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In traditional medicine, several medicinal plants or their extracts have been used to treat diabetes. Zingiber officinale Roscoe, known commonly as ginger, is consumed worldwide in cookeries as a spice and flavouring agent. It has been used as the spice and medicine for thousands of years. The present study was undertaken to investigate the potential protective effect of Zingiber officinale Rosc. in a model of oxidative damage to pancreatic ß cells. The free radical scavenging activities and composition of the isolated n-hexane and ethanolic extracts were confronted with their protective, antioxidant and cytotoxic effects in INS-1E ß cells. Unlike the n-hexane extract (exerting, paradoxically, stronger antiradical capacity), both low cytotoxicity and remarkable protective effects on ß cell viability, followed by lowering oxidative stress markers were found for the ethanolic extract Zingiber officinale Rosc. The present study is the first pilot study to assess the protective potential of Zingiber officinale Rosc. in a model of cytotoxic conditions imposed by diabetes in ß cells.

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Proteases play a regulatory role in a variety of pathologies including cancer, pancreatitis, thromboembolic disorders, viral infections and many others. One of the possible strategies how to combat with these pathologies seems to be the use of low molecular inhibitors. Natural products were evaluated in the in vitro antiprotease assay on serine proteases (trypsin, thrombin and urokinase) and on the cysteine protease cathepsin B. We found interesting results for beta-ursolic acid isolated from Salvia officinalis, which significantly inhibited all tested proteases in vitro in the micromolar range. beta-Ursolic acid showed the strongest inhibition activity to urokinase (IC50 = 12 microM) and cathepsin B (IC50 = 10 microM) as proteases included in tumour invasion and metastasis indicated possible anticancer effectivity. Therefore, we tested the ability of beta-ursolic acid at doses of 50, 75 and 100 mg/kg given i.p. to inhibit lung colonization of beta16 mouse melanoma cells in vivo. We found, that beta-ursolic acid significantly decreased the number of B16 colonies in the lungs of mice at the dose 50 mg/kg (p < 0.05).

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Protoberberinium salts, i.e. berberine (I), palmatine (II) and jatrorrhizine (III) prepared from Mahonia aquifolium (Pursh) Nutt. belong to isoquinoline alkaloids possessing interesting biological activity (e.g. antibacterial, antimalarial, antitumor). The characteristic UV/Vis absorption band maxima of I-III iodide salts were found in regions 350 and 425 nm in dimethylsulfoxide (DMSO) and ethanol solvents, and were only negligibly influenced by substitution changes on the C-2 and C-3 positions. The fluorescence intensity of protoberberinium salts monitored in ethanol solutions was significantly lowered by iodide counter-ions, and decreased in the order berberine > palmatine > jatrorrhizine. EPR spectroscopy supplied evidence of the formation of super-oxide anion radicals and singlet oxygen upon irradiation of berberine in oxygenated DMSO solvent. The photochemical generation of O(2) (.-) and (1)O(2) in DMSO solutions of palmatine and jatrorrhizine was substantially lower, and probably reflected the replacement of a photolabile methylenedioxy group at C-2 and C-3 positions in the berberine molecule by two methoxy groups in palmatine, and methoxyl (C-2) and hydroxyl (C-3) substitution in jatrorrhizine. Additionally, the powder EPR spectra of protoberberinium iodides I-III measured at 290 K revealed the presence of single-line EPR signals (g(eff) = 2.0044), which were attributed to hydroperoxidic structures produced by the autoxidation process. The photochemical reactions of protoberbenium salts producing reactive oxygen species after UVA excitation should be integrated in biological activity investigations, as well as in their applications in skin disorder treatment.

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The crude extract of Mahonia aquifolium (Pursh) Nutt. stem bark and its two main protoberberine alkaloids, berberine and jatrorrhizine, were tested for their in vitro antimicrobial activity. Twenty strains of coagulase-negative staphylococci and 20 strains of Propionibacterium acnes isolated from skin lesions of patients with a severe form of acne, and 20 strains of Candida sp. isolated from chronic vulvovaginal candidoses were tested for their susceptibility to crude extract and two isolated alkaloids. The minimum inhibitory concentrations obtained in this study illustrate the varying degrees of antibacterial and antifungal activity of the tested agents. The results indicate a rational basis for the traditional use of Mahonia aquifolium for localized skin and mucosal infection therapy, as well as for the possible development of a preparation for supportive therapy of the diseases mentioned above.

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The antioxidant activities of three alkaloids isolated from Mahonia aquifolium--berberine, jatrorrhizine, and magnoflorine--were studied with respect to their structural aspects, particularly the presence and the position of -OH groups, steric conditions of unpaired electron delocalization and parameters of lipophilicity and hydration energy. The antiradical activities of the compounds tested were evaluated as the reactivities toward free stable alpha,alpha'-diphenyl-beta-picrylhydrazyl radical (DPPH). The antioxidant features of the alkaloids tested were investigated in heterogeneous membrane system of DOPC liposomes stressed by peroxidative damage induced by AAPH azoinitiator. Both alkaloids bearing free phenolic groups--jatrorrhizine and magnoflorine--showed better activities in both systems used than berberine not bearing any readily abstractable hydrogen on its skeleton. The former two showed antiperoxidative efficiency in DOPC liposomal membrane comparable to that of an effective scavenger of peroxyl radicals--stobadine-and higher than that of Trolox. We conclude that the favorable antioxidant features of the hydroxylated alkaloids are most probably ensured by the combination of reasonably high antiradical reactivity with high lipophilicity, however, the solvation process was found to markedly interfere with these beneficial effects.

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Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the -1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

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Previous studies on the anticancer activity of protoberberine alkaloids against a variety of cancer cell lines were extended to human tumour HeLa and murine leukemia L1210 cell lines. An attempt was also made to investigate the relationship between the cytotoxic activity of berberine and its molecular mechanism of action. Cytotoxicity was measured in-vitro using a primary biochemical screening according to Oyama and Eagle, and the growth inhibition assay. The in-vitro cytotoxic techniques were complemented by cell cycle analysis and determination of apoptotic DNA fragmentation in L1210 cells. Berberine acted cytotoxically on both tumour cell lines. The sensitivity of leukemia L1210 cells to the berberine was higher than that of HeLa cells. The IC(100) was below 100 microg mL(-1) for HeLa cells and approached a 10 microg mL(-1) limit for the leukemia L1210 cells. For both cell lines the IC(50) was found to be less than 4 microg mL(-1), a limit put forward by the National Cancer Institute (NCI) for classification of the compound as a potential anticancer drug. In L1210 cells treated with 10-50 microg mL(-1) berberine, G(0)/G(1) cell cycle arrest was observed. Furthermore, a concentration-dependent decrease of cells in S phase and increase in G(2)/M phase was detected. In addition, apoptosis detected as sub-G(0) cell population in cell cycle measurement was proved in 25-100 microg mL(-1) berberine-treated cells by monitoring the apoptotic DNA fragmentation (DNA ladder) using agarose gel electrophoresis.

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The crude extract of Mahonia aquifolium (Berberidaceae) stem bark and its components berberine, palmatine and jatrorrhizine were screened for their inhibitory activity against a variety of dermatophytes and two Candida species of human origin using the in vitro dilution agar plate method. Jatrorrhizine was found to be the most effective against all fungal species tested (MIC ranges from 62.5 to 125 micro g/mL), while the crude extract, berberine, and palmatine exhibited only marginal activity (MIC 500 to >/= 1000 micro g/mL). Dermatophytes were more susceptible to jatrorrhizine than yeasts, and Scopulariopsis brevicaulis appeared the least sensitive species to all the compounds tested. The effects of the alkaloids were compared with those of fluconazole and bifonazole for which the MIC ranges were 12.5 to >100 micro g/mL. Our results suggest that jatrorrhizine may serve as a leading compound for further studies to develop new antifungal agents with highly potent antifungal activity and low host toxicity.

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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.

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The effect of the crude extract and of two alkaloid fractions prepared from Mahonia aquifolium on interleukin-8 (IL-8) production in the lipopolysaccharide (LPS)-stimulated human monocytic cell line THP-1 was studied. The production of IL-8 by cells stimulated with 20 ng/ml LPS after 48 h treatment with 20 microg/ml crude extract was inhibited by about 30 %. LPS-stimulated cells treated with 0.1 microg/ml bisbenzylisoquinoline alkaloid fraction exhibited a 40% inhibition of IL-8 production in comparison with control cells. The fraction of protoberberine alkaloids had no significant inhibitory activity. Weak or no inhibition of IL-8 production was found after treatment with 0.5 microg/ml of protoberberine alkaloids berberine and jatrorrhizine and with berbamine from the group of BBI alkaloids. In contrast, the production was inhibited after treatment with BBI alkaloids baluchistine (about 20%) and aromoline (up to 30%).

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