Modulation of doxorubicin-induced clastogenesis in Wistar rat bone marrow cells by vitamin B(6)

Vitamin B(6) has shown to be a potentially effective antioxidant agent, and dietary antioxidants are also frequently valuable inhibitors of clastogenesis and carcinogenesis. The purpose of the present work was to study the clastogenicity of different doses of vitamin B6 and to examine the possible modulating effect of this vitamin on chromosomal damage induced by the antitumor agent doxorubicin in Wistar rats. Experimental groups were set up for pre-and simultaneous treatment with vitamin B6 alone or in combination with DXR. The data obtained from administering diVerent doses of vitamin B(6) (12.5-100 mg/kg b. w.) showed no signigicant increase in total chromosomal aberrations when compared with the negative control. The administration of two doses of 25 mg/kg b. w. or one dose of 50 mg/kg b. w. of vitamin B6 before doxorubicin injection seemed equally effective in protecting cells against doxorubicin clastogenicity. The anticlastogenic effect of vitamin B(6) on DXR-induced chromosomal damage could be ascribed to its antioxidant properties. Vitamin B6 was not clastogenic or cytotoxic in rat bone marrow cells and it plays a role in inhibiting the clastogenicity induced by DXR.

Dexamethasone Effects in the Strongyloides venezuelensis Infection in A Murine Model

The aim of this study was to investigate the immunomodulatory effects of glucocorticoids on the immune response to Strongyloides venezuelensis in mice. Balb/c mice were infected with S. venezuelensis and treated with Dexamethasone (Dexa) or vehicle. Dexa treatment increased circulating blood neutrophil numbers and inhibited eosinophil and mononuclear cell accumulation in the blood, bronchoalveolar, and peritoneal fluid compared with control animals. Moreover, Dexa decreased tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-3 (IL-3), IL-4, IL-5, IL-10, and IL-12 production in the lungs and circulating immunoglobulin G1. (IgG1), IgG2a, and IgE antibody levels while increasing the overall parasite burden in the feces and intestine. Dexa treatment enhanced the fertility of female nematodes relative to untreated and infected mice. In summary, the alterations in the immune response induced by Dexa resulted in a blunted, aberrant immune response associated with increased parasite burden. This phenomenon is similar to that observed in S. stercoralis-infected humans who are taking immunosuppressive or antiinflammatory drugs, including corticosteroids.

CTX-M-producing Klebsiella spp. in a Brazilian hospital: what has changed in 6 years?

CTX-M-encoding genes from Klebsiella spp. strains isolated in 2000 and 2006 were characterized as well as their genetic environment. CTX-M-2 variants were predominant in Klebsiella pneumoniae strains, which showed a greater variability in bla(CTX-M) genes, integrons, and plasmids in 2006 when compared to strains collected in 2000. CTX-M-9-producing Klebsiella oxytoca was identified in 2000 as clonal dissemination. (C) 2010 Elsevier Inc. All rights reserved.

DHEA and testosterone therapies in Trypanosoma cruzi-infected rats are associated with thymic changes

The ability of the gonadal hormones to influence diverse immunological functions during the course of several infections has been extensively studied in the latest decades. Testosterone has a suppressive effect on immune response of vertebrates and increases susceptibility toward numerous parasitic diseases. Dehydroepiandrosterone is an abundant steroid hormone secreted by the human adrenal cortex and it is considered potent immune-activator. In this paper, it was examined the effects of DHEA and testosterone supplementation in the thymic atrophy in rats infected with Trypanosoma cruzi, by comparing blood parasitism, thymocyte proliferation, TNF-alpha and IL-12 levels. Our data point in the direction that DHEA treatment triggered enhanced thymocyte proliferation as compared to its infected counterparts and reduced production of TNF-alpha during the acute phase of infection. Oppositely, the lowest values for cells proliferation and IL-12 concentrations were reached in testosterone-supplied animals. The combined treatment testosterone and DHEA improves the effectiveness of the host`s immune response, reducing blood parasites and the immunosuppressive effects of male androgens besides increasing IL-12 concentrations and decreasing TNF-alpha levels. (C) 2010 Elsevier Ltd. All rights reserved.

Histamine Plays an Essential Regulatory Role in Lung Inflammation and Protective Immunity in the Acute Phase of Mycobacterium tuberculosis Infection

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

Effect of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on the ability of Candida albicans to infect cells and induce inflammation

Vulvovaginal candidiasis, a high prevailing infection worldwide, is mainly caused by Candida albicans. Probiotic Lactobacillus reuteri RC-14 and Lactobacillus rhamnosus GR-1 have been previously shown to be useful as adjuvants in the treatment of women with VVC. In order to demonstrate and better understand the anti-Candida activity of the probiotic microorganisms in an in vitro model simulating vaginal candidiasis, a human vaginal epithelial cell line (VK2/E6E7) was infected with C. albicans 3153a and then challenged with probiotic L. rhamnosus GR-1 and/or L. reuteri RC-14 or their respective CFS (alone or in combination). At each time point (0, 6, 12 and 24 hr), numbers of yeast, lactobacilli and viable VK2/E6E7 cells were determined and, at 0, 6 and 12 hr, the supernatants were measured for cytokine levels. We found that C. albicans induced a significant increase in IL-1 alpha and IL-8 production by VK2/E6E7 cells. After lactobacilli challenge, epithelial cells did not alter IL-6, IL-1 alpha, RANTES and VEGF levels. However, CFS from the probiotic microorganisms up-regulated IL-8 and IP-10 levels secreted by VK2/E6E7 cells infected with C. albicans. At 24 hr of co-incubation, L. reuteri RC-14 alone and in combination with L. rhamnosus GR-1 decreased the yeast population recoverable from the cells. In conclusion, L. reuteri RC-14 alone and together with L. rhamnosus GR-1 have the potential to inhibit the yeast growth and their CFS may up-regulate IL-8 and IP-10 secretion by VK2/E6E7 cells, which could possibly have played an important role in helping to clear VVC in vivo.

Screening of plant extracts from the Brazilian Cerrado for their in vitro trypanocidal activity

In this study we report the screening of the in vitro trypanocidal activity of 20 extracts obtained from 10 different plant species growing in the Brazilian Cerrado: Aspidosperma macrocarpum Mart. (Apocynaceae), Aegiphila sellowiano Cham. (Verbenaceae), Byrsonima intermedia Juss. (Malpighiaceae), Cyperus rotundus L. (Cyperaceae), Leandra lacunosa Cogn. (Melastomataceae), Miconia ligustroides (DC.) Naudin. (Melastomataceae), Miconia sellowiana Naudin.(Melastomataceae),Myrcia variabilis Mart.ex DC. (Myrtaceae), Solanum lycocarpum St. Hil. (Solanaceae), and Tibouchina stenocarpa Cogn. (Melastomataceae). The most active extracts were submitted to phytochemical analyses. High-resolution gas chromatography analysis of the n-hexane extract of T. stenocarpa (IC(50) = 23.6 mu g/mL), the most active extract amongst all the tested samples, allowed the identification of beta-amyrin, alpha-amyrin, lupeol, friedelin, beta-friedelanol, campesterol, stigmasterol, and beta-sitosterol. Oleanolic and ursolic acids were isolated from the methylene chloride extract of T stenocarpa (IC(50) = 51.5 mu g/mL), while ursolic acid was isolated from the methylene chloride extract of M. variabilis (IC(50)=38.4 mu g/mL). Solasonine and solamargine were identified as major compounds by mass spectrometry analysis in the hydroalcoholic extract of the fruits of S. lycocarpum (IC(50)=57.1 mu g/mL).The results showed that the trypanocidal activity may be related to the major compounds identified in the crude active extracts.

TLR2-dependent mast cell activation contributes to the control of Mycobacterium tuberculosis infection

Mast Cells (MCs) express toll-like receptor 2 (TLR2), a receptor known to be triggered by several major mycobacterial ligands and involved in resistance against Mycobacterium tuberculosis (MTB) infection. This study investigated whether adoptive transfer of TLR2 positive MCs (TLR2(+/+)) corrects the increased susceptibility of TLR2(-/-) mice to MTB infection. TLR2(-/-) mice displayed increased mycobacterial burden, diminished myeloid cell recruitment and proinflammatory cytokine production accompanied by defective granuloma formation. The reconstitution of these mice with TLR2(+/+) MCs, but not TLR2(-/-), confers better control of the infection, promotes the normalization of myeloid cell recruitment associated with reestablishment of the granuloma formation. In addition, adoptive transfer of TLR2(+/+) MC to TLR2(-/-) mice resulted in regulation of the pulmonary levels of IL-beta, IL-6, TNF-alpha, enhanced Th1 response and activated CD8(+) T cell homing to the lungs. Our results suggest that activation of MCs via TLR2 is required to compensate the defect in protective immunity and inability of TLR2(-/-) mice to control MTB infection. (C) 2009 Elsevier Masson SAS. All rights reserved.

Circulating Interleukin-6 and High-Sensitivity C-Reactive Protein Decrease After Periodontal Therapy in Otherwise Healthy Subjects

Background: Periodontal disease has been associated with many chronic inflammatory systemic diseases, and a common chronic inflammation pathway has been suggested for these conditions. However, few studies have evaluated whether periodontal disease, in the absence of other known inflammatory conditions and smoking, affects circulating markers of chronic inflammation. This study compared chronic inflammation markers in control individuals and patients with periodontal disease and observed whether non-surgical periodontal therapy affected inflammatory disease markers after 3 months. Methods: Plasma and serum of 20 controls and 25 patients with periodontal disease were obtained prior to and 3 months after non-surgical periodontal therapy. All patients were non-smokers, they did not use any medication, and they had no history or detectable signs and symptoms of systemic diseases. Periodontal and systemic parameters included probing depth, bleeding on probing, clinical attachment level, hematologic parameters, as well as the following inflammatory markers: interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), CD40 ligand, monocyte chemoattractant protein (MCP)-1, soluble P-selectin (sP-selectin), soluble vascular adhesion molecule (sVCAM)-1, and soluble intercellular adhesion molecule (sICAM)-1. Results: There were no differences in the hematologic parameters of the patients in the control and periodontal disease groups. Among the tested inflammatory markers, IL-6 concentrations were higher in the periodontal disease group at baseline compared to the controls (P=0.006). Therapy was highly effective (P<0.001 for all the analyzed clinical parameters), and a decrease in circulating IL-6 and hs-CRP concentrations was observed 3 months after therapy (P=0.001 and P=0.006, respectively). Our results also suggest that the CD40 ligand marker may have been different in the control and periodontal disease groups prior to the therapy (P=0.009). Conclusions: In apparently otherwise healthy patients, periodontal disease is associated with increased circulating concentrations of IL-6 and hs-CRP, which decreased 3 months after non-surgical periodontal therapy. With regard to the CD40 ligand, MCP-1, sP-selectin, sVCAM-1, and sICAM-1, no changes were seen in the periodontal disease group between baseline and 3 months after therapy. J Periodontol 2009;80:594-602.

alpha-Arylation and Alkynylation of Cyclic alpha-Iodoenones Using Palladium-Catalyzed Cross-Coupling Reactions with Trifluoroborate Salts

An expeditious synthesis of alpha-aryl- and alpha-alkynylcyclo-hexenones is described and illustrated by palladium-catalyzed cross-coupling reaction of cyclic alpha-iodoenones with potassium aryltrifluoroborate salts. This procedure offers easy access to alpha-arylated and alkynylated cyclohexenones functionalized with electrondonor and -acceptor substituents in good yields.

Synthesis of 5-alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and 1,4-disubstituted-1,2,3-triazoles

Herein we report an approach to the formation of 5-alkynyl-1,3-dioxin-4-ones using Suzuki-Miyaura cross-coupling reaction of potassium alkynyltrifluoroborate salts with 2,2,6-trimethy1-5-iodo-1,3-dioxin-4-one. The resulting 5-ethynyltrimethylsilyl-1,3-dioxin-4-ones obtained through the Sonogashira reaction were further reacted in a Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition to form functionalized 1,4-disubstituted-1,2,3-triazoles in good yields, using mild conditions and ultrasonic radiation to expedite the reaction. (C) 2011 Elsevier Ltd. All rights reserved.

Influence of Plasma Protein Binding on Pharmacodynamics: Estimation of In Vivo Receptor Affinities of beta Blockers Using a New Mechanism-Based PK-PD Modelling Approach

The objective of this investigation was to examine in a systematic manner the influence of plasma protein binding on in vivo pharmacodynamics. Comparative pharmacokinetic-pharmacodynamic studies with four beta blockers were performed in conscious rats, using heart rate under isoprenaline-induced tachycardia as a pharmacodynamic endpoint. A recently proposed mechanism-based agonist-antagonist interaction model was used to obtain in vivo estimates of receptor affinities (K(B),(vivo)). These values were compared with in vitro affinities (K(B),(vitro)) on the basis of both total and free drug concentrations. For the total drug concentrations, the K(B),(vivo) estimates were 26, 13, 6.5 and 0.89 nM for S(-)-atenolol, S(-)-propranolol, S(-)-metoprolol and timolol. The K(B),(vivo) estimates on the basis of the free concentrations were 25, 2.0, 5.2 and 0.56 nM, respectively. The K(B),(vivo)-K(B),(vitro) correlation for total drug concentrations clearly deviated from the line of identity, especially for the most highly bound drug S(-)-propranolol (ratio K(B),(vivo)/K(B),(vitro) similar to 6.8). For the free drug, the correlation approximated the line of identity. Using this model, for beta-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3816-3828, 2009

Fluoride ingestion from food items and dentifrice in 2-6-year-old Brazilian children living in a fluoridated area using a semiquantitative food frequency questionnaire

Objectives: The aim of this study was to evaluate the fluoride intake of 2-6-year-old Brazilian children using a semiquantitative food frequency questionnaire (FFQ) which also estimated fluoride intake from dentifrice. Methods: The FFQ was previously validated through application to 78 2-6-year-old Brazilian children and then administered to 379 children residing in an optimally fluoridated community in Brazil (Bauru, State of Sao Paulo). The FFQ was applied to the parents and used to estimate the food intake of the children. The constituents of the diet were divided into solids, water and other beverages. The fluoride content of the diet items was analyzed with the fluoride electrode. The questionnaire also estimated fluoride intake from dentifrice. Results: The average (+/- SD) fluoride intake from solids, water, other beverages and dentifrice was 0.008 +/- 0.005; 0.011 +/- 0.004; 0.009 +/- 0.014 and 0.036 +/- 0.028 mg F/kg body weight/day, respectively, totalizing 0.064 +/- 0.035 mg F/kg body weight/day. The dentifrice and the diet contributed with 56.3% and 43.7% of the daily fluoride intake, respectively. Among the children evaluated, 31.2% are estimated to have risk to develop dental fluorosis (intake > 0.07 mg F/kg body weight/day). Conclusions: The dentifrice was the main source of fluoride intake by the children evaluated. However, the fluoride concentration in food items also significantly contributed to the daily ingestion by 2-6-year-old children. The questionnaire used seems to be a promising alternative to duplicate diet to estimate the fluoride intake at this age range and may have potential to be used in broad epidemiological surveys.