Discovery of highly potent and selective D4 ligands by interactive SAR study

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with K_i 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with K_i (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands’ arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.     

Impact of green tea on oxidative stress induced by ammonium metavanadate exposure in male rats

Transitional metals, as vanadium, are known to exert noxious effects by generating oxidative stress. Addition of antioxidants in the diet could decrease the cytotoxic effect related to the oxidative stress. The present study, carried out in Wistar rats, is a contribution to the evaluation of protective effects of green tea Camellia sinensis, which is known to be rich in antioxidant compounds (polyphenols...). Rats were divided into four groups: (C) was control, (V) was given ammonium metavanadate (AMV), (TH) was given herbal tea as drink (66 g/l) and TH + V was given tea and metavanadate. Group (TH) was given herbal tea one month before vanadium treatment. Metavanadate was daily i.p. injected (5 mg NH4VO3/kg body weight) for 10 days. (C) and (TH) groups received i.p. injections of 0.9% NaCl during the same period. Changes in lipid peroxidation levels (TBARS) in kidney, liver and testes, serum concentrations of vitamins E and A and superoxidismutase (SOD) and catalase (CAT) activities in blood cells were determined. One month pre-treatment with green tea, followed by 10 days of treatment (TH) did not change TBARS in liver and testes as compared to controls, but induced a clear decrease of TBARS in kidneys. Intraperitoneal administration of AMV to rats (V) induced a time-dependant increase of TBARS in kidney, liver and testes that was lowered in rats (V + TH) drinking tea. Vitamin E concentrations were found to be drastically decreased from day 1 to 10 in rats (V). Vitamin A concentration was decreased at day 10 only. Drinking tea lowered AMV inhibitory effects in rats (V + TH), and conversely an increase of vitamins A and E concentrations were found at day 10. SOD and catalase activities were found increased in the blood cells from day 1 to day 5 and conversely decreased at day 10. In contrast, associated to green tea, AMV did not affect SOD and catalase activities compared to controls.     

Mobilization of non-exchangeable K by ryegrass in five Moroccan soils with and without mica

Intensive cropping of Italian ryegrass (Lolium multiforum L.) in pots was used to assess the contribution of non-exchangeable K to plant uptake. The soils used were: two soils high in mica (illite) developed on recent alluvium plus two smectitic (beidellitic) soils and a soil of mixed mineralogy rich in mica. Four K treatments were used (0, 28.6, 143, and 286 mg kg^-1 soil) with 8 successive monthly cuttings. A response of plant K uptake to added K was observed in all soils. Both 1.0 M NH₄0Ac and 0.2 M CaCl₂ extractable K were depleted to a minimum level specific for each soil. The minima were lower in the old upland soils compared to the young alluvial soils. Uptake of K by Italian ryegrass induced K release from the non-exchangeable K to replenish the plant available pool of K ions. The release of mica interlayer K in the alluvial and in the high K smectitic soil supplied sufficient K to plants even under intensive cropping. The rate of mobilization of interlayer K was low in the smectitic soil with lower K. The lowest release rate was in the old high mica soil. Iron coatings may have inhibited mobilization of interlayer K. The rates of mobilization cannot be predicted from mineralogical and K-extraction data only. The rates of K uptake and the rates of K release by ryegrass under intensive cropping are potential values which can be used for modelling K availability to plants in the soils studied.     

Enterocin F4-9, a Novel O-Linked Glycosylated Bacteriocin

Enterococcus faecalis F4-9 isolated from Egyptian salted-fermented fish produces a novel bacteriocin, termed enterocin F4-9. Enterocin F4-9 was purified from the culture supernatant by three steps, and its molecular mass was determined to be 5,516.6 Da by mass spectrometry. Amino acid and DNA sequencing showed that the propeptide consists of 67 amino acid residues, with a leader peptide containing a double glycine cleavage site to produce a 47-amino-acid mature peptide. Enterocin F4-9 is modified by two molecules of N-acetylglucosamine β-O-linked to Ser37 and Thr46. The O-linked N-acetylglucosamine moieties are essential for the antimicrobial activity of enterocin F4-9. Further analysis of the enterocin F4-9 gene cluster identified enfC, which has high sequence similarity to a glycosyltransferase. The antimicrobial activity of enterocin F4-9 covered a limited range of bacteria, including, interestingly, a Gram-negative strain, Escherichia coli JM109. Enterocin F4-9 is sensitive to protease, active at a wide pH range, and moderately resistant to heat.     

Mechanisms of GDF-5 action during skeletal development

Mutations in GDF-5, a member of the TGF-beta superfamily, result in the autosomal recessive syndromes brachypod (bp) in mice and Hunter-Thompson and Grebe-type chondrodysplasias in humans. These syndromes are all characterised by the shortening of the appendicular skeleton and loss or abnormal development of some joints. To investigate how GDF-5 controls skeletogenesis, we overexpressed GDF-5 during chick limb development using the retrovirus, RCASBP. This resulted in up to a 37.5% increase in length of the skeletal elements, which was predominantly due to an increase in the number of chondrocytes. By injecting virus at different stages of development, we show that GDF-5 can increase both the size of the early cartilage condensation and the later developing skeletal element. Using in vitro micromass cultures as a model system to study the early steps of chondrogenesis, we show that GDF-5 increases chondrogenesis in a dose-dependent manner. We did not detect changes in proliferation. However, cell suspension cultures showed that GDF-5 might act at these stages by increasing cell adhesion, a critical determinant of early chondrogenesis. In contrast, pulse labelling experiments of GDF-5-infected limbs showed that at later stages of skeletal development GDF-5 can increase proliferation of chondrocytes. Thus, here we show two mechanisms of how GDF-5 may control different stages of skeletogenesis. Finally, our data show that levels of GDF-5 expression/activity are important in controlling the size of skeletal elements and provides a possible explanation for the variation in the severity of skeletal defects resulting from mutations in GDF-5.     

Synthesis of New Bis(pyrazolo[1,5-a]pyrimidines) Linked to Different Spacers as Potential MurB Inhibitors

An efficient protocol was adopted to efficiently prepare three new series of bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers. The new bis(pyrazolo[1,5-a]pyrimidines) were prepared in 80–90 % yields by reacting the respective bis(enaminones) and 4-(4-substituted benzyl)-1H-pyrazole-3,5-diamines in pyridine at reflux temperature for 5–7 h. The new products showed a wide spectrum of antibacterial activity against six different bacterial strains. In general, propane- and butane-linked bis(pyrazolo[1,5-a]pyrimidines), which are attached to 3-(4-methyl- or 4-methoxybenzyl) units, had the best antibacterial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values up to 2.5 and 5.1 μM, respectively. Additionally, the previous products demonstrated promising MurB inhibitory activity with IC₅₀ values up to 7.2 μM.     

Structure-based virtual screening of essential Mycobacterium tuberculosis enzymes AspS and KatG for potential inhibitors

Mycobacterium tuberculosis (TB) is a leading global cause of disease-related death. Recent works have studied metabolic pathways of the mycobacterium, highlighting essential enzymes to target via competitive inhibition through computational molecular modeling to suppress the organism''s life cycle. We used the Protein Databank (PDB), the UniProt Knowledgebase and the iDock server in this study. In vitro toxicity screening and pharmacokinetic properties were assessed to determine potential ligand safety and drug properties. Our results have revealed five and nine potential ligands for the enzymes AspS and KatG respectively. The KatG active site has displayed binding affinities of -13.443 to -12.895 kcal/mol, while AspS ligands range from -6.580 to -6.490kcal/mol. The intermolecular forces responsible for the differing binding affinities of each enzyme are primarily Coulombic interactions for AspS, versus Coulombic and extensive hydrogen bonding interactions in KatG.     

Hypolipidemic effect of diet supplementation with bacterial levan in cholesterol-fed rats

Levan polysaccharide, a type of fructan, has been shown to have industrial applications as a new industrial gum in the fields of cosmetics, foods like dietary fiber and pharmaceutical goods. The objective of this current study was to investigate the possible hypolipidemic and antioxidative effects of levan in rats fed with a high-cholesterol diet. Animals were allocated into four groups of six rats each: a normal diet group (Control), normal rats received levan (L), a high-cholesterol diet group (Chol) and a high-cholesterol diet with a daily dose of levan equivalent to 5%. Treated hypercholesterolemic rats were administrated with levan in drinking water through oral gavage for 60 days. After the treatment period, the plasma antioxidant enzymes and lipid profiles were determined. Our results show that treatment with levan polysaccharide positively changed plasma antioxidant enzyme activities and lipid profiles (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides) in cholesterol-rats, and thus may have potential hypolipidemic and antioxidant effects. Levan could protect against oxidative stress linked atherosclerosis and decrease the atherogenic index.     

Toxicity assessment of the puffer fish Lagocephalus lagocephalus from the Tunisian coast

This study was undertaken to assess the risk of poisoning due to consumption of the puffer fish Lagocephalus lagocephalus collected along the Tunisian coast. Wistar rats were daily intraperitoneally injected, for 10 days, with acidic extracts of liver or flesh (muscles + skin) of L. lagocephalus. Control rats received injections of NaCl (0.9%). No mortality and no evident signs of neurotoxicity were recorded in treated rats. Conversely, treatment led to: (1) diarrhoea and body and organ (liver, kidney) weights loss; (2) oxidative stress evidenced by an increase in lipid peroxidation (TBARS) and conversely a decrease in antioxidant enzyme activities (SOD, catalase, GSH-Px) in tissues (blood cells, liver, kidneys); (3) a decrease in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities in blood plasma.     

The Possible Roles of Priming with ZnO Nanoparticles in Mitigation of Salinity Stress in Lupine (Lupinus termis) Plants

To our knowledge, little attention has been paid to evaluating ZnO nanoparticles (ZNPs) roles in plants grown under salinity stress. In this study, seeds of lupine (Lupinus termis) plants were grown in plastic pots and exposed to 0 (control) and 150 (S) mM NaCl with or without priming with different concentrations of ZnO [20 mg L^?1 (ZNPs1), 40 mg L^?1 (ZNPs2), and 60 mg L^?1 (ZNPs3)] for 20 days. Salinized plants showed a reduction in plant growth parameters (root length, shoot length, fresh weight, and dry weight) and in the contents of photosynthetic pigments (chlorophyll a and b, and carotenoids) and Zn, as well as in the activity of catalase (CAT) against control plants. On the other side, salinity stress boosted the contents of organic solutes (soluble sugar, soluble protein, total free amino acids, and proline), total phenols, malondialdehyde (MDA), ascorbic acid and Na, as well as the activities of superoxide dismutase (SOD), peroxidase (POD), and ascorbate peroxidase (APX) in stressed plants over control plants. However, seed-priming with ZNPs mostly stimulated growth of stressed plants, which was accompanied by reinforcement in the levels of photosynthetic pigments, organic solutes, total phenols, ascorbic acid and Zn, as well as in the activities of SOD, CAT, POD, and APX enzymes over stressed plants alone. On the contrary, priming with ZNPs caused a decrement in the contents of MDA and Na in stressed plants relative to salinized plants alone. It is worthy to mention that, this improvement in salt tolerance of plants primed with ZNPs was more obvious in plants primed with ZNPs3 and grown both in unstressed and stressed regimes. Thus, our findings suggest that seed-priming with ZNPs, especially 60 mg L^?1 ZnO is an effective strategy that can be used to enhance salt tolerance of lupine plants.