Stable gastric pentadecapeptide BPC 157 in honeybee (Apis mellifera) therapy, to control Nosema ceranae invasions in apiary conditions.

Nosema ceranae can cause major problems, such as immune suppression, gut epithelial cell degeneration, reduced honeybee lifespan, or suddenly colony collapse. As a novel approach in therapy, we hypothesize the stable gastric pentadecapeptide BPC 157 in honeybee therapy, to control N. ceranae invasions in apiary conditions: BPC 157 treated sugar syrup (0.25 L sugar syrup supplemented with 0.1 µg/ml BPC 157), as well as the pure sugar syrup (0.25 L sugar syrup; control), was administered to honeybee colonies in feeders situated under the roof of the hives, during 21 consecutive days, at the end of beekeeping season. The strength of honeybee colonies was increased 20 and 30 days after initial feeding with BPC 157 supplement (Day 1, 36.100 ± 698; Day 20, 64.860 ± 468; Day 30, 53.214 ± 312 estimated number of honeybees), in field conditions. The similar successful outcome occurs with the N. ceranae spore loads counted in the homogenates of sampled adult honeybees (Day 1, 6.286 ± 2.336; Day 20, 3.753 ± 1.835; Day 30, 2.005 ± 1.534 million spores/bee). Accordingly, with the noted increased strength of the colonies fed with sugar syrup supplemented with BPC 157, the number of N. ceranae spores per honeybee gradually decreased as well. Besides, honeybees infected with N. ceranae fed with sugar syrup exhibited severe damage of midgut wall layers and epithelial cells. By contrast, in honeybees infected with N. ceranae fed with sugar syrup supplemented with BPC 157, all damages were markedly attenuated, damages of the outer muscular coat, in particular. In conclusion, the results of the first field trial on diseased honeybee colonies with BPC 157 indicate significant therapeutic effects with the used oral therapy with BPC 157 supplementation.

Novel urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation.

A series of novel compounds 3a-j and 6a-j with primaquine and hydroxyl or halogen substituted benzene moieties bridged by urea or bis-urea functionalities were designed, synthesized and evaluated for biological activity. The title compounds were prepared using benzotriazole as the synthon, through several synthetic steps. 3-[3,5-Bis(trifluoromethyl)phenyl]-1-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}urea (3j) was the most active urea and 1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-3-[3-(trifluoromethyl)phenyl]urea (6h) the most active bis-urea derivative in antiproliferative screening in vitro against eight tested cancer cell lines. Urea derivatives 3a-g with hydroxy group or one halogen atom showed moderate antiproliferative effects against all the tested cell lines, but stronger activity against breast carcinoma MCF-7 cell line, while trifluoromethyl derivatives 3h-j showed antiproliferative effects against all the tested cell lines in low micromolar range. Finally, bis-ureas with hydroxy and fluoro substituents 6a-d showed extreme selectivity and chloro or bromo derivatives 6e-g high selectivity against MCF-7 cells (IC50 0.1-2.6 µM). p-Fluoro derivative 6d, namely 3-(4-fluorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea, is the most promising compound. Further biological experiments showed that 6d affected cell cycle and induced cell death of MCF-7 cell line. Due to its high activity against MCF-7 cell line (IC50 0.31 µM), extreme selectivity and full agreement with the Lipinski's and Gelovani's rules for prospective small molecular drugs, 6d may be considered as a lead compound in development of breast carcinoma drugs. Urea 3b and almost all bis-ureas showed high antioxidant activity in DPPH assay, but urea derivatives were more active in lipid peroxidation test. Only few compounds exhibited weak inhibition of soybean lipoxygenase. Compound 3j exhibited the strongest antimicrobial activity in susceptibility assay in vitro (MIC = 1.6-12.5 µg ml-1).

Zimelidine decreases seizure susceptibility in stressed mice.

To further evaluate whether selective serotonin reuptake inhibitors (SSRIs) have pro- or anticonvulsant properties and whether these properties will be modified by stress, we studied the effect of zimelidine on the convulsions produced by picrotoxin, a GABA(A) receptor antagonist, in unstressed and swim stressed mice. Zimelidine potentiated the ability of swim stress to enhance the threshold doses of intravenously administered picrotoxin producing convulsant signs and death, without having an effect in unstressed mice. The anticonvulsant effect of zimelidine was counteracted with mianserin, the antagonist of 5-HT(2A/2C), and diminished with WAY-100635, a selective antagonist of 5-HT(1A) receptors. In stressed mice, WAY-100635 prevented the anticonvulsant effect of 8-OH-DPAT, a 5-HT(1A) receptor agonist. SB-269970 and ketanserin, the antagonists of 5-HT(7) and 5-HT(2A) receptors, respectively, failed to reduce the effect of zimelidine. The results suggest the involvement of 5-HT(2C) and 5-HT(1A) receptors in the anticonvulsant effects of zimelidine and possibly other SSRIs in stress.