Urease and serine protease inhibitory alkaloids from Isatis tinctoria

Phytochemical investigations on the alkaloidal fraction of the whole plant of the Isatis tinctoria led to the isolation of the alkaloids 1-6., 3'-Hydroxyepiglucoisatisin (3), Epiglucoisatisin (2) were found to be potent urease inhibitors in a concentration-dependent manner with IC(50) values 25.63 +/- 0.74, 37.01 +/- 0.41 and 31.72 +/- 0.93, 47.33 +/- 0.31 microM against Bacillus pasteurii & Jack bean urease, respectively. Compounds 3 and 2 also showed potent inhibitory potential against alpha-chymotrypsin with IC(50) values of 23.40 +/- 0.21 and 27.45 +/- 0.23 microM, respectively.     

Nuclear DNA content of Vitis species,cultivars, and other genera of the Vitaceae

The nuclear DNA content was analyzed in Vitis species, hybrid cultivars, and genera of the Vitaceae using flow cytometry. Significant variation was found among Vitis species, hybrids, and other genera of the Vitaceae (Ampelopsis and Parthenocissus). DNA content was estimated to range from 0.98 to 1.05 pg/2C within V. labrusca (ns) and 0.86 to 1.00 pg/2C within V. vinifera (ns). Genotypes from Vitis and Parthenocissus were similar in nuclear DNA content (approximately 1.00 pg/2C) whereas they differed significantly from Ampelopsis (1.39 pg/2C). No correlation between DNA content and the center of origin of genotypes of the Vitaceae was noted. Based on the present study, the Vitis genome size is 475 Mbp, 96% of which is non-coding. Knowledge of DNA content is useful in order to understand the complexity of the Vitis genome and to establish a relationship between the genetic and physical map for map-based cloning.     

Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties

The withanolides 1-3 and 4-5 isolated from Ajuga bracteosa and Withania somnifera, respectively, inhibited acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes in a concentration-dependent fashion with IC50 values ranging between 20.5 and 49,2 microm and 29.0 and 85.2 microm for AChE and BChE, respectively. Lineweaver-Burk as well as Dixon plots and their secondary replots indicated that compounds 1, 3, and 5 are the linear mixed-type inhibitors of AChE, while 2 and 4 are non-competitive inhibitors of AChE with K(i) values ranging between 20.0 and 45.0 microm. All compounds were found to be non-competitive inhibitors of BChE with K(i) values ranging between 27.7 and 90.6 microm. Molecular docking study revealed that all the ligands are completely buried inside the aromatic gorge of AChE, while compounds 1, 3, and 5 extend up to the catalytic triad. A comparison of the docking results showed that all ligands generally adopt the same binding mode and lie parallel to the surface of the gorge. The superposition of the docked structures demonstrated that the non-flexible skeleton of the ligands always penetrates the aromatic gorge through the six-membered ring A, allowing their simultaneous interaction with more than one subsite of the active center. The affinity of ligands with AChE was found to be the cumulative effects of number of hydrophobic contacts and hydrogen bonding. Furthermore, all compounds also displayed dose-dependent (0.005-1.0 mg/mL) spasmolytic and Ca2+ antagonistic potentials in isolated rabbit jejunum preparations, compound 4 being the most active with an ED50 value of 0.09 +/- 0.001 mg/mL and 0.22 +/- 0.01 microg/mL on spontaneous and K+ -induced contractions, respectively. The cholinesterase inhibitory potential along with calcium antagonistic ability and safe profile in human neutrophil viability assay could make compounds 1-5 possible drug candidates for further study to treat Alzheimer's disease and associated problems.     

Auxins and Gibberellin-like Substances in Parthenocarpic and Non-parthenocarpic Syconia of Ficus carica L., cv. King

In the King cultivar of fig, the first crop is parthenocarpic, develops on previous year's growth, and a series of supernumerary ovules develops within the original ovules. The second crop, formed on current-season's growth, requires fertilization. To determine whether the 2 crops differed in types, and in patterns of concentrations of total `free' auxins and acidic gibberellins, they were extracted from weekly fruit samples. Timing of the 3 peaks of total auxins and the single peak of gibberellins was identical in the 2 crops. The first auxin peak in both occurred at the end of fruit growth period I (first rapid growth period), the second shortly before the end of period II (period of slow growth), and the rise and fall in concentrations of the third peak accompanied the rise and fall of the fruit growth rate in period III. The end of period II was marked by the single gibberellin peak. Additional peaks before the first sampling dates, of auxins in the first crop, of gibberellins in the second, were indicated by high concentrations in the first samples and subsequent rapid decline. The same 4 individual auxins appeared in both crops. Auxins I and II were highest in concentration in the first total auxin peak of both crops. In the second peak of the first crop, auxins II and III were highest, whereas in that peak of the second crop auxins II and IV were highest. Qualitative differences in gibberellins occurred in the 2 crops. In general, auxin concentrations were higher in the first than the second crop, and gibberellin concentrations higher in the second. High concentrations of gibberellins coincided with low ones of auxins, and vice versa.     

Interactions of neomycin and calcium in synaptosomal membranes and polyphosphoinostide monolayers.

Neomycin and related aminoglycosidic antibiotics displace calcium from synaptosomes of guinea pig cerebral cortex and from preparations of phosphatidylinositol diphosphate. At low drug concentrations, inhibition of synaptosomal calcium binding is competitive (Ki = 3-10(-5) M), at high concentrations it is non-competitive (Ki = 4-10(-4) M). Monomolecular films of phosphatidylinositol diphosphate are contracted by low concentrations of neomycin in the subphase, and are expanded at high concentrations. This expansion perists even at the collapse pressure indicating a strong interaction between the drug and the lipid.     

Synthesis of Novel Bi-Heterocycles as Valuable Anti-Diabetic Agents: 2-({5-((2-Amino-1,3-Thiazol-4-yl)methyl)-1,3,4-Oxadiazol-2-yl}sulfanyl)-N-(Substituted)acetamides

Russian Journal of Bioorganic Chemistry - The synthesis of a new series of S-substituted acetamides derivatives of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol were synthesized and...     

A New Bacillus pasteurii Urease Inhibitor from Euphorbia decipiens

Inhibition of Bacillus pasteurii urease enzyme by 3,7,15-tri-O-acetyl-5-O-nicotinoyl-13,14-dihydroxymyrsinol (1), a diterpene ester with a myrsinol-type skeleton, isolated from Euphorbia decipiens Boiss. & Buhse, was un-competitive consistent with the molecular docking results. The Ki value was 117.40 ± 0.7 μM.     

Urease and Serine Protease inhibitory alkaloids from Isatis tinctoria

Phytochemical investigations on the alkaloidal fraction of the whole plant of the Isatis tinctoria led to the isolation of the alkaloids 1-6., 3′-Hydroxyepiglucoisatisin (3), Epiglucoisatisin (2) were found to be potent urease inhibitors in a concentration-dependent manner with IC₅₀ values 25.63 ± 0.74, 37.01 ± 0.41 and 31.72 ± 0.93, 47.33 ± 0.31 μM against Bacillus pasteurii & Jack bean urease, respectively. Compounds 3 and 2 also showed potent inhibitory potential against α-chymotrypsin with IC₅₀ values of 23.40 ± 0.21 and 27.45 ± 0.23 μM, respectively.     

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

Peroxisome proliferator-activated receptor (PPAR)α is a nuclear receptor that coordinates liver metabolism during fasting. Fatty acid synthase (FAS) is an enzyme that stores excess calories as fat during feeding, but it also activates hepatic PPARα by promoting synthesis of an endogenous ligand. Here we show that the mechanism underlying this paradoxical relationship involves the differential regulation of FAS in at least two distinct subcellular pools: cytoplasmic and membrane-associated. In mouse liver and cultured hepatoma cells, the ratio of cytoplasmic to membrane FAS-specific activity was increased with fasting, indicating higher cytoplasmic FAS activity under conditions associated with PPARα activation. This effect was due to a nutrient-dependent and compartment-selective covalent modification of FAS. Cytoplasmic FAS was preferentially phosphorylated during feeding or insulin treatment at Thr-1029 and Thr-1033, which flank a dehydratase domain catalytic residue. Mutating these sites to alanines promoted PPARα target gene expression. Rapamycin-induced inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a mediator of the feeding/insulin signal to induce lipogenesis, reduced FAS phosphorylation, increased cytoplasmic FAS enzyme activity, and increased PPARα target gene expression. Rapamycin-mediated induction of the same gene was abrogated with FAS knockdown. These findings suggest that hepatic FAS channels lipid synthesis through specific subcellular compartments that allow differential gene expression based on nutritional status.