Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice.
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Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Separately, there are data that suggest an enzymatic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concentrations (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degradation of fibronectin by enzymatically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted subcutaneously with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solutions (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 weeks. Serum PSA and IGF-1 levels were determined at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, respectively. Serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the control group. There were morphological differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochemistry. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1. This promising model is being evaluated in further studies. (+info)
Mechanism of the decrease of tetrodotoxin activity in modified seawater medium.
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This study was designed to clarify the mechanism of the decrease of tetrodotoxin (TTX) toxicity during storage in a modified seawater medium (MSWM). When TTX was added to sterilized MSWM, the toxicity of TTX in the medium markedly decreased within 1 day, as determined by a mouse bioassay. HPLC (high-performance liquid chromatography) analysis showed that the peak of TTX was reduced and new unidentified peaks were observed. Omission of the P-1 metal solution from MSWM suppressed the decrease in TTX toxicity and the disappearance of TTX. Further studies indicated that boric acid in the P-1 metal solution triggers this toxicity decrease, indicating that TTX is chemically, not microbiologically, converted to unknown compounds in MSWM. (+info)
Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2.
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Bacterial populations use cell-cell communication to coordinate community-wide regulation of processes such as biofilm formation, virulence, and bioluminescence. This phenomenon, termed quorum sensing, is mediated by small molecule signals known as autoinducers. While most autoinducers are species specific, autoinducer-2 (AI-2), first identified in the marine bacterium Vibrio harveyi, is produced and detected by many Gram-negative and Gram-positive bacteria. The crystal structure of the V. harveyi AI-2 signaling molecule bound to its receptor protein revealed an unusual furanosyl borate diester. Here, we present the crystal structure of a second AI-2 signal binding protein, LsrB from Salmonella typhimurium. We find that LsrB binds a chemically distinct form of the AI-2 signal, (2R,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran (R-THMF), that lacks boron. Our results demonstrate that two different species of bacteria recognize two different forms of the autoinducer signal, both derived from 4,5-dihydroxy-2,3-pentanedione (DPD), and reveal new sophistication in the chemical lexicon used by bacteria in interspecies signaling. (+info)
In vitro activity of bergamot natural essence and furocoumarin-free and distilled extracts, and their associations with boric acid, against clinical yeast isolates.
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OBJECTIVES: There is very little information, to date, on the antifungal activity of bergamot oil. In this study, we investigated the in vitro activity of three bergamot oils (natural essence, furocoumarin-free extract and distilled extract) against clinically relevant Candida species. We studied the two derivatives, components of Italian pharmaceutical products, that are supposed to be less toxic than the essential oil. METHODS: In vitro susceptibility of 40 clinical isolates of Candida spp. (Candida albicans, n=20; Candida glabrata, n=13; Candida krusei, n=4; Candida tropicalis, n=2; Candida parapsilosis, n=1), associated with symptomatic and asymptomatic vulvovaginal candidiasis, was determined using a modification of the NCCLS M27-A2 broth microdilution method. MICs were evaluated for each of the oils alone and combined with sub-inhibitory concentrations of the well-known antiseptic, boric acid. To boric acid, all isolates had MIC values ranging from 0.094% to 0.187% (w/v). RESULTS: At 24 h readings, the MIC(90 )s (for all isolates) were (v/v): 5% for natural essence of bergamot, 2.5% for the furocoumarin-free extract, and 1.25% for the distilled extract. At the 48 h reading, these values increased to >10%, 5% and 2.5%, respectively. At both readings, MIC(90 )s for all oil+boric acid combinations were significantly lower than corresponding values for the oils alone (P <0.05). CONCLUSIONS: These data indicate that bergamot oils are active in vitro against Candida spp., suggesting their potential role for the topical treatment of Candida infections. (+info)
Tris-borate is a poor counterion for RNA: a cautionary tale for RNA folding studies.
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Native polyacrylamide gel electrophoresis is a powerful approach for visualizing RNA folding states and folding intermediates. Tris-borate has a high-buffering capacity and is therefore widely used in electrophoresis-based investigations of RNA structure and folding. However, the effectiveness of Tris-borate as a counterion for RNA has not been systematically investigated. In a recirculated Hepes/KCl buffer, the catalytic core of the bI5 group I intron RNA undergoes a conformational collapse characterized by a bulk transition midpoint, or Mg1/2, of approximately 3 mM, consistent with extensive independent biochemical experiments. In contrast, in Tris-borate, RNA collapse has a much smaller apparent Mg1/2, equal to 0.1 mM, because in this buffer the RNA undergoes a different, large amplitude, folding transition at low Mg2+ concentrations. Analysis of structural neighbors using a short-lived, RNA-tethered, photocrosslinker indicates that the global RNA structure eventually converges in the two buffer systems, as the divalent ion concentration approaches approximately 1 mM Mg2+. The weak capacity of Tris-borate to stabilize RNA folding may reflect relatively unfavorable interactions between the bulky Tris-borate ion and RNA or partial coordination of RNA functional groups by borate. Under some conditions, Tris-borate is a poor counterion for RNA and its use merits careful evaluation in RNA folding studies. (+info)
Topical quinolone vs. antiseptic for treating chronic suppurative otitis media: a randomized controlled trial.
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OBJECTIVE: To compare a topical quinolone antibiotic (ciprofloxacin) with a cheaper topical antiseptic (boric acid) for treating chronic suppurative otitis media in children. DESIGN: Randomized controlled trial. SETTING AND PARTICIPANTS: A total of 427 children with chronic suppurative otitis media enrolled from 141 schools following screening of 39 841 schoolchildren in Kenya. Intervention Topical ciprofloxacin (n = 216) or boric acid in alcohol (n = 211); child-to-child treatment twice daily for 2 weeks. MAIN OUTCOME MEASURES: Resolution of discharge (at 2 weeks for primary outcome), healing of the tympanic membrane, and change in hearing threshold from baseline, all at 2 and 4 weeks. RESULTS: At 2 weeks, discharge was resolved in 123 of 207 (59%) children given ciprofloxacin, and in 65 of 204 (32%) given boric acid (relative risk 1.86; 95% CI 1.48-2.35; P < 0.0001). This effect was also significant at 4 weeks, and ciprofloxacin was associated with better hearing at both visits. No difference with respect to tympanic membrane healing was detected. There were significantly fewer adverse events of ear pain, irritation, and bleeding on mopping with ciprofloxacin than boric acid. CONCLUSIONS: Ciprofloxacin performed better than boric acid and alcohol for treating chronic suppurative otitis media in children in Kenya. (+info)
Artificial metalloenzymes based on biotin-avidin technology for the enantioselective reduction of ketones by transfer hydrogenation.
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Most physiological and biotechnological processes rely on molecular recognition between chiral (handed) molecules. Manmade homogeneous catalysts and enzymes offer complementary means for producing enantiopure (single-handed) compounds. As the subtle details that govern chiral discrimination are difficult to predict, improving the performance of such catalysts often relies on trial-and-error procedures. Homogeneous catalysts are optimized by chemical modification of the chiral environment around the metal center. Enzymes can be improved by modification of gene encoding the protein. Incorporation of a biotinylated organometallic catalyst into a host protein (avidin or streptavidin) affords versatile artificial metalloenzymes for the reduction of ketones by transfer hydrogenation. The boric acid.formate mixture was identified as a hydrogen source compatible with these artificial metalloenzymes. A combined chemo-genetic procedure allows us to optimize the activity and selectivity of these hybrid catalysts: up to 94% (R) enantiomeric excess for the reduction of p-methylacetophenone. These artificial metalloenzymes display features reminiscent of both homogeneous catalysts and enzymes. (+info)
Cellular changes in boric acid-treated DU-145 prostate cancer cells.
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Epidemiological, animal, and cell culture studies have identified boron as a chemopreventative agent in prostate cancer. The present objective was to identify boron-induced changes in the DU-145 human prostate cancer cell line. We show that prolonged exposure to pharmacologically-relevant levels of boric acid, the naturally occurring form of boron circulating in human plasma, induces the following morphological changes in cells: increases in granularity and intracellular vesicle content, enhanced cell spreading and decreased cell volume. Documented increases in beta-galactosidase activity suggest that boric acid induces conversion to a senescent-like cellular phenotype. Boric acid also causes a dose-dependent reduction in cyclins A-E, as well as MAPK proteins, suggesting their contribution to proliferative inhibition. Furthermore, treated cells display reduced adhesion, migration and invasion potential, along with F-actin changes indicative of reduced metastatic potential. Finally, the observation of media acidosis in treated cells correlated with an accumulation of lysosome-associated membrane protein type 2 (LAMP-2)-negative acidic compartments. The challenge of future studies will be to identify the underlying mechanism responsible for the observed cellular responses to this natural blood constituent. (+info)