Potential antimutagenic activity of berberine, a constituent of Mahonia aquifolium.
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BACKGROUND: As part of a study aimed at developing new pharmaceutical products from natural resources, the purpose of this research was twofold: (1) to fractionate crude extracts from the bark of Mahonia aquifolium and (2) to evaluate the strength of the antimutagenic activity of the separate components against one of the common direct-acting chemical mutagens. METHODS: The antimutagenic potency was evaluated against acridine orange (AO) by using Euglena gracilis as an eukaryotic test model, based on the ability of the test compound/fraction to prevent the mutagen-induced damage of chloroplast DNA. RESULTS: It was found that the antimutagenicity of the crude Mahonia extract resides in both bis-benzylisoquinoline (BBI) and protoberberine alkaloid fractions but only the protoberberine derivatives, jatrorrhizine and berberine, showed significant concentration-dependent inhibitory effect against the AO-induced chloroplast mutagenesis of E. gracilis. Especially berberine elicited, at a very low dose, remarkable suppression of the AO-induced mutagenicity, its antimutagenic potency being almost three orders of magnitude higher when compared to its close analogue, jatrorrhizine. Possible mechanisms of the antimutagenic action are discussed in terms of recent literature data. While the potent antimutagenic activity of the protoberberines most likely results from the inhibition of DNA topoisomerase I, the actual mechanism(s) for the BBI alkaloids is hard to be identified. CONCLUSIONS: Taken together, the results indicate that berberine possesses promising antimutagenic/anticarcinogenic potential that is worth to be investigated further. (+info)
Electrophysiological study on biphasic firing activity elicited by D(1) agonistic-D(2) antagonistic action of (-)-stepholidine in nucleus accumbens.
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Our previous work has demonstrated that (-)-stepholidine (SPD) has dual action, ie D(1) agonistic-D(2) antagonistic action on DA receptors in the nigra-striatal dopamine (DA) system. The present study attempted to ascertain its dual action on the mesolimbic DA system. The firing activities of the nucleus accumbens (NAc) neurons were extracellularly recorded with intravenous and iontophoretic administration of the drug in 6-hydroxydopamine (6-OHDA)-lesioned and intact rats. The results showed that SPD produced a consistently biphasic firing of NAc neurons during the cumulative doses of 0.02 2 mg/kg, iv. When the rats were pretreated with D(2) antagonist spiperone, SPD only exerted an increasing effect, which was subsequently reversed by the D(1) antagonist SCH-23390. Moreover, SCH-23390 could prevent the rate of increase elicited by SPD at high doses, presumably due to the D(1) agonistic action of SPD on the activity of NAc neuron. On the other hand, the inhibition of NAc firing elicited by either D(2) agonist LY171555 or D(1)/D(2) agonists apomorphine was completely reversed by SPD, suggesting an antagonistic action of SPD to D(2) receptors. In 6-OHDA-lesioned rats, iontophoresis of SPD also had an inhibitory effect in the majority of NAc neurons (91%) as SKF-38393 did. This inhibition could be completely blocked by the ejection of SCH-23390, but not by spiperone. These results indicate that SPD also has a D(1) agonistic-D(2) antagonistic dual action on NAc neuron activity, which may be beneficial to the treatment of schizophrenia. (+info)
Increased phosphorylation of DARPP-32 by D1 agonistic action of l-stepholidine in the 6-OHDA-lesioned rat striatum.
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In order to explore the characteristics of l-stepholidine (SPD) activating the postsynaptic D(1) receptors, the effects of SPD on DARPP-32 phosphorylation in vivo with back-phosphorylation assay and on the postsynaptic D(1) receptor densities with radioligand assay were observed in the striatum of 6-OHDA-lesioned rat. The results showed that following subcutaneously administration of 20 or 40 mg/kg SPD for 21 d, (32)P phosphate incorporation into the DARPP-32 protein in the denervated striatum showed a 50% reduction (P<0.01) vs the intact striatum, indicating an increase of DARPP-32 phosphorylation in vivo in the denervated striatum. However,the D(1) receptor B(max) was decreased from 385.0+/-26.1 to 319.7+/-20.1 fmol/mg protein. It is suggested that D(1) agonist action of SPD decreases the D(1) receptor density but increases the phosphorylation of DARPP-32 in the striatum of 6-OHDA-lesioned rat, which may be responsible for the regulation of D(1) receptor signal transduction in brain neurons. (+info)
Characterization of berberine transport into Coptis japonica cells and the involvement of ABC protein.
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Cultured Coptis japonica cells are able to take up berberine, a benzylisoquinoline alkaloid, from the medium and transport it exclusively into the vacuoles. Uptake activity depends on the growth phase of the cultured cells whereas the culture medium had no effect on uptake. Treatment with several inhibitors suggested that berberine uptake depended on the ATP level. Some inhibitors of P-glycoprotein, an ABC transporter involved in multiple drug resistance in cancer cells, strongly inhibited berberine uptake, whereas a specific inhibitor for glutathione biosynthesis and vacuolar ATPase, bafilomycin A1, had little effect. Vanadate-induced ATP trap experiments to detect ABC proteins expressed in C. japonica cells showed that three membrane proteins of between 120 and 150 kDa were photolabelled with 8-azido-[alpha-32P] ATP. Two revealed the same photoaffinity-labelling pattern as P-glycoprotein, and the interaction of these proteins with berberine was also demonstrated. These results suggest that ABC proteins of the MDR-type are involved in the uptake of berberine from the medium. (+info)
Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials.
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Plant antimicrobials are not used as systemic antibiotics at present. The main reason for this is their low level of activity, especially against gram-negative bacteria. The reported MIC is often in the range of 100 to 1,000 micro g/ml, orders of magnitude higher than those of common broad-spectrum antibiotics from bacteria or fungi. Major plant pathogens belong to the gram-negative bacteria, which makes the low level of activity of plant antimicrobials against this group of microorganisms puzzling. Gram-negative bacteria have an effective permeability barrier, comprised of the outer membrane, which restricts the penetration of amphipathic compounds, and multidrug resistance pumps (MDRs), which extrude toxins across this barrier. It is possible that the apparent ineffectiveness of plant antimicrobials is largely due to the permeability barrier. We tested this hypothesis in the present study by applying a combination of MDR mutants and MDR inhibitors. A panel of plant antimicrobials was tested by using a set of bacteria representing the main groups of plant pathogens. The human pathogens Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica serovar Typhimurium were also tested. The results show that the activities of the majority of plant antimicrobials were considerably greater against the gram-positive bacteria Staphylococcus aureus and Bacillus megaterium and that disabling of the MDRs in gram-negative species leads to a striking increase in antimicrobial activity. Thus, the activity of rhein, the principal antimicrobial from rhubarb, was potentiated 100- to 2,000-fold (depending on the bacterial species) by disabling the MDRs. Comparable potentiation of activity was observed with plumbagin, resveratrol, gossypol, coumestrol, and berberine. Direct measurement of the uptake of berberine, a model plant antimicrobial, confirmed that disabling of the MDRs strongly increases the level of penetration of berberine into the cells of gram-negative bacteria. These results suggest that plants might have developed means of delivering their antimicrobials into bacterial cells. These findings also suggest that plant antimicrobials might be developed into effective, broad-spectrum antibiotics in combination with inhibitors of MDRs. (+info)
A sensitive optode membrane for berberine using conjugated polymer as sensing material.
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A new optode membrane for the sensitive determination of berberine based on fluorescence quenching of a conjugated polymer, poly(2,5-dimethoxy-phenyldiacetylene) (PDPA), is proposed. Incorporated in a membrane composed of plasticized poly(vinyl chloride) (PVC), the conjugated polymer exhibits better stability than those small sensing molecules regarding its excellent optical properties and lipophilic characteristics. Moreover, upon the introduction of a negatively charged lipophilic additive (tetraphenylborate salt) into a PVC membrane, the optode displayed enhanced sensitivity. In addition, satisfactory analytical sensing characteristics for determining beberine were obtained in terms of the selectivity, reversibility and reproducibility with a detecting range of between 7.5 x 10(-7) mol l(-1) and 7.5 x 10(-4) mol l(-1). The optode membrane has been applied to determine berberine in commercial tablets. The results showed a good agreement with those obtained by the pharmacopoeial method. (+info)
Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by a Coptidis Rhizoma extract and protoberberine alkaloids.
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A methanol extract of Coptidis Rhizoma effectively enhanced the outgrowth of neurite in PC12 cells induced by nerve growth factor (NGF). Following solvent partition and preparative HPLC, berberine was isolated as the major active compound. Berberine enhanced the proportion of neurite-bearing cells in a dose-dependent manner without cytotoxicity. Its structural relatives, palmatine and coptisine, showed a slightly weaker NGF-enhancing effect than berberine. These three alkaloids inhibited acetylcholinesterase activity at a level comparable to that of physostigmine, but this inhibition was not responsible for the potentiation of NGF-induced neurite outgrowth. It is demonstrated for the first time that protoberberine alkaloids potentiated the NGF-induced differentiation of neural cells. (+info)
Effect of berberine on bone mineral density in SAMP6 as a senile osteoporosis model.
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The effects of berberine in senescence accelerated mice P6 (SAMP6) were investigated to learn whether the alkaloid affects bone mineral density (BMD). Oral administration of berberine (10 mg/kg/d) to male and female mice for 22 weeks resulted in an increase in BMD in both sexes. A decreased concentration of deoxypyridinoline (Dpd) in urine was only observed in female mice. There was no effect on body or tibia weight or on the concentration of procollagen type I carboxyterminal extension peptide (PICP) in serum. (+info)