Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies

Several recent developments suggest that the human glyoxalase I (GLO I) is a potential target for anti-tumor drug development. In present study, a series of curcumin derivatives with high inhibitory activity against human GLO I were discovered. Inhibition constant (K(i)) values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600μM, 2.600μM, 3.200μM, 3.600μM and 3.600μM, respectively. To elucidate the structural features of potent inhibitors, docking-based three-dimensional structure-activity relationship (3D-QSAR) analyses were performed. Satisfactory agreement between experiment and theory suggests that comparative molecular similarity index analysis (CoMSIA) modeling exhibit much better correlation and predictive power. The cross-validated q(2) value is 0.638 while no-validation r(2) value is 0.930. Integrated with docking-based 3D-QSAR CoMSIA modeling, molecular surface property (electrostatic and steric) mapping and molecular dynamics simulation, a set of receptor-ligand binding models and bio-affinity predictive models for rational design of more potent inhibitors of GLO I are established.     

Skin thermal pain modeling—A holistic method

Pain sensation has been studied extensively, over a range of scales, from the molecular level to the entire human neural system. Thermal stimulation of pain has been widely used in the study of pain sensation. Skin thermal pain is induced through both direct (an increase/decrease in temperature) and indirect (thermomechanical and thermochemical) ways, and is governed by complicated thermomechanical–chemical–neurophysiologic responses. This paper is focused on the theoretical modeling of the underlying mechanisms in the process of skin thermal pain. A holistic model has been developed, which is composed of three sub-models, namely, transduction, transmission, and modulation and perception. The model can contribute to the understanding of thermally related pain phenomena in skin tissue and to improvements in a range of thermal therapeutic methods.     

Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.     

Isolation and identification of a potential biocontrol agent Bacillus subtilis QM3 from Qinghai yak dung in China

Biocontrol agents have not been previously associated with yak dung. We describe here the isolation of strain QM3 from Qinghai yak dung in China. In vitro antagonistic assay showed that this strain could suppress the growth of various plant pathogens effectively, especially the pathogen Alternaria solani. Based on phenotypic, physiological, biochemical and phylogenetic (16S rDNA) studies, strain QM3 could be classified as a strain of Bacillus subtilis. Both OD₆₆₀ and inhibition effect of eight different kinds of culture media presented strongly significant difference with 0.006 (P < 0.01) and 0.003 (P < 0.01), respectively. Culture media YPF-Ca were selected from eight different kinds of culture media according to OD₆₆₀ and inhibitory effect. Different thermal treatments on the crude supernatant showed the antibiotic activity presented no significant (P = 0.54, P > 0.05) with ANOVA at the 5% level when temperature was no higher than 100°C. These results were similarly in agreement with the reported thermo-resistance of iturin antibiotics produced by Bacillus. This is the first report on the isolation of Bacillus subtilis from the yak dung.     

QTL mapping of phosphorus efficiency and relative biologic characteristics in maize (Zea mays L.) at two sites

The phosphorus efficiency, relative biologic characteristics and relative root exudations as well as the quantitative trait loci associated with these traits were determined for an F_2:3 population derived from the cross of two contrasting maize (Zea mays L.) genotypes, 082 and Ye107. A total of 241 F_2:3 families were evaluated in replicated trials under normal phosphorus (50 kg P/ha) and low phosphorus (0 kg P/ha) conditions in 2007 at two sites (Kaixian and Southwest University). The genetic map constructed by 275 SSR and 146 AFLP markers spanned 1,681.3 cM in length with an average interval of 3.84 cM. The heritability of PE, PAE, RPH, RBW, RRW, RLA, TPS, RTW, RFN, RAP and RH was all high ( $h_{\text{b}}^2 > 60\% $ ) whereas the heritability of root exudations was all low ( $h_{\text{b}}^2 > 60\% $ ).By using composite interval mapping (CIM), a total of 30 and 45 distinct QTLs were identified at Kaixian and Southwest University. At two sites, the number of same QTL located on common region was 16, five for PE (bins 1.07, 4.09, 5.05, 5.07, 5.08), three for RBW (bins 3.04, 5.04, 6.05), three for RRW (bins 5.05, 5.06, 5.07), one for RLA (bins 3.04), two for TPS (bins 3.08, 5.07), two for RTW (bins 5.05, 5.06). These QTLs explained 21% of the phenotypic variation of PE, 5–9% of RBW, 13–16% of RRW, 9% of TPS, 7% of RTW, respectively. The 16 common QTLs displayed mostly partial dominance or over-dominance gene action. Most QTL alleles conferring high values for the traits came from two parents. Mapping analysis identified chromosomal regions associated with two or more traits in a cluster, which was consistent with correlation among traits. The result showed either pleiotropy or tight linkage among QTL. Five common regions for same QTL at different site were found in the interval bnlg1556-bnlg1564 (bins 1.06), mmc0341-umc1101 (bins 4.08), mmc0282-phi333597 (bins 5.05), bnlg1346-bnlg1695 (bins 5.07) and bnlg118a-umc2136 (bins 5.08), which were important for PE. The information reported in the present paper may be useful for improving phosphorus efficiency by means of marker-assisted selection.     

Anti-inflammatory mechanism of taurine against ischemic stroke is related to down-regulation of PARP and NF-κB

Taurine is reported to reduce tissue damage induced by inflammation and to protect the brain against experimental stroke. The objective of this study was to investigate whether taurine reduced ischemic brain damage through suppressing inflammation related to poly (ADP-ribose) polymerase (PARP) and nuclear factor-kappaB (NF-κB) in a rat model of stroke. Rats received 2 h ischemia by intraluminal filament and were then reperfused. Taurine (50 mg/kg) was administered intravenously 1 h after ischemia. Treatment with taurine markedly reduced neurological deficits, lessened brain swelling, attenuated cell death, and decreased the infarct volume 72 h after ischemia. Our data showed the up-regulation of PARP and NF-κB p65 in cytosolic fractions in the core and nuclear fractions in the penumbra and core, and the increases in the nuclear poly (ADP-ribose) levels and the decreases in the intracellular NAD⁺ levels in the penumbra and core at 22 h of reperfusion; these changes were reversed by taurine. Moreover, taurine significantly reduced the levels of tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and intracellular adhesion molecule-1, lessened the activities of myeloperoxidase and attenuated the infiltration of neutrophils in the penumbra and core at 22 h of reperfusion. These data demonstrate that suppressing the inflammatory reaction related to PARP and NF-κB-driven expression of inflammatory mediators may be one mechanism of taurine against ischemic stroke.     

A specific PCR assay for the diagnosis of Clonorchis sinensis infection in humans, cats and fishes

Clonorchiasis caused by Clonorchis sinensis is a fish-borne parasitic disease which is endemic in a number of countries. Using the sequences of the internal transcribed spacers (ITS-1 and ITS-2) of nuclear ribosomal DNA (rDNA) of C. sinensis as genetic markers, a pair of C. sinensis-specific primers was designed and used to establish a specific PCR assay for the diagnosis of C. sinensis infection in humans, cats and fish. This approach allowed the specific identification of C. sinensis after optimizing amplification conditions, with no amplicons being amplified from related heterogeneous DNA samples, and sequencing of amplicons confirmed the identity of the sequences amplified. The detection limit of this assay was 1.03 pg of adult C. sinensis, 1.1 metacercariae per gram of fish filet, and a single egg in human and cat feces. The PCR assay should provide a useful tool for the diagnosis and molecular epidemiological investigation of clonorchiasis in humans and animals.     

Altered adipocyte progenitor population and adipose-related gene profile in adipose tissue by long-term high-fat diet in mice

AimsHigh-fat diet (HFD) is associated with adipose inflammation, which contributes to key components of metabolic abnormalities. The expanded adipose tissue mass associated with obesity is the result of hyperplasia and hypertrophy of adipocytes. In this study, we investigated the effects of long-term HFD on adipocyte progenitor cell (APC) population and adipose-specific gene profiles in both white and brown adipose, and the role of perivascular adipose in the alteration of vascular function in response to HFD.Main methodsMale C57BL/6 mice were fed a standard normal diet (ND) or HFD for about 8 months. Glucose metabolism was assessed by an intraperitoneal glucose tolerance test. APC population and adipose-related gene profile were evaluated, and vascular function was measured in the presence or absence of perivascular adipose. Adiponectin and AMPK activity were also investigated.Key findingsHFD induced insulin resistance and glucose intolerance, and resulted in a decrease in APC population in brown, but not in white adipose tissue, when compared with animals fed a ND, with differential alterations of white and brown adipocyte-specific gene expression in brown and white adipose. Additionally, HFD led to altered vascular function in arteries in the presence of perivascular adipose tissue, which is associated with increased superoxide production. Adiponectin and AMPK activity were significantly decreased in response to long-term HFD.SignificanceThese findings suggest that long-term high-fat intake differentially alters adipocyte progenitor population and adipose-related gene expression in adipose tissue, and adiponectin-AMPK signaling might be involved. In addition, HFD induces changes in perivascular adipose-mediated vascular function.     

Glucokinase contributes to glucose phosphorylation in d-lactic acid production by Sporolactobacillus inulinus Y2-8

Sporolactobacillus inulinus, a homofermentative lactic acid bacterium, is a species capable of efficient industrial d-lactic acid production from glucose. Glucose phosphorylation is the key step of glucose metabolism, and fine-tuned expression of which can improve d-lactic acid production. During growth on high-concentration glucose, a fast induction of high glucokinase (GLK) activity was observed, and paralleled the patterns of glucose consumption and d-lactic acid accumulation, while phosphoenolpyruvate phosphotransferase system (PTS) activity was completely repressed. The transmembrane proton gradient of 1.3–1.5 units was expected to generate a large proton motive force to the uptake of glucose. This suggests that the GLK pathway is the major route for glucose utilization, with the uptake of glucose through PTS-independent transport systems and phosphorylation of glucose by GLK in S. inulinus d-lactic acid production. The gene encoding GLK was cloned from S. inulinus and expressed in Escherichia coli. The amino acid sequence revealed significant similarity to GLK sequences from Bacillaceae. The recombinant GLK was purified and shown to be a homodimer with a subunit molecular mass of 34.5?kDa. Strikingly, it demonstrated an unusual broad substrate specificity, catalyzing phosphorylation of 2-deoxyglucose, mannitol, maltose, galactose and glucosamine, in addition to glucose. This report documented the key step concerning glucose phosphorylation of S. inulinus, which will help to understand the regulation of glucose metabolism and d-lactic acid production.