Artesunate Exerts a Direct Effect on Endothelial Cell Activation and NF-κB Translocation in a Mechanism Independent of Plasmodium Killing

Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12 h, however, reduced BBB breakdown and TNF-α mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs) in vitro; however, it abrogated the expression of ICAM-1 in pRBC-stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-κB nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei-induced inflammatory response by inhibiting NF-κB nuclear translocation and the subsequent expression of ICAM-1

Artesunate Exerts a Direct Effect on Endothelial Cell Activation and NF-κB Translocation in a Mechanism Independent of Plasmodium Killing

Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12 h, however, reduced BBB breakdown and TNF-α mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs) in vitro; however, it abrogated the expression of ICAM-1 in pRBC-stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-κB nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei-induced inflammatory response by inhibiting NF-κB nuclear translocation and the subsequent expression of ICAM-1

Mitichrondial localization of non-histone protein HMGB1 during human endothelial cell - Toxoplasma gondii infection

Submitted by Sandra Infurna ([email protected]) on 2019-04-10T13:49:31Z No. of bitstreams: 1 HeleneS_BarbosaLPorto_etal_IOC_2008.pdf: 562357 bytes, checksum: c7eff3721586cf8e27dd6c1c398f5b87 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-04-10T13:58:43Z (GMT) No. of bitstreams: 1 HeleneS_BarbosaLPorto_etal_IOC_2008.pdf: 562357 bytes, checksum: c7eff3721586cf8e27dd6c1c398f5b87 (MD5)Made available in DSpace on 2019-04-10T13:58:43Z (GMT). No. of bitstreams: 1 HeleneS_BarbosaLPorto_etal_IOC_2008.pdf: 562357 bytes, checksum: c7eff3721586cf8e27dd6c1c398f5b87 (MD5) Previous issue date: 2008Universidade do Estado do Rio de Janeiro. Instituto de Biologia. Departamento de Histologia e Embriologia. Laboratório de Cultura de Células. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia. Departamento de Histologia e Embriologia. Laboratório de Cultura de Células. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia. Departamento de Histologia e Embriologia. Laboratório de Cultura de Células. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Estrutural. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Instituto de Biologia. Departamento de Histologia e Embriologia. Laboratório de Cultura de Células. Rio de Janeiro, RJ, Brasil.Toxoplasma gondii is an obligate intracellular pathogen, replicating only within a specialized membrane-bounded cytoplasmic vacuole, the parasitophorous vacuole (PV), which interacts with host cell mitochondria. High mobility group box 1 (HMGB1), a known nuclear transcription factor, also may be involved in pathological conditions, whose function is to signal tissue damage. Using confocal microscopy, we have investigated the localization of HMGB1 and the mitochondria performance during interaction between human umbilical vein endothelial cells (HUVEC) and Toxoplasma. Immunofluorescence showed HMGB1 localization in HUVEC tubular mitochondria stained with Mito Tracker (MT). At 2 h post-infection, MT labeled spherical structures scattered throughout the cytoplasm and HMGB1 were still present. After 24 h of infection, long and tubular structures were localized around PVs and were double labeled by MT and HMGB1, suggesting a structural reorganization of the mitochondria over a long period of infection. For the first time, these results show there is HMGB1 in HUVEC mitochondria and that this protein could be playing a part in mitochondrial DNA events which are important for fission and fusion processes reported here during HUVEC-T. gondii infection

Synthesis and antitubercular activity of heteroaromatic isonicotinoyl and 7-chloro-4-quinolinyl hydrazone derivatives

Submitted by Repositório Arca ([email protected]) on 2019-04-24T16:34:34Z No. of bitstreams: 1 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-12-20T11:53:41Z (GMT) No. of bitstreams: 2 ve_Ferreira_Marcelle_etal_INI_2010.pdf: 413772 bytes, checksum: d4f78fce67aad6be6cd0c9b038eec3c4 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Made available in DSpace on 2019-12-20T11:53:41Z (GMT). No. of bitstreams: 2 ve_Ferreira_Marcelle_etal_INI_2010.pdf: 413772 bytes, checksum: d4f78fce67aad6be6cd0c9b038eec3c4 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2010Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. 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. Departamento de Química Orgânica. 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. Departamento de Química Orgânica. 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 Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Pesquisas Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos. Rio de Janeiro, RJ, Brasil.Two series of N´-(E)-heteroaromatic-isonicotinohydrazide derivatives (3a-f and 4a-b) and 1-(7-chloroquinolin-4-yl)-2-[(heteroaromatic)methylene]hydrazone derivatives (5a-f and 6a-b) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Several compounds were noncytotoxic and exhibited significant minimum inhibitory concentration (MIC) activity (3.12, 2.50, 1.25, or 0.60 μg/mL), which can be compared to that of the first-line drugs ethambutol (3.12 μg/mL) and rifampicin (2.0 μg/ml). These results can be considered an important starting point for the rational design of new leads for anti-TB compounds

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 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