zn2, Cd2, and Hcan cause slight fluorescent quenching. Such distinct ion responsive behaviors revealed the obvious difference of coordination abilities of transition metal ions with 2,2‘-bipyridyl ligand receptors. The obvious quenching effect of P-1and P-2also suggested that the chiral conjugated polymers backbone structure and the efficiencies of energy or electron transfer between backbone and receptor ions in the main chain play important roles in fluorescence quenching. The results show that the chiral conjugated polybinaphthyls incorporating the 2,2‘-bipyridyl moiety as the recognition site can act as promising active materials for application as fluorescent chemosensors. [ABSTRACT FROM AUTHOR]

A biosynthetic pathway to fungal polyketide-nonribosomal peptide natural products, Sch210971 (1a) and Sch210972 (1b) from Hapsidospora irregularis, was characterized by reconstitution and heterologous expression in Fusarium heterosporum. Using genetic, biochemical, and feeding experiments, we show that the incorporated amino acid 4-hydroxyl-4-methyl glutamate (HMG) is synthesized by an aldolase, probably using pyruvate as the precursor. [ABSTRACT FROM AUTHOR]

Lumbar hernias are very rare posterolateral abdominal wall hernias, and they are spontaneous in most adult patients. Here we report two cases of spontaneous lumbar hernias associated with chronic obstructive pulmonary disease (COPD). Some factors such as chronic cough, poor nutritional status and old age in patients with COPD would contribute to lumbar hernia. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is a major cause of the inefficacy and poor response to paclitaxel-based chemotherapy. The combination of conventional cytotoxic drugs has been a plausible strategy for overcoming paclitaxel resistance. Herein, we investigated the cytotoxic effects and underlying mechanism of LSS-11, a novel naphthalimide derivative-based topoisomerase inhibitor, in paclitaxel-resistant A549 (A549/T) lung cancer cells. LSS-11 enhanced cell death in A549/T cells by inducing apoptosis through increasing the DR5 protein level and PARP1 cleavage. Importantly, LSS-11 dose-dependently reduced STAT3 phosphorylation and downregulated its target genes MDR1 and MRP1, without affecting P-gp transport function. Chromatin coimmunoprecipitation (ChIP) assay further revealed that LSS-11 hindered the binding of STAT3 to the MDR1 and MRP1 promoters. Additionally, pharmacological inhibition of p-STAT3 by sulforaphane downregulated MDR1 and MRP1, resulting in A549/T cell death by triggering apoptosis. Collectively, our data show that LSS-11 is a potent naphthalimide-based chemosensitizer that could enhance cell death in paclitaxel-resistant lung cancer cells through the DR5/PARP1 pathway and STAT3/MDR1/MRP1 STAT3 inhibition. [ABSTRACT FROM AUTHOR]

Objective: The novel compound GCJ-490A has been discovered as a pan-histone deacetylase (HDAC) inhibitor that exerts potent inhibitory activity against HDAC1, HDAC3, and HDAC6. Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue, we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer (NSCLC) in vitro and in vivo in this study. Methods: The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation, apoptosis, and colony formation assays. NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo. Western blot assays, luciferase reporter assays, chromatin immunoprecipitation assays, quantitative real time-PCR, immunohistochemistry, and transcription factor activity assays were used to elucidate possible mechanisms. Results: GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo. Interestingly, inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKα promoter and enhanced IKKα transcription, thus decreasing c-Met. Moreover, this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. Conclusions: These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials. [ABSTRACT FROM AUTHOR]

Combinatorial biosynthesis aspires to exploit the promiscuity of microbial anabolic pathways to engineer the synthesis of new chemical entities. Fungal benzenediol lactone (BDL) polyketides are important pharmacophores with wide-ranging bioactivities, including heat shock response and immune system modulatory effects. Their biosynthesis on a pair of sequentially acting iterative polyketide synthases (iPKSs) offers a test case for the modularization of secondary metabolic pathways into "build-couple-pair" combinatorial synthetic schemes. Expression of random pairs of iPKS subunits from four BDL model systems in a yeast heterologous host created a diverse library of BDL congeners, including a polyketide with an unnatural skeleton and heat shock response-inducing activity. Pairwise heterocombinations of the iPKS subunits also helped to illuminate the innate, idiosyncratic programming of these enzymes. Even in combinatorial contexts, these biosynthetic programs remained largely unchanged, so that the iPKSs built their cognate biosynthons, coupled these building blocks into chimeric polyketide intermediates, and catalyzed intramolecular pairing to release macrocycles or α-pyrones. However, some heterocombinations also provoked stuttering, i.e., the relaxation of iPKSs chain length control to assemble larger homologous products. The success of such a plug and play approach to biosyn-thesize novel chemical diversity bodes well for bioprospecting unnatural polyketides for drug discovery. [ABSTRACT FROM AUTHOR]

Background: Litchi is a well-known subtropical fruit crop. However, irregular bearing attributed to unstable flowering is a major ongoing problem for the development of the litchi industry. In a previous study, our laboratory proved that litchi flowering was induced by low temperature and that a FLOWERING LOCUS T (FT) homologue gene named LcFT1 played a pivotal role in this process. The present study aimed to understand the natural variation in FT among litchi germplasm resources and designed markers to verify easy- and difficult-flowering litchi germplasms. A grafting experiment was also carried out to explore whether it could shorten the seedling stage of litchi seedlings. Results: Two types of LcFT1 promoter existed in different litchi germplasm resources, and we named them the 'easyflowering type of LcFT1 promoter' and 'difficult-flowering type of LcFT1 promoter', which resulted in three different LcFT1 genotypes of litchi germplasm resources, including the homozygous easy-flowering type of the LcFT1 genotype, homozygous difficult-flowering type of the LcFT1 genotype and heterozygous LcFT1 genotype of litchi germplasm resources. The homozygous easy-flowering type of the LcFT1 genotype and heterozygous LcFT1 genotype of the litchi germplasm resources completed their floral induction more easily than the homozygous difficult-flowering type of the LcFT1 genotype of litchi germplasm resources. Herein, we designed two kinds of efficient molecular markers based on the difference in LcFT1 promoter sequences and applied them to identify of the easy- and difficultflowering litchi germplasm resources. These two kinds of molecular markers were capable of clearly distinguishing the easy- from difficult-flowering litchi germplasm resources at the seedling stage and provided the same results. Meanwhile, grafting the scion of seedlings to the annual branches of adult litchi trees could significantly shorten the seedling stage. Conclusions: Understanding the flowering characteristics of litchi germplasm resources is essential for easy-flowering litchi breeding. In the present study, molecular markers provide a rapid and accurate approach for identifying the flowering characteristics. The application of these molecular markers not only significantly shortened the artificial crossbreeding cycle of easy-flowering litchi cultivars but also greatly saved manpower, material resources and land. [ABSTRACT FROM AUTHOR]

The dorsal and ventral human telencephalons contain different neuronal subtypes, including glutamatergic, GABAergic, and cholinergic neurons, and how these neurons are generated during early development is not well understood. Using scRNA-seq and stringent validations, we reveal here a developmental roadmap for human telencephalic neurons. Both dorsal and ventral telencephalic radial glial cells (RGs) differentiate into neurons via dividing intermediate progenitor cells (IPCs_div) and early postmitotic neuroblasts (eNBs). The transcription factor ASCL1 plays a key role in promoting fate transition from RGs to IPCs_div in both regions. RGs from the regionalized neuroectoderm show heterogeneity, with restricted glutamatergic, GABAergic, and cholinergic differentiation potencies. During neurogenesis, IPCs_div gradually exit the cell cycle and branch into sister eNBs to generate distinct neuronal subtypes. Our findings highlight a general RGs-IPCs_div-eNBs developmental scheme for human telencephalic progenitors and support that the major neuronal fates of human telencephalon are predetermined during dorsoventral regionalization with neuronal diversity being further shaped during neurogenesis and neural circuit integration. [ABSTRACT FROM AUTHOR]

A crucial step during the programmed biosynthesis of fungal polyketide natural products is the release of the final polyketide intermediate from the iterative polyketide synthases (iPKSs), most frequently by a thioesterase (TE) domain. Realization of combinatorial biosynthesis with iPKSs requires TE domains that can accept altered polyketide intermediates generated by hybrid synthase enzymes and successfully release "unnatural products" with the desired structure. Achieving precise control over product release is of paramount importance with O-C bond-forming TE domains capable of macrocyclization, hydrolysis, transesterification, and pyrone formation that channel reactive, pluripotent polyketide intermediates to defined structural classes of bioactive secondary metabolites. By exploiting chimeric iPKS enzymes to offer substrates with controlled structural variety to two orthologous O-C bond-forming TE domains in situ, we show that these enzymes act as nonequivalent decision gates, determining context-dependent release mechanisms and overall product flux. Inappropriate choice of a TE could eradicate product formation in an otherwise highly productive chassis. Conversely, a judicious choice of a TE may allow the production of a desired hybrid metabolite. Finally, a serendipitous choice of a TE may reveal the unexpected productivity of some chassis. The ultimate decision gating role of TE domains influences the observable outcome of combinatorial domain swaps, emphasizing that the deduced programming rules are context dependent. These factors may complicate engineering the biosynthesis of a desired "unnatural product" but may also open additional avenues to create biosynthetic novelty based on fungal nonreduced polyketides. [ABSTRACT FROM AUTHOR]

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q2 = 0.603, R2 ncv = 0.829, R2 pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q2 = 0.506, R2 ncv =0.838, R2 pre = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R1 substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists. [ABSTRACT FROM AUTHOR]

A new phenylethanoid glycoside, two new cyclohexylethanoids, one new phenolic glycoside, and a new farnesanetype sesquiterpenoid, namely 2phenylethyl 3O6deoxyαLmannopyranosylβDglucopyranoside 1, 6″OEcaffeoyl rengyoside B 2, clerodenone A 3, 26O4hydroxy3methoxyphenylcarbonylβDglucopyranosyloxy2methylbutanoic acid 4, 22S,5R51E4hydroxy4methylhexa1,5dien1yl5methyltetrahydrofuran2ylpropan2yl βDglucopyranoside 5, together with 16known compounds, were isolated from the roots of Clerodendrum bungei.All structures were elucidated by spectroscopic methods. The new compounds showed modest in vitroinhibition of the proliferation of the HeLa human cervical carcinoma cell line CCL2, with IC50values in the range of 3.5–8.7μM, adriamycin being used as positive control, with an IC50value of 0.026±0.001μM. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) continue to attract increasing interest with respect to their applications as luminescent materials. The ordered structure of the metal-organic complex facilitates the selective integration of PAHs that can be tuned to function cooperatively. Here, a unique highly twisted anthracene-based organoplatinum metallacycle was prepared via coordination-driven selfassembly. Single-crystal X-ray diffraction analysis revealed that the metallacycle was twisted through the cooperation of strong π···π stacking interactions and steric hindrance between two anthracenebased ligands. Notably, the intramolecular twist and aggregation behavior introduced restrictions to the conformational change of anthracenes, which resulted in increased emission intensity of the metallacycle in solution. The emission behaviors and suprastructures based on the highly twisted metallacycle can be modulated by the introduction of different solvents. This study demonstrates that this metallacycle with highly twisted structure is a promising candidate for sensing and bioimaging applications. [ABSTRACT FROM AUTHOR]

As a chronic disorder, insomnia affects approximately 10% of the population at some time during their lives, and its treatment is often challenging. Since the antagonists of the H1 receptor, a protein prevalent in human central nervous system, have been proven as effective therapeutic agents for treating insomnia, the H1 receptor is quite possibly a promising target for developing potent anti-insomnia drugs. For the purpose of understanding the structural actors affecting the antagonism potency, presently a theoretical research of molecular interactions between 129 molecules and the H1 receptor is performed through three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. The ligand-based comparative molecular similarity indices analysis (CoMSIA) model (Q2 = 0.525, R2ncv = 0.891, R2pred = 0.807) has good quality for predicting the bioactivities of new chemicals. The cross-validated result suggests that the developed models have excellent internal and external predictability and consistency. The obtained contour maps were appraised for affinity trends for the investigated compounds, which provides significantly useful information in the rational drug design of novel anti-insomnia agents. Molecular docking was also performed to investigate the mode of interaction between the ligand and the active site of the receptor. Furthermore, as a supplementary tool to study the docking conformation of the antagonists in the H1 receptor binding pocket, molecular dynamics simulation was also applied, providing insights into the changes in the structure. All of the models and the derived information would, we hope, be of help for developing novel potent histamine H1 receptor antagonists, as well as exploring the H1-antihistamines interaction mechanism. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 2 (CDK2) is a crucial regulator of the eukaryotic cell cycle. However it is well established that monomeric CDK2 lacks regulatory activity, which needs to be aroused by its positive regulators, cyclins E and A, or be phosphorylated on the catalytic segment. Interestingly, these activation steps bring some dynamic changes on the 3D-structure of the kinase, especially the activation segment. Until now, in the monomeric CDK2 structure, three binding sites have been reported, including the adenosine triphosphate (ATP) binding site (Site I) and two non-competitive binding sites (Site II and III). In addition, when the kinase is subjected to the cyclin binding process, the resulting structural changes give rise to a variation of the ATP binding site, thus generating an allosteric binding site (Site IV). All the four sites are demonstrated as being targeted by corresponding inhibitors, as is illustrated by the allosteric binding one which is targeted by inhibitor ANS (fluorophore 8-anilino-1-naphthalene sulfonate). In the present work, the binding mechanisms and their fluctuations during the activation process attract our attention. Therefore, we carry out corresponding studies on the structural characterization of CDK2, which are expected to facilitate the understanding of the molecular mechanisms of kinase proteins. Besides, the binding mechanisms of CDK2 with its relevant inhibitors, as well as the changes of binding mechanisms following conformational variations of CDK2, are summarized and compared. The summary of the conformational characteristics and ligand binding mechanisms of CDK2 in the present work will improve our understanding of the molecular mechanisms regulating the bioactivities of CDK2. [ABSTRACT FROM AUTHOR]

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-kB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations. [ABSTRACT FROM AUTHOR]

The migraine never fails to afflict individuals in the world that knows no lack of such cases. CGRP (calcitonin gene-related peptide) is found closely related to migraine and olcegepant (BIBN4096) is effective in alleviating the pain. In our work, the combination of ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies along with molecular docking was applied to provide us insights about how urethanamide, pyridine and aspartate and succinate derivatives (novel CGRP receptor antagonists) play a part in inhibiting the activity of CGRP receptor. The optimal CoMSIA model shows the Q² of 0.505, R²ncv of 0.992 and its accurate predictive ability was confirmed by checking out an independent test set which gave R²pred value of 0.885. Besides, the 3D contour maps help us identify how different groups affect the antagonist activity while connecting to some key positions. In addition, the docking analysis shows the binding site emerging as the distorted "V" shape and including two binding pockets: one of them is hydrophobic, fixing the structural part 3 of compound 80, the other anchors the part 1 of compound 80. The docking analysis also shows the interaction mechanism between compound 80 and CGRP receptor, similar to the interaction between olcegepant and CGRP receptor. The findings derived from this work reveal the mechanism of related antagonists and facilitate the future rational design of novel antagonists with higher potency. [ABSTRACT FROM AUTHOR]

The proper selection of stable reference genes for real-time quantitative PCR (RT-qPCR) can help to reliably assess gene expression results under specific experimental conditions. The present study evaluated the stability of 16 candidate reference genes of kumquat using the methods of geNorm, Normfinder, and Bestkeeper in different tissues of kumquat (Fortunella crassifolia Swingle) under some type of abiotic stress. The results showed that homologous genes should be taken into account for normalization in RT-qPCR studies. For the three specific types of stresses, i.e., salt stress, drought stress, and heavy metal stress, ACT6, ACT8, and ACT7 should be selected as internal controls, respectively. For low-temperature stress, the use of multiple reference genes for normalization may be optimal, such as ACT7+ACT9 (according to geNorm) or ACT7+TUB4 (according to Normfinder). We suggest that ACT7 alone or the combination of ACT7+ACT1+EF1-α or ACT1+ACT8 can meet the requirements for the normalization of RT-qPCR studies under the experimental conditions tested here. Although some commonly used reference genes (TUA1, TUB1, TUB4, CYP, GAPDH, etc.) showed much higher variability, some are still useful in combinations under specific conditions. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase-activated protein kinase 2 (MK-2) has been identified as a drug target for the treatment of inflammatory diseases. Currently, a series of thiourea analogs as potent MK-2 inhibitors were studied using comprehensive computational methods by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in activities. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r² ncv, q² values of 0.974, 0.536 for the internal validation, and r² pred, r² m values of 0.910, 0.723 for the external validation and Roy's index, respectively. In addition, more rigorous validation criteria suggested by Tropsha were also employed to check the built models. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules: (i) The substituent with a bulky size and electron-rich group at the C5 position of the pyrazine ring [ABSTRACT FROM AUTHOR]

The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q² of 0.501, R² ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R² pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity. [ABSTRACT FROM AUTHOR]

Fructose 1,6-bisphosphatase (FBPase) has been identified as a drug discovery target for lowering glucose in type 2 diabetes mellitus. In this study, a large series of 105 FBPase inhibitors were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in potency. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed., q² values of 0.986, 0.514 for internal validation, and Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed. statistics of 0.902, 0.828 statistics for external validation. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules. (1) Substituents with a proper length and size at the C5 position of the thiazole core are required to enhance the potency; (2) A small and electron-withdrawing group at the C2 position linked to the thiazole core is likely to help increase the FBPase inhibition; (3) Substituent groups as hydrogen bond acceptors at the C2 position of the furan ring are favored. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential FBPase inhibitors. [ABSTRACT FROM AUTHOR]

5-HT6 receptor has been implicated in a series of diseases including anxiety, depression, schizophrenia and cognitive dysfunctions. 5-HT6 ligands have been reported to play a significant role in the treatment for central nervous system (CNS) diseases. Presently, a large series of 223 5-HT6 ligands were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics calculations for further improvement of potency. The optimal 3D models exhibit satisfying statistical results with r2 ncv, q2 values of 0.85 and 0.50 for CoMFA, 0.81 and 0.53 for CoMSIA, respectively. Their predictive powers were validated by external test set, showing r2 pred of 0.71 and 0.76. The contour maps also provide a visual representation of contributions of steric, electrostatic, hydrophobic and hydrogen bond fields as well as the prospective binding models. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential 5-HT6 ligands. [ABSTRACT FROM AUTHOR]

Experimental pEC50s for 216 selective respiratory syncytial virus (RSV) inhibitors are used to develop classification models as a potential screening tool for a large library of target compounds. Variable selection algorithm coupled with random forests (VS-RF) is used to extract the physicochemical features most relevant to the RSV inhibition. Based on the selected small set of descriptors, four other widely used approaches, i.e., support vector machine (SVM), Gaussian process (GP), linear discriminant analysis (LDA) and k nearest neighbors (kNN) routines are also employed and compared with the VS-RF method in terms of several of rigorous evaluation criteria. The obtained results indicate that the VS-RF model is a powerful tool for classification of RSV inhibitors, producing the highest overall accuracy of 94.34% for the external prediction set, which significantly outperforms the other four methods with the average accuracy of 80.66%. The proposed model with excellent prediction capacity from internal to external quality should be important for screening and optimization of potential RSV inhibitors prior to chemical synthesis in drug development. [ABSTRACT FROM AUTHOR]

This work is devoted to the prediction of a series of 208 structurally diverse PKCθ inhibitors using the Random Forest (RF) based on the Moldα molecular descriptors. The RF model was established and identified as a robust predictor of the experimental pIC50 values, producing good external R²pred of 0.72, a standard error of prediction (SEP) of 0.45, for an external prediction set of 51 inhibitors which were not used in the development of QSAR models. By using the RF built-in measure of the relative importance of the descriptors, an important predictor—the number of group donor atoms for H-bonds (with N and O)—has been identified to play a crucial role in PKCθ inhibitory activity. We hope that the developed RF model will be helpful in the screening and prediction of novel unknown PKCθ inhibitory activity. [ABSTRACT FROM AUTHOR]

Chiral conjugated polymers P‐1 and P‐2 were synthesized by the polymerization of (S)‐3,3′‐diiodo‐2,2′‐bisbutoxy‐1,1′‐binaphthyl and (S)‐6,6′‐dibromo‐2,2′‐bisbutoxy‐1,1′‐binaphthyl, respectively, with 5,5′‐divinyl‐2,2′‐bipyridine through a Heck cross‐coupling reaction. Chiral polymer complexes P‐C‐1 and P‐C‐2 were obtained by the bipyridine chelating coordination of P‐1 and P‐2 with Eu(TTA)3·2H2O (where TTA is 2‐thenoyltrifluoroacetonate). Polymers P‐1 and P‐2 and polymer complexes P‐C‐1 and P‐C‐2 exhibited intense circular dichroism signals, with negative and positive Cotton effects in their circular dichroism spectra. The chiral polymers showed strong green‐blue fluorescence because of the efficient energy migration from the extended π‐electronic structure of the conjugated polymer main to the chiral binaphthyl core. The chiral polymer complexes could have not only polymer fluorescence but also the characteristic fluorescence of Eu(III) (5D0→7F2) at a different excited wavelength. These kinds of chiral polymer complexes incorporating polybinaphthyls, bipyridine, and Eu(III) moieties are expected to provide an understanding of the relationship between the structure and properties of chiral polymer complexes. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 650–660, 2007 [ABSTRACT FROM AUTHOR]