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- Anti-VEGF-A Affects the Angiogenic Properties of Tumor-Derived Microparticles. [Journal Article]
- PLoS One 2014; 9(4):e95983.
Tumor derived microparticles (TMPs) have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs). Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.
- Consequences of a Human TRPA1 Genetic Variant on the Perception of Nociceptive and Olfactory Stimuli. [Journal Article]
- PLoS One 2014; 9(4):e95592.
TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity.Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2).Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced.The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.
- Enhancing trimethylolpropane esters synthesis through lipase immobilized on surface hydrophobic modified support and appropriate substrate feeding methods. [Journal Article]
- Enzyme Microb Technol 2014 May 10.:60-7.
Candida sp. 99-125 lipase immobilized on surface hydrophobic modified support and appropriate substrate feeding methods were used to improve the synthesis of tri-substituted trimethylolpropane (TMP) esters, which can be used as raw materials for biodegradable lubricants. The proposed novel production method is environmentally friendly. Lipase was adsorbed on surface hydrophobic silk fibers that were pretreated by amino-modified polydimethylsiloxane. A 5-level-4-factors central composite model, including reaction time, temperature, enzyme amount, and molar ratio of fatty acid to TMP, was designed to evaluate the interaction of process variables in the enzymatic esterification. The water activity was kept constant using a LiCl-saturated salt solution. Under the optimum conditions with 30% enzyme amount and substrates molar ratio 8.4 at 45°C for 47h, the total conversion of caprylic acid is 97.3% and the yield of tri-substituted TMP esters is 95.5%. The surface hydrophobic treatment resulted in less cluster water accumulated on the surface immobilized lipase, which was demonstrated by near-infrared spectra. Consequently, the optimum temperature and water tolerance of immobilized lipase were increased. Two TMP-feeding methods were used to maintain high molar ratio of fatty acid to TMP, and increase the final tri-substituted TMP esters content exceeding 85% (w/w) in reactant.
- Radical Reactivity of the Fe(III)/(II) Tetramesitylporphyrin Couple: Hydrogen Atom Transfer, Oxyl Radical Dissociation, and Catalytic Disproportionation of a Hydroxylamine. [JOURNAL ARTICLE]
- Chem Sci 2014 Jan; 5(1):372-380.
The chemistry of low-valent iron porphyrin complexes with oxyl radical reagents has been explored. (Meso-tetramesityl porphyrinato) iron(III) hydroxide, (TMP)Fe(III)(OH) reacts with the hydroxylamine TEMPO-H (1-hydroxy-2,2,6,6-tetramethylpiperdine) to yield the ferrous porphyrin, (TMP)Fe(II), together with H2O and TEMPO. This reaction has a second order rate constant k 1 = 76 ± 5 M(-1) 1 s(-1) and likely occurs by concerted e (-)/H(+) transfer. Hydrazines PhNHNHPh and PhNHNH2 similarly yield (TMP)Fe(II). A subsequent reaction between TEMPO (2,2,6,6-tetramethylpiperdinyl radical) and (TMP)Fe(II) is observed to reversibly form the TEMPO-ligated ferric porphyrin, (TMP)Fe(III)(TEMPO). A combination of (1)H NMR and optical spectroscopies were used to determine the thermodynamic parameters for TEMPO binding: K 4 (25°C) = 535 ± 20 M(-1), ΔH°4 = -7.0 ± 1.5 kcal mol(-1), ΔS°4= -11 ± 5 cal mol(-1) K(-1), ΔG (‡) 4(235K) = 21.3 ± 0.5 kcal mol(-1), ΔG (‡) -4(235K) = 16.9 ± 0.5 kcal mol(-1). The Fe-O bond is remarkably weak. The stable phenoxyl radical 2,4,6- (t) Bu3C6H2O(•) (ArO(•)) forms a stronger bond to (TMP)Fe(II) to irreversibly make a similar Fe(III)(OR) complex. Both (TMP)Fe(II) and (TMP)Fe(III)(OH) are catalysts for the disproportionation of excess TEMPO-H to TEMPO and TEMP-H (2,2,6,6-tetramethylpiperdine). The lack of reactivity between (TMP)Fe(II) and the alkylated TEMPO-H analogue, TEMPO-CH3, suggests that the disproportionation involves a hydrogen atom transfer step. These results highlight the importance and versatility of the heme Fe(III/II) couple that is often overshadowed by its higher-valent counterparts.
- Tetramethylpyrazine inhibits angiotensin II-induced activation of hepatic stellate cells associated with interference of platelet-derived growth factor-β receptor pathways. [JOURNAL ARTICLE]
- FEBS J 2014 Apr 12.
Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells (HSCs) is a pivotal event during liver fibrogenesis. Compelling evidence indicates that renin-angiotensin system (RAS) takes part in the pathogenesis of liver fibrosis. Angiotensin II (Ang II), the primary effector peptide of RAS, has been demonstrated to be a potent pro-fibrogenic molecule for HSC activation. This study was to investigate the effects of tetramethylpyrazine (TMP) on HSC activation induced by Ang II and to elucidate the underlying mechanisms. Our results demonstrated that Ang II significantly promoted cell growth, upregulated the expression of fibrotic markers α-smooth muscle actin (α-SMA) and α1(I) procollagen, and enhanced invasion capacity in HSCs. TMP inhibited proliferation and arrested cell cycle at G2/M checkpoint associated with altering several cell cycle regulatory proteins in Ang II-treated HSCs. TMP also modulated Bcl-2 family proteins and activated caspase cascade leading to apoptosis in Ang II-treated HSCs. Moreover, TMP reduced the expression of α-SMA and α1(I) procollagen at mRNA and protein levels, and these effects were associated with interference of platelet-derived growth factor-β receptor (PDGF-βR)-mediated PI3K/AKT/mTOR pathway in HSCs exposed to Ang II. Furthermore, Ang II-enhanced HSC invasion capacity was diminished by TMP, which was associated with interference of PDGF-βR/FAK signaling. These data collectively indicated that interference of PDGF-βR-mediated fibrotic pathways was involved in TMP inhibition of HSC activation caused by Ang II, providing novel mechanistic insights into TMP as a potential therapeutic remedy for hepatic fibrosis. This article is protected by copyright. All rights reserved.
- UV-Vis spectroscopic study and DFT calculation on the solvent effect of trimethoprim in neat solvents and aqueous mixtures. [JOURNAL ARTICLE]
- Spectrochim Acta A Mol Biomol Spectrosc 2014 Mar 25.:52-60.
The solvatochromic behavior of trimethoprim (TMP) was analyzed using UV-Vis spectroscopy and DFT methods in neat and binary aqueous solvent mixtures. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions on the absorption maxima were evaluated by means of the linear solvation energy relationship concept of Kamlet and Taft. This analysis indicated that both interactions play an important role in the position of the absorption maxima in neat solvents. The simulated absorption spectra of TMP and TMP:(solvent)n complexes in ACN and H2O using TD-DFT methods were in agreement with the experimental ones. Binary aqueous mixtures containing as co-solvents DMSO, ACN and EtOH were studied. Preferential solvation was detected as a nonideal behavior of the wavenumber curve respective to the analytical mole fraction of co-solvent in all binary systems. TMP molecules were preferentially solvated by the organic solvent over the whole composition range. Index of preferential solvation, as well as the influence of solvent parameters were calculated as a function of solvent composition.
- Neuroprotective Effects of Tetramethylpyrazine against Dopaminergic Neuron Injury in a Rat Model of Parkinson's Disease Induced by MPTP. [Journal Article]
- Int J Biol Sci 2014; 10(4):350-7.
Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disease. Although several hypotheses have been proposed to explain the pathogenesis of PD, apoptotic cell death and oxidative stress are the most prevalent mechanisms. Tetramethylpyrazine (TMP) is a biological component that has been extracted from Ligusticum wallichii Franchat (ChuanXiong), which exhibits anti-apoptotic and antioxidant roles. In the current study, we aimed to investigate the possible protective effect of TMP against dopaminergic neuron injury in a rat model of Parkinson's disease induced by MPTP and to elucidate probable molecular mechanisms. The results showed that TMP could notably prevent MPTP-induced dopaminergic neurons damage, reflected by improvement of motor deficits, enhancement of TH expression and the content of dopamine and its metabolite, DOPAC. We observed MPTP-induced activation of mitochondrial apoptotic death pathway, evidenced by up-regulation of Bax, down-regulation of Bcl-2, release of cytochrome c and cleavage of caspase 3, which was significantly inhibited by TMP. Moreover, TMP could prevent MPTP-increased TBARS level and MPTP-decreased GSH level, indicating the antioxidant role of TMP in PD model. And the antioxidant role of TMP attributes to the prevention of MPTP-induced reduction of Nrf2 and GCLc expression. In conclusion, in MPTP-induced PD model, TMP prevents the down-regulation of Nrf2 and GCLc, maintaining redox balance and inhibiting apoptosis, leading to the attenuation of dopaminergic neuron damage. The effectiveness of TMP in treating PD potentially leads to interesting therapeutic perspectives.
- Cost-Effectiveness of Cranberries vs Antibiotics to Prevent Urinary Tract Infections in Premenopausal Women: A Randomized Clinical Trial. [Journal Article]
- PLoS One 2014; 9(4):e91939.
Urinary tract infections (UTIs) are common and result in an enormous economic burden. The increasing prevalence of antibiotic-resistant microorganisms has stimulated interest in non-antibiotic agents to prevent UTIs.To evaluate the cost-effectiveness of cranberry prophylaxis compared to antibiotic prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) over a 12 month period in premenopausal women with recurrent UTIs.An economic evaluation was performed alongside a randomized trial. Primary outcome was the number of UTIs during 12 months. Secondary outcomes included satisfaction and quality of life. Healthcare utilization was measured using questionnaires. Missing data were imputed using multiple imputation. Bootstrapping was used to evaluate the cost-effectiveness of the treatments.Cranberry prophylaxis was less effective than TMP-SMX prophylaxis, but the differences in clinical outcomes were not statistically significant. Costs after 12 months in the cranberry group were statistically significantly higher than in the TMP-SMX group (mean difference €249, 95% confidence interval 70 to 516). Cost-effectiveness planes and cost-effectiveness acceptability curves showed that cranberry prophylaxis to prevent UTIs is less effective and more expensive than (dominated by) TMP-SMX prophylaxis.In premenopausal women with recurrent UTIs, cranberry prophylaxis is not cost-effective compared to TMP-SMX prophylaxis. However, it was not possible to take into account costs attributed to increased antibiotic resistance within the framework of this randomized trial; modeling studies are recommended to investigate these costs. Moreover, although we based the dosage of cranberry extract on available evidence, this may not be the optimal dosage. Results may change when this optimal dosage is identified.ISRCTN.org ISRCTN50717094.
- The toxic effect of oxytetracycline and trimethoprim in the aquatic environment. [JOURNAL ARTICLE]
- Chemosphere 2014 Apr 2.
The objective of our study was the investigation of the toxic properties of two antimicrobial drugs: oxytetracycline (OTC) and trimethoprim (TMP) in the aquatic environment. The toxic effects were tested according to the OECD guidelines for the testing of chemicals, on the cyanobacteria Anabaena flos-aque, on the alga Pseudokirchneriella subcapitata, on the daphnid Daphnia magna as well as on the activated sludge. We discussed the short term and long term results of tests on cyanobacteria and microalgae. Both experiments were concluded in 72h allowing direct comparison of sensitivity of the two tested species. The results of our study showed toxic effect in the same range for both groups. In the test on the toxicity of OTC to P. subcapitata we obtained the 72hErC50 of 1.04mgL(-1) (72hErC10 0.47mgL(-1)) which are lower in comparison to the results on the toxicity to A. flos-aque of ErC50 of 2.7mgL(-1) (72hErC101.5mgL(-1)). TMP is less toxic to both photosynthetic plankton species. Similar to the test results on OTC, the P. subcapitata is more sensitive to TMP (ErC50129mgL(-1); ErC1065mgL(-1)) than A. flos-aque (72hErC50253mgL(-1); 72hErC1026mgL(-1)). OTC is toxic to the activated sludge (3hEC50 17.9mgL(-1)), while the calculated 3hEC50 value for TMP exceeded solubility for the compound. In comparison to other species, both tested antimicrobials showed low toxicity to daphnids.
- Desorption Kinetics of Sulfonamide and Trimethoprim Antibiotics in Soils Assessed with Diffusive Gradients in Thin-films. [JOURNAL ARTICLE]
- Environ Sci Technol 2014 Apr 4.
Although sorption/desorption of antibiotics in soils affect their mobility and availability, with consequences for risks to the surrounding environment, the dynamics of these processes are not well known. In this study, diffusive gradients in thin films devices suitable for measuring polar organic compounds (o-DGT) were deployed in two soils for a range of times (5 h to 20 d) to measure the distribution and rates of exchange between solid phase and solution of three sulphonamides (SAs: sulfamethoxazole - SMX, sulfamethazine - SMZ, and sulfadimethoxine - SDM) and trimethoprim (TMP). o-DGT continuously removes antibiotics to a XAD gel layer after passage through a well-defined diffusion layer and therefore perturbs their concentration in the adjacent soil solution. This induces a remobilization flux from the solid phase, which is related to the concentration of antibiotics in the soil solution, their diffusional supply and the exchange kinetics between dissolved and sorbed antibiotics. A dynamic model of solute interactions called DIFS (DGT induced fluxes in soils) was used to derive distribution coefficients for labile antibiotics (Kdl) and the rate constant for supply of antibiotics from solid phase to solution, expressed as a response time (Tc). Larger labile solid phase pools were observed for TMP than SAs. The soils could resupply TMP so rapidly that in one soil, where Tc = 2 min, supply was controlled by diffusion. Response times for SAs were generally longer (>27 min), particularly for SDM (>3h), implying that the supply of SAs to the o-DGT samplers was limited by the desorption release rate. A wider implication of this study is that similar solid phase release kinetics may control the uptake of antibiotics by biota.