Metabolic Activation of Myristicin and Its Role in Cellular Toxicity.

Myristicin is widely distributed in spices and medicinal plants. The aim of this study was to explore the role of metabolic activation of myristicin in its potential toxicity through a metabolomic approach. The myristicin- N-acetylcysteine adduct was identified by comparing the metabolic maps of myristicin and 1'-hydroxymyristicin. The supplement of N-acetylcysteine could protect against the cytotoxicity of myristicin and 1'-hydroxymyristicin in primary mouse hepatocytes. When the depletion of intracellular N-acetylcysteine was pretreated with diethyl maleate in hepatocytes, the cytotoxicity induced by myristicin and 1'-hydroxymyristicin was deteriorated. It suggested that the N-acetylcysteine adduct resulting from myristicin bioactivation was closely associated with myristicin toxicity. Screening of human recombinant cytochrome P450s (CYPs) and treatment with CYP inhibitors revealed that CYP1A1 was mainly involved in the formation of 1'-hydroxymyristicin. Collectively, this study provided a global view of myristicin metabolism and identified the N-acetylcysteine adduct resulting from myristicin bioactivation, which could be used for understanding the mechanism of myristicin toxicity.

Improving the acetylcholinesterase inhibitory effect of Illigera henryi by solid-state fermentation with Clonostachys rogersoniana.

Illigera henryi, an endemic traditional Chinese medicine, contains abundant aporphine alkaloids that possess various bioactivities. In the present study, tubers of I. henryi were fermented by several fungi, and the acetylcholinesterase (AChE) inhibitory activities of non-fermented and fermented I. henryi were measured. The results showed that the fermentation of I. henryi with Clonostachys rogersoniana 828H2 is effective for improving the AChE inhibitory activity. A key biotransformation was found during the C. rogersoniana fermentation for clarifying the improvement of the AChE inhibitory activity of I. henryi: (S)-actinodaphnine (1) was converted to a new 4-hydroxyaporphine alkaloid (4R,6aS)-4-hydroxyactinodaphnine (2) that possessed a stronger AChE inhibitory activity, with an IC50 value of 17.66±0.06 µM. This paper is the first to report that the pure strain fermentation processing of I. henryi and indicated C. rogersoniana fermentation might be a potential processing method for I. henryi.

Effect of growth stage on essential-oil yield and composition of Daucus sahariensis.

The essential oils obtained by hydrodistillation from Daucus sahariensis Murb. harvested at three different growth stages were characterized by GC/MS analysis. In total, 88 compounds were identified, with myristicin (29.8-51.7%), myrcene (6.7-31.1%), α-pinene (11.6-14.8%), and limonene (5.3-11.5%) as main constituents. Monoterpene hydrocarbons were the most represented compounds in the oils of the plant samples collected during the flower-budding and full-flowering periods. On the contrary, during the fruiting stage, the oils were dominated by phenylpropanoids. The essential oils were subject of considerable variation in their composition during the various developmental stages, particularly concerning the content of myrcene that decreased significantly passing from the vegetative to the fruiting stage. Conversely, for myristicin, the opposite trend was observed. Furthermore, the essential-oil yields were quite low during the flower-budding phase (0.27%), but rapidly increased during plant development (0.63 and 0.68% for the flowering and fruiting phases, resp.).

Accumulation of lignans by in vitro cultures of three Linum species.

Justicidin B, an arylnaphthalene lignan, has strong cytotoxicity on chronic myeloid and chronic lymphoid leukemia cell lines. The first report of the production of justicidin B in a Linum species concerned in vitro culture of Linum austriacum. Therefore, culture characterization and presence of arylnaphthalene-type lignans in calli and plantlets of Linum tenuifolium from section Linastrum, Linum bienne, and Linum glaucum from section Linum were studied. Seed germination of L. tenuifolium in the light and darkness was significantly higher (p < 0.05) than of L. bienne in the light and L. glaucum in the darkness. L. tenuifolium seedling length in the darkness was significantly higher (p < 0.01) than under light conditions. There were no significant differences in the calli and shoot biomass weight, number and length of shoots in three species over one month, while the shoot diameter of L. bienne was significantly different (p < 0.05) from that of L. glaucum. Justicidin B was detected in L. glaucum callus and plantlet cultures by HPLC/MS/UV-DAD and HPLC coupled with a photodiode array detector. This finding is important from pharmaceutical point of view and shows the chemosystematic relation between L. glaucum and L. austriacum and this method will be a powerful tool for detecting natural products in interested and endangered medicinal plants.

Inhibitory effect of piperlonguminine on melanin production in melanoma B16 cell line by downregulation of tyrosinase expression.

Tyrosinase is a key enzyme for melanin biosynthesis, and hyperpigmentation disorders are associated with abnormal accumulation of melanin pigments, which can be improved by treatment with depigmenting agents. In the present study, piperlonguminine from Piper longum was discovered to inhibit melanin production in melanoma B16 cells stimulated with alpha-melanocyte stimulating hormone (alpha-MSH), 3-isobutyl-1-methylxanthine or protoporphyrin IX, where the compound exhibited stronger depigmenting efficacy than kojic acid. However, piperlonguminine did not affect 1-oleoyl-2-acetyl-sn-glycerol-induced melanogenesis and did not affect protein kinase C-mediated melanin production. Surprisingly, piperlonguminine did not inhibit the catalytic activity of cell-free tyrosinase from melanoma B16 cells but rather suppressed tyrosinase mRNA expression. This effect was attributed to the inhibitory action of piperlonguminine on alpha-MSH-induced signaling through cAMP to the cAMP responsive element binding protein that in turn regulates the expression of the microphthalmia-associated transcription factor, a key activator of the tyrosinase promoter. This study demonstrates that piperlonguminine is an efficient depigmenting agent with a novel mechanism of action.

Prulifloxacin.

Prulifloxacin, the prodrug of ulifloxacin, is a broad-spectrum oral fluoroquinolone antibacterial agent. After absorption, prulifloxacin is metabolised by esterases to ulifloxacin. The drug has a long elimination half-life, allowing once-daily administration. Ulifloxacin is generally more active in vitro than other fluoroquinolones against a variety of clinical isolates of Gram-negative bacteria, including community and nosocomial isolates of Escherichia coli, Klebsiella spp., Proteus, Providencia and Morganella spp., Moraxella catarrhalis and Haemophilus spp. The activity of ulifloxacin against Pseudomonas aeruginosa varies between countries. Gram-positive organisms, including meticillin- or oxacillin-susceptible Staphylococcus aureus, Enterococcus spp. and Italian community isolates of Streptococcus pneumoniae are susceptible to ulifloxacin. Activity against Spanish strains of S. pneumoniae is moderate. In well designed clinical trials, good clinical and bacteriological efficacy (similar to that of ciprofloxacin, amoxicillin/clavulanic acid or pefloxacin) was seen with prulifloxacin 600 mg once daily for 10 days in patients with acute exacerbations of chronic bronchitis or complicated lower urinary tract infections (UTIs), and with single-dose prulifloxacin 600 mg in acute, uncomplicated lower UTIs. Prulifloxacin was generally well tolerated in clinical trials, with a similar tolerability profile to that of ciprofloxacin.

Epidemic dropsy in New Delhi.

Forty-five cases of epidemic dropsy were studied from an epidemic in New Delhi. Argemone oil contamination was found in the mustard oil used for cooking. Sanguinarine was detected in the eight urine samples collected within 2-3 weeks of onset of dropsy and its concentration ranged from 0.4 to 3.6 mug/100 ml. Three of the 18 sera were positive for sanguinarine, the concentration being 1.2, 1.6 and 3.6 mug/100 ml. The clinical manifestations and epidemiological factors were studied. Edema of the legs was the most consistent clinical finding, and was present in all the patients. In contrast to the earlier epidemics, three striking features were pigmentation in 33%, hair loss in 77.7% and nontender hepatomegaly in 24.4% of cases. A follow-up of 10 months showed almost complete recovery in all.