Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis

Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 mu M) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the "housekeeping" a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein L-plastin was altered in cells treated with 50 mu M enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in post-translational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments.

Transcranial DC Stimulation Coupled With TENS for the Treatment of Chronic Pain A Preliminary Study

Objective: Based on evidence showing that electrical stimulation of the nervous system is an effective method to decrease chronic neurogenic pain, we aimed to investigate whether the combination of 2 methods of electrical stimulation-a method of peripheral stimulation [transcutaneous electrical nerve stimulation (TENS)] and a method of noninvasive brain stimulation (transcranial direct current stimulation (tDCS)]-induces greater pain reduction as compared with tDCS alone and sham stimulation. Methods: We performed a preliminary, randomized, sham-controlled, crossover, clinical study in which 8 patients were randomized to receive active tDCS/active TENS (""tDCS/TENS"" group), active tDCS/sham TENS (""tDCS"" group), and sham tDCS/sham TENS (""sham"" group) stimulation. Assessments were performed immediately before and after each condition by a blinded rater. Results: The results showed that there was a significant difference in pain reduction across the conditions Of stimulation (P = 0.006). Post hoc tests showed significant pain reduction as compared with baseline after the tDCS/TENS condition [reduction by 36.5% (+/- 10.7), P = 0.004] and the tDCS condition [reduction by 15.5% (+/- 4.9), P = 0.014], but not after sham stimulation (P = 0.35). In addition, tDCS/TENS induced greater pain reduction than tDCS (P = 0.02). Conclusions: The results of this pilot study suggest that the combination of TENS with tDCS has a superior effect compared with tDCS alone.

Prefrontal cortex modulation using transcranial DC stimulation reduces alcohol craving: A double-blind, sham-controlled study

Background: Functional neuroimaging studies have shown that specific brain areas are associated with alcohol craving including the dorsolateral prefrontal cortex (DLPFC). We tested whether modulation of DLPFC using transcranial direct current stimulation (tDCS) could alter alcohol craving in patients with alcohol dependence while being exposed to alcohol cues. Methods: We performed a randomized sham-controlled study in which 13 subjects received sham and active bilateral tDCS delivered to DLPFC (anodal left/cathodal right and anodal right/cathodal left). For sham stimulation, the electrodes were placed at the same positions as in active stimulation; however, the stimulator was turned off after 30 s of stimulation. Subjects were presented videos depicting alcohol consumption to increase alcohol craving. Results: Our results showed that both anodal left/cathodal right and anodal right/cathodal left significantly decreased alcohol craving compared to sham stimulation (p < 0.0001). In addition, we found that following treatment, craving could not be further increased by alcohol cues. Conclusions: Our findings showed that tDCS treatment to DLPFC can reduce alcohol craving. These findings extend the results of previous studies using noninvasive brain stimulation to reduce craving in humans. Given the relatively rapid suppressive effect of tDCS and the highly fluctuating nature of alcohol craving, this technique may prove to be a valuable treatment strategy within the clinical setting. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Secondary metabolites from Spirotropis longifolia (DC) Baill and their antifungal activity against human pathogenic fungi

A phytochemical study of the ethyl acetate extract of the roots and adventitious roots of Spirotropis longifolia, a monodominant tree species of the Guianan rainforest, has allowed the isolation of three compounds: 2- hydroxy-8,9-methylenedioxy-2',2'-dimethylpyrano-[5',6':4,3]-6a-prenyl-[6aS,11aS]-pterocarpan (spirotropin A), 2-hydroxy-8,9-methylenedioxy-2',2'-dimethy1-3',4'-dihydropyrano-[5',6':4,3]-6a-prenyl-(6aS,11aS]-pterocarpan (spirotropin B), and 5,7-dihydroxy-6.8-dipreny1-2 ''''.2 ''''-dimethylpyrano[5 '''',6 '''': 3',4]-isoflavone (spirotropone). In addition, 10 known compounds, trans-oxyresveratrol, trans-resveratrol, piceatannol, daidzein, genistein, isoprunetin, lupeol, latifolol, gnetin D and gnetin E, were also isolated. These compounds were evaluated for their antifungal activity and their cytotoxicity, and their structures were established by 1D and 2D NMR, HRMS, CD and optical rotation measurements. (C) 2011 Elsevier Ltd. All rights reserved.

Bat-Inspired Optimization Approach for the Brushless DC Wheel Motor Problem

This paper presents a metaheuristic algorithm inspired in evolutionary computation and swarm intelligence concepts and fundamentals of echolocation of micro bats. The aim is to optimize the mono and multiobjective optimization problems related to the brushless DC wheel motor problems, which has 5 design parameters and 6 constraints for the mono-objective problem and 2 objectives, 5 design parameters, and 5 constraints for multiobjective version. Furthermore, results are compared with other optimization approaches proposed in the recent literature, showing the feasibility of this newly introduced technique to high nonlinear problems in electromagnetics.