In silico screening of epidermal growth factor receptor (EGFR) in the tyrosine kinase domain through a medicinal plant compound database

The unregulated epidermal growth factor receptor tyrosine kinase (ErbB1-TK or EGFR-TK) protein is involved in the proliferation of more than 50% of all cancer types. The reduction of EGFR-TK activity by small or medium-sized molecules has been proven to be an effective treatment for cancer. There is a widespread belief that Chinese medicinal herbs are active against several diseases, including various types of cancer. In this study, 29,960 compounds from the Chemiebase medicinal compound database were virtually screened against the EGFR-TK using AutoDock4.0, GOLD and GLIDE (XP). The results revealed eight potential hits: CAS nos. 104096-45-9, 112649-21-5, 113866-89-0, 142608-98-8, 142608-99-9, 144761-33-1, 155233-17-3 and 80510-05-0. These compounds have been reported to show anticancer activities in the literature. With the help of SiMMap and MOE interaction analysis, the protein–ligand interaction patterns between the functional groups of these compounds and the binding pocket residues were analyzed. Hydrogen bonding and hydrophobic forces are the main components of the interactions of these hits, similar to those observed for the known inhibitors erlotinib, gefitinib and AEE. The physicochemical filter indicates that compounds CAS nos. 104096-45-9 and 144761-33-1 are likely to be potential leads in the drug discovery process.     

Capillary zone electrophoresis for enumeration of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus in yogurt

Enumeration of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus is a priority due to their importance in yogurt production. Capillary electrophoresis (CE) of both bacteria could be achieved in 7.2 min with a resolution of 3.2 in the background electrolyte (BGE) containing 4.5 mM Tris(hydroxymethyl) amminomethane (TRIS)–4.5 mM boric acid–0.1 mM ethylenediamine tetraacetate (EDTA) (TBE) buffer (pH 8.4) and 0.05% (v/v) polyethylene oxide (PEO), using a capillary of 47.5 cm (effective length) × 100 μm i.d., injection of 50 mbar × 3 s followed by ?5 kV × 120 s, a voltage and temperature of 20 kV and 25 °C, respectively. Appropriate amounts of PEO in the BGE, sample preparation (i.e. vortex) and introduction were key factors for their separation. A short hydrodynamic injection followed by applying reversed polarity voltage could compress the bacteria into narrow zones, which were detected as separated single peaks. Method linearity (r² > 0.99), precision (%RSDs < 9.3%), recovery (%R = 91.7–106.7%) and limit of quantitation (1.0 × 10⁶ colony forming unit per mL (CFU/mL)) were satisfactory. Results from the CE analysis of both bacteria in yogurt were not statistically different from those of the plate count method (P > 0.05). The CE method can be used as an alternative for quantitation of L. delbrueckii subsp. bulgaricus and S. thermophilus in yogurt since it was reliable, simple, cost and labor effective and rapid, allowing the analysis of 3 samples/h (comparing to 2d/sample by plate count method).     

A dimeric chromanone and a phthalide: Metabolites from the seagrass-derived fungus Bipolaris sp. PSU-ES64

Two new metabolites, a dimeric chromanone, bipolarinone (1), and a phthalide, bipolarilide (2), as well as eight known compounds have been isolated from the seagrass-derived fungus Bipolaris sp. PSU-ES64. The structures were elucidated by analysis of spectroscopic data. The absolute configuration of 1 was determined by circular dichroism spectroscopy, Mosher's method, and NOEDIFF data. The antioxidant and antimicrobial activities of the isolated compounds were examined.     

Biosurfactant production by Pseudomonas aeruginosa SP4 using sequencing batch reactors: effects of oil loading rate and cycle time

In this present study, sequencing batch reactors (SBRs) were used for biosurfactant production from Pseudomonasaeruginosa SP4, which was isolated from petroleum-contaminated soil in Thailand. Two identical lab-scale aerobic SBR units were operated at a constant temperature of 37 degrees C, and a mineral medium (MM) with palm oil was used as the culture medium. The effects of oil loading rate (OLR) and cycle time on the biosurfactant production were studied. The results indicated that the optimum conditions for the biosurfactant production were at an OLR of 2 kg/m(3)days and a cycle time of 2 days/cycle, which provided a surface tension reduction of 59%, a chemical oxygen demand (COD) removal of 90%, and an oil removal of 97%. Under the optimum conditions, it was found that the biosurfactant production was maximized at an aeration time of 40 h. These preliminary results suggest that the SBR can potentially be adapted for biosurfactant production, and perhaps further developed, potentially for large-scale biosurfactant production.     

Cytosolic, but not mitochondrial, oxidative stress is a likely contributor to cardiac hypertrophy resulting from cardiac specific GLUT4 deletion in mice

We hypothesized that oxidative stress may contribute to the development of hypertrophy observed in mice with cardiac specific ablation of the insulin sensitive glucose transporter 4 gene (GLUT4, G4H(-/-) ). Measurements of oxidized glutathione (GSSG) in isolated mitochondria and whole heart homogenates were increased resulting in a lower ratio of reduced glutathione (GSH) to GSSG. Membrane translocation of the p67(phox) subunit of cardiac NADPH oxidase 2 (NOX2) was markedly increased in G4H(-/-) mice, suggesting elevated activity. To determine if oxidative stress was contributing to cardiac hypertrophy, 4-week-old control (Con) and G4H(-/-) mice were treated with either tempol (T, 1 mm, drinking water), a whole cell antioxidant, or Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP, 10 mg·kg(-1) , intraperitoneally), a mitochondrial targeted antioxidant, for 28 days. Tempol attenuated cardiac hypertrophy in G4H(-/-) mice (heart : tibia, Con 6.82 ± 0.35, G4H(-/-) 8.83 ± 0.34, Con + T 6.82 ± 0.46, G4H(-/-) + T 7.57 ± 0.3), without changing GSH : GSSG, glutathione peroxidase 4 or membrane translocation of the p67(phox) . Tempol did not modify phosphorylation of glycogen synthase kinase 3β or thioredoxin-2. In contrast, MnTBAP lowered mitochondrial GSSG and improved GSH : GSSG, but did not prevent hypertrophy, indicating that mitochondrial oxidative stress may not be critical for hypertrophy in this model. The ability of tempol to attenuate cardiac hypertrophy suggests that a cytosolic source of reactive oxygen species, probably NOX2, may contribute to the hypertrophic phenotype in G4H(-/-) mice.     

The rise and fall of the Lower Mississippi: effects of hydrologic connection on floodplain backwaters

In the last 150 years, the Lower Mississippi River (LMR) floodplain was extensively reduced in area with conversion of once regularly inundated floodplain wetlands to dry land. Yet, between the present levees, there remain substantial remnants of the historical floodplain, including various types of permanent backwater habitats. We hypothesized that degree and timing of hydrologic connection with the river main channel drives variation in physical and chemical properties, and phytoplankton community dynamics, in backwaters. Over 23 months, measurements were made in several sites varying in connection with the main channel. At high stages, the channel and backwaters converged in having elevated turbidity, suspended solids and dissolved nutrient concentrations, reduced algal biomass and production, a seston C:N ratio indicating predominantly allochthonous organic matter sources, and a diatom-dominated community. When connection was reduced, backwaters declined in suspended sediments and nutrients, surged in production and biomass, had a seston C:N ratio reflecting autochthonous production, and switched to a community dominated by cryptomonad algae. With prolonged isolation, biomass-specific production became nitrogen limited and declined. By a conceptual model, we illustrate the seasonally variable role of permanent floodplain backwaters as major sources of algal organic matter, and potentially for nutrient sequestration, within the Lower Mississippi system.     

Structural and physicochemical characterization of crude biosurfactant produced by Pseudomonas aeruginosa SP4 isolated from petroleum-contaminated soil

Pseudomonas aeruginosa strain SP4, isolated from petroleum-contaminated soil in Thailand, was used to produce a biosurfactant from a nutrient broth with palm oil as the carbon source. The key components of the crude biosurfactant were fractionated by using HPLC-ELSD technique. With the use of ATR-FTIR spectroscopy, in combination with (1)H NMR and MS analyses, chemical structures of the fractionated components of the crude biosurfactant were identified as rhamnolipid species. When compared to synthetic surfactants, including Pluronic F-68, which is a triblock nonionic surfactant containing poly(ethylene oxide) and poly(propylene oxide), and sodium dodecyl sulfate, the crude biosurfactant showed comparable physicochemical properties, in terms of the surface activities. The crude biosurfactant reduced the surface tension of pure water to 29.0 mN/m with a critical micelle concentration of approximately 200 mg/l, and it exhibited good thermal and pH stability. The crude biosurfactant also formed stable water-in-oil microemulsions with crude oil and various types of vegetable oils, but not with short-chain hydrocarbons.     

Computational analyses of curcuminoid analogs against kinase domain of HER2

Background

Human epidermal growth factor receptor 2 (HER2) has an important role in cancer aggressiveness and poor prognosis. HER2 has been used as a drug target for cancers. In particular, to effectively treat HER2-positive cancer, small molecule inhibitors were developed to target HER2 kinase. Knowing that curcumin has been used as food to inhibit cancer activity, this study evaluated the efficacy of natural curcumins and curcumin analogs as HER2 inhibitors using in vitro and in silico studies. The curcumin analogs considered in this study composed of 4 groups classified by their core structure, β-diketone, monoketone, pyrazole, and isoxazole.

Results

In the present study, both computational and experimental studies were performed. The specificity of curcumin analogs selected from the docked results was examined against human breast cancer cell lines. The screened curcumin compounds were then subjected to molecular dynamics simulation study. By modifying curcumin analogs, we found that protein-ligand affinity increases. The benzene ring with a hydroxyl group could enhance affinity by forming hydrophobic interactions and the hydrogen bond with the hydrophobic pocket. Hydroxyl, carbonyl or methoxy group also formed hydrogen bonds with residues in the adenine pocket and sugar pocket of HER2-TK. These modifications could suggest the new drug design for potentially effective HER2-TK inhibitors. Two outstanding compounds, bisdemethylcurcumin (AS-KTC006) and 3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (AS-KTC021 ),were well oriented in the binding pocket almost in the simulation time, 30 ns. This evidence confirmed the results of cell-based assays and the docking studies. They possessed more distinguished interactions than known HER2-TK inhibitors, considering them as a promising drug in the near future.

Conclusions

The series of curcumin compounds were screened using a computational molecular docking and followed by human breast cancer cell lines assay. Both AS-KTC006 and AS-KTC021 could inhibit breast cancer cell lines though inhibiting of HER2-TK. The intermolecular interactions were confirmed by molecular dynamics simulation studies. This information would explore more understanding of curcuminoid structures and HER2-TK.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-261) contains supplementary material, which is available to authorized users.     

Bacterial production in the Lower Mississippi River: importance of suspended sediment and phytoplankton biomass

The roles and metabolic activity of heterotrophic bacteria, along with factors controlling their activity, are poorly known for large, turbid rivers. The aim of this study was to evaluate temporal patterns in heterotrophic bacterial production (BP) in the main channel of the Lower Mississippi River (LMR) in relation to several seasonally dynamic environmental factors. We hypothesized that whole-water BP would vary with levels of temperature, as well as phytoplankton biomass and suspended sediment concentration. Further, we hypothesized that bacteria attached to suspended sediment would comprise an important component of whole-water BP, their importance varying with sediment concentration. Measurements were made at three locations on the LMR for up to 29 months. Bacterial production in whole-water ranged over an order of magnitude between summer and winter, with little variation among sites. Peaks in whole-water BP were associated with periods of high suspended sediment concentrations in spring, and elevated phytoplankton biomass in summer. Attached BP was correlated with all the measures of sediment concentration, especially particulate phosphorus, and accounted for a large majority of water-column BP. After temperature, the only positive correlate of free-living cells was with phytoplankton biomass. Rates of BP in the LMR during summer were much higher than measurements made previously in the Mississippi River plume, similar to the Hudson River, but lower than in three large tributaries of the LMR. Determination of bacterial population dynamics is an essential step in analysis of the food web structure and biogeochemical processes of large rivers. This is the first study of heterotrophic bacterial production in the main channel of the LMR.