Therapeutic effect of lipoxin A4 in malaria‐induced acute lung injury

Acute lung injury (ALI) models are characterized by neutrophil accumulation, tissue damage, alteration of the alveolar capillary membrane, and physiological dysfunction. Lipoxin A4 (LXA4) is an anti-inflammatory eicosanoid that was demonstrated to attenuate lipopolysaccharide-induced ALI. Experimental models of severe malaria can be associated with lung injury. However, to date, a putative effect of LXA4 on malaria (M)-induced ALI has not been addressed. In this study, we evaluated whether LXA4 exerts an effect on M-ALI. Male C57BL/6 mice were randomly assigned to the following five groups: noninfected; saline-treated Plasmodium berghei-infected; LXA4-pretreated P. berghei-infected (LXA4 administered 1 h before infection and daily, from days 0 to 5 postinfection), LXA4- and LXA4 receptor antagonist BOC-2-pretreated P. berghei-infected; and LXA4-posttreated P. berghei-infected (LXA4 administered from days 3 to 5 postinfection). By day 6, pretreatment or posttreatment with LXA4 ameliorate lung mechanic dysfunction reduced alveolar collapse, thickening and interstitial edema; impaired neutrophil accumulation in the pulmonary tissue and blood; and reduced the systemic production of CXCL1. Additionally, in vitro treatment with LXA4 prevented neutrophils from migrating toward plasma collected from P. berghei-infected mice. LXA4 also impaired neutrophil cytoskeleton remodeling by inhibiting F-actin polarization. Ex vivo analysis showed that neutrophils from pretreated and posttreated mice were unable to migrate. In conclusion, we demonstrated that LXA4 exerted therapeutic effects in malaria-induced ALI by inhibiting lung dysfunction, tissue injury, and neutrophil accumulation in lung as well as in peripheral blood. Furthermore, LXA4 impaired the migratory ability of P. berghei-infected mice neutrophils

Therapeutic effect of Lipoxin A 4

Acute lung injury (ALI) models are characterized by neutrophil accumulation, tissue damage, alteration of the alveolar capillary membrane, and physiological dysfunction. Lipoxin A4 (LXA4) is an anti-inflammatory eicosanoid that was demonstrated to attenuate lipopolysaccharide-induced ALI. Experimental models of severe malaria can be associated with lung injury. However, to date, a putative effect of LXA4 on malaria (M)-induced ALI has not been addressed. In this study, we evaluated whether LXA4 exerts an effect on M-ALI. Male C57BL/6 mice were randomly assigned to the following five groups: noninfected; saline-treated Plasmodium berghei-infected; LXA4-pretreated P. berghei-infected (LXA4 administered 1 h before infection and daily, from days 0 to 5 postinfection), LXA4- and LXA4 receptor antagonist BOC-2-pretreated P. berghei-infected; and LXA4-posttreated P. berghei-infected (LXA4 administered from days 3 to 5 postinfection). By day 6, pretreatment or posttreatment with LXA4 ameliorate lung mechanic dysfunction reduced alveolar collapse, thickening and interstitial edema; impaired neutrophil accumulation in the pulmonary tissue and blood; and reduced the systemic production of CXCL1. Additionally, in vitro treatment with LXA4 prevented neutrophils from migrating toward plasma collected from P. berghei-infected mice. LXA4 also impaired neutrophil cytoskeleton remodeling by inhibiting F-actin polarization. Ex vivo analysis showed that neutrophils from pretreated and posttreated mice were unable to migrate. In conclusion, we demonstrated that LXA4 exerted therapeutic effects in malaria-induced ALI by inhibiting lung dysfunction, tissue injury, and neutrophil accumulation in lung as well as in peripheral blood. Furthermore, LXA4 impaired the migratory ability of P. berghei-infected mice neutrophils

Anti-mycobacterial evaluation of 7-chloro-4-aminoquinolines and hologram quantitative structure-activity relationship (HQSAR) modeling of amino-imino tautomers

Submitted by Janaína Nascimento ([email protected]) on 2019-07-26T11:46:46Z No. of bitstreams: 1 ve_Bispo_Marcelle_etal_INI_2017.pdf: 17223748 bytes, checksum: 5250bb49bb35694f7440a830cf09e0a6 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-07-26T12:04:36Z (GMT) No. of bitstreams: 1 ve_Bispo_Marcelle_etal_INI_2017.pdf: 17223748 bytes, checksum: 5250bb49bb35694f7440a830cf09e0a6 (MD5)Made available in DSpace on 2019-07-26T12:04:36Z (GMT). No. of bitstreams: 1 ve_Bispo_Marcelle_etal_INI_2017.pdf: 17223748 bytes, checksum: 5250bb49bb35694f7440a830cf09e0a6 (MD5) Previous issue date: 2017Universidade Estadual de Londrina. Departamento de Química. Londrina, PR, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal Fluminense. Ciências Aplicadas a Produtos para Saúde. Niterói, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisas Clínicas Evandro Chagas. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisas Clínicas Evandro Chagas. Rio de Janeiro. RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro. RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Programa de Pós-Graduação em Química. Rio de Janeiro, RJ, Brasil.In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity

Metabonomics Reveals Drastic Changes in Anti-Inflammatory/Pro-Resolving Polyunsaturated Fatty Acids-Derived Lipid Mediators in Leprosy Disease

<div><p>Despite considerable efforts over the last decades, our understanding of leprosy pathogenesis remains limited. The complex interplay between pathogens and hosts has profound effects on host metabolism. To explore the metabolic perturbations associated with leprosy, we analyzed the serum metabolome of leprosy patients. Samples collected from lepromatous and tuberculoid patients before and immediately after the conclusion of multidrug therapy (MDT) were subjected to high-throughput metabolic profiling. Our results show marked metabolic alterations during leprosy that subside at the conclusion of MDT. Pathways showing the highest modulation were related to polyunsaturated fatty acid (PUFA) metabolism, with emphasis on anti-inflammatory, pro-resolving omega-3 fatty acids. These results were confirmed by eicosanoid measurements through enzyme-linked immunoassays. Corroborating the repertoire of metabolites altered in sera, metabonomic analysis of skin specimens revealed alterations in the levels of lipids derived from lipase activity, including PUFAs, suggesting a high lipid turnover in highly-infected lesions. Our data suggest that omega-6 and omega-3, PUFA-derived, pro-resolving lipid mediators contribute to reduced tissue damage irrespectively of pathogen burden during leprosy disease. Our results demonstrate the utility of a comprehensive metabonomic approach for identifying potential contributors to disease pathology that may facilitate the development of more targeted treatments for leprosy and other inflammatory diseases.</p></div

Comparison of the relative levels^a of metabolites in skin biopsies from LL and BT patients.

a<p>Data are shown as the ratio of the averaged values from the LL skin samples (n = 4) and the averaged values from the BT skin samples (n = 4). DPA, docosapentaenoic acid; DHA, docosahexaenoic acid; THETA, trihydroxyicosatrienoic acid; PG, prostaglandin.</p

Comparison of the relative levels^a of metabolites of the arachidonic acid pathway in sera from BT and LL patients before and after antibiotic treatment.

a<p>Absent values were substituted with the limit of detection, represented by the lowest intensity value of any given sample. Then, averaged values from the untreated BT serum samples (n = 4) were normalized to 100% and other samples were normalized accordingly. SD are shown in parentheses. PG, prostaglandin; LT, leukotriene; TX, thromboxane; EET, epoxyeicosatrienoic acid; oxo-ETE, oxoicosatetraenoic acid; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; DHET, dihydroxyeicosatrienoic acid.</p

Principal component analysis of the metabonomics data.

<p>Raw DI-FT-ICR-MS data in both negative and positive ionization modes were combined and PCA was performed using Multibase (<a href="http://www.numericaldynamics.com/" target="_blank">http://www.numericaldynamics.com/</a>). Plots show the separation of groups based on the pole of disease (BT, LL) and treatment status (before, after). Sample groups are indicated by the dashed lines.</p

Metabonomics analysis of sera from leprosy patients.

<p>(a) Principal component analysis of metabolic alterations on sera from borderline tuberculoid (BT) and polar lepromatous leprosy (LL) patients. Raw DI-FT-ICR-MS data in both negative and positive ionization modes were combined and PCA was performed using Multibase (<a href="http://www.numericaldynamics.com/" target="_blank">http://www.numericaldynamics.com/</a>). Sample groups are indicated by the dashed lines. (b) Metabolic pathways altered in the polar forms of leprosy. <i>m/z</i> of interest detected in both negative and positive ionization modes were searched against the KEGG database (<a href="http://www.genome.jp/kegg/" target="_blank">http://www.genome.jp/kegg/</a>) using the MassTRIX software (version 2, <a href="http://metabolomics.helmholtz-muenchen.de/masstrix2/" target="_blank">http://metabolomics.helmholtz-muenchen.de/masstrix2/</a>). Bars indicate the number of metabolic features from each KEGG pathway that was affected by infection. Gray bars represent the number of metabolic features that were found in higher levels in BT patients (>2 fold), whereas white bars represent the metabolic features found in higher levels in LL patients.</p

Serum levels of resolvin D1 in borderline tuberculoid and polar lepromatous patients determined by EIAs.

<p>Box plots represent serum levels of RvD1 assessed in healthy controls, BT and LL patients before (A) and right after MDT conclusion (B), as indicated. Median values are indicated by lines. Group comparisons were evaluated with Kruskall–Wallis non-parametric analysis of variance (ANOVA) and Dunn's multiple-range post hoc test. Paired values of serum concentrations of RvD1 from each patient before and right after MDT conclusion, as assessed in BT and LL patients, are shown in C and D, respectively. Each line represents one patient. Paired t tests were used for statistical analysis. <i>P</i>-values higher than 0.05 are not shown.</p