Institute Bioquimica Medica Leopoldo Of Meis

Rio de Janeiro, Brazil

Institute Bioquimica Medica Leopoldo Of Meis

Rio de Janeiro, Brazil
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ARRUDA-COSTA N.,Institute Biofisica Carlos Chagas Filho | ESCRIVANI D.,Institute Biofisica Carlos Chagas Filho | ALMEIDA-AMARAL E.E.,Fundacao Oswaldo Cruz | MEYER-FERNANDES J.R.,Institute Bioquimica Medica Leopoldo Of Meis | ROSSI-BERGMANN B.,Institute Biofisica Carlos Chagas Filho
Parasitology | Year: 2017

Leishmania amazonensis promastigotes are known to express furosemide (Lasix®)-sensitive P-type membrane Na+-ATPase. In the present study, furosemide activity was studied in intracellular amastigotes and infected BALB/c mice to investigate its efficacy in cutaneous leishmaniasis (CL). Intracellular parasites, but not macrophages, were found to be sensitive to killing by furosemide (IC50 = 87 µ m vs CC50 ≫ 1000 µ m, respectively). Although furosemide did not induce nitric oxide production or intracellular pH changes in infected macrophages, it led to a significant reactive oxygen species (ROS) burst. Freshly isolated tissue parasites expressed a high degree of Na+-ATPase activity that decreased with culture, indicative of a higher enzyme expression in amastigotes than in promastigotes. Both intraperitoneal and oral treatment of L. amazonensis-infected mice with furosemide dosages equivalent to that prescribed as a diuretic significantly reduced the parasite's growth compared with the situation in untreated mice. Combination with oral furosemide increased the efficacy and safety of intraperitoneal treatment with sodium stibogluconate (SSG). To summarize, furosemide control of intracellular leishmanial growth by means of parasite Na+-ATPase inhibition, and macrophage ROS activation may help explain its sole and SSG-combined therapeutic effect against murine CL. Copyright © Cambridge University Press 2017


Assafim M.,Federal University of Rio de Janeiro | Frattani F.S.,Federal University of Rio de Janeiro | Ferreira M.S.,Federal University of Rio de Janeiro | Silva D.M.,Federal University of Rio de Janeiro | And 3 more authors.
Toxicon | Year: 2016

Bothrojaracin is a 27 kDa C-type lectin-like protein from Bothrops jararaca snake venom. It behaves as a potent thrombin inhibitor upon high-affinity binding to thrombin exosites. Bothrojaracin also forms a stable complex with prothrombin that can be detected in human plasma. Formation of the zymogen-inhibitor complex severely decreases prothrombin activation and contributes to the anticoagulant activity of bothrojaracin. In the present study, we employed two rodent models to evaluate the antithrombotic effect of bothrojaracin in vivo: stasis-induced thrombosis and thrombin-induced pulmonary thromboembolism. It was observed that bothrojaracin interacts with rat prothrombin in plasma. Ex-vivo assays showed stable complex formation even after 24 h of a single bothrojaracin dose. As a result, bothrojaracin showed significant antithrombotic activity in a rat venous thrombosis model elicited by thromboplastin combined with stasis. The antithrombotic activity of bothrojaracin (1 mg/kg) persisted for up to 24 h and it was associated with moderate bleeding as assessed by a tail transection method. Formation of bothrojaracin-prothrombin complex has been also observed following intravenous administration of the inhibitor into mice. As a result, bothrojaracin effectively protected mice from thrombin-induced fatal thromboembolism. We conclude that bothrojaracin is a potent antithrombotic agent in vivo and may serve as a prototype for the development of new zymogen-directed drugs that could result in prolonged half-life and possible decreased hemorrhagic risk. © 2016 Elsevier Ltd. All rights reserved.


Rangel L.P.,Institute Bioquimica Medica Leopoldo Of Meis | Rangel L.P.,Brazilian National Institute of Technology | Rangel L.P.,Federal University of Rio de Janeiro | Costa D.C.F.,Institute Bioquimica Medica Leopoldo Of Meis | And 5 more authors.
Prion | Year: 2014

The tumor suppressor protein p53 loses its function in more than 50% of human malignant tumors. Recent studies have suggested that mutant p53 can form aggregates that are related to loss-of-function effects, negative dominance and gain-of-function effects and cancers with a worsened prognosis. In recent years, several degenerative diseases have been shown to have prion-like properties similar to mammalian prion proteins (PrPs). However, whereas prion diseases are rare, the incidence of these neurodegenerative pathologies is high. Malignant tumors involving mutated forms of the tumor suppressor p53 protein seem to have similar substrata. The aggregation of the entire p53 protein and three functional domains of p53 into amyloid oligomers and fibrils has been demonstrated. Amyloid aggregates of mutant p53 have been detected in breast cancer and malignant skin tumors. Most p53 mutations related to cancer development are found in the DNA-binding domain (p53C), which has been experimentally shown to form amyloid oligomers and fibrils. Several computation programs have corroborated the predicted propensity of p53C to form aggregates, and some of these programs suggest that p53C is more likely to form aggregates than the globular domain of PrP. Overall, studies imply that mutant p53 exerts a dominant-negative regulatory effect on wild-type (WT) p53 and exerts gain-of-function effects when co-aggregating with other proteins such as p63, p73 and acetyltransferase p300. We review here the prion-like behavior of oncogenic p53 mutants that provides an explanation for their dominant-negative and gain-of-function properties and for the high metastatic potential of cancers bearing p53 mutations. The inhibition of the aggregation of p53 into oligomeric and fibrillar amyloids appears to be a promising target for therapeutic intervention in malignant tumor diseases.©2014 Landes Bioscience.


Silva J.L.,Institute Bioquimica Medica Leopoldo Of Meis | Oliveira A.C.,Institute Bioquimica Medica Leopoldo Of Meis | Vieira T.C.R.G.,Institute Bioquimica Medica Leopoldo Of Meis | De Oliveira G.A.P.,Institute Bioquimica Medica Leopoldo Of Meis | And 2 more authors.
Chemical Reviews | Year: 2014

The application of pressure has opened important frontiers for understanding how polypeptides fold into highly structured conformations, how they interact with ligands and other proteins, and how they assemble into supramolecular structures such as viruses and amyloids. In proteins, pressure induces changes that range from small conformational effects, compressibility effects, and changes in populations of intermediate states to complete loss of native folding. Applying high pressure is also an excellent approach for studying situations in which protein folding occurs incorrectly, such as in the so-called protein folding disorders, which include Alzheimer's, Parkinson's, tumoral, and prion diseases. Because partially folded intermediates, leading in some cases to misfolding and the occurrence of protein aggregates, are stabilized by pressure, the application of high pressure permits the characterization of these aggregation reactions.


Teixeira M.P.,Institute Bioquimica Medica Leopoldo Of Meis | Rumjanek V.M.,Institute Bioquimica Medica Leopoldo Of Meis
Mediators of Inflammation | Year: 2014

Ouabain is a steroid capable of binding to and inhibiting Na +,-K+-ATPase. Studies have demonstrated some actions of ouabain on immune cells, which indicated both pro- and anti-inflammatory properties of this molecule. Nevertheless, its effects on human monocytes are still poorly understood. Thus, the present work investigated effects of ouabain in the activation and function of human adherent monocytes. Our results show that there is an increase in intracellular calcium levels already 5 minutes following monocyte treatment with 10-7 M of ouabain. Furthermore, monocytes expressed increased amounts of surface activation markers such as CD69, HLA-DR, CD86, and CD80 and also presented an augmented endocytic activity of dextran-FITC particles after 24 hours of culture in the presence of ouabain. However, monocytes treated with ouabain did not have an increased stimulatory capacity in allogeneic mixed leukocyte reaction. Ouabain-treated monocytes produced higher levels of IL-1β and TNF-α as reported before. A novel observation was the fact that ouabain induced IL-10 and VEGF as well. Collectively, these results suggest that ouabain impacts monocyte activation and modulates monocyte functions, implying that this steroid could act as an immunomodulator of these cells. © 2014 Mariana Pires Teixeira and Vivian Mary Rumjanek.


PubMed | Institute Bioquimica Medica Leopoldo Of Meis and Federal University of Rio de Janeiro
Type: Journal Article | Journal: Science and engineering ethics | Year: 2015

This study focuses on retraction notices from two major Latin American/Caribbean indexing databases: SciELO and LILACS. SciELO includes open scientific journals published mostly in Latin America/the Caribbean, from which 10% are also indexed by Thomson Reuters Web of Knowledge Journal of Citation Reports (JCR). LILACS has a similar geographical coverage and includes dissertations and conference/symposia proceedings, but it is limited to publications in the health sciences. A search for retraction notices was performed in these two databases using the keywords retracted, retraction withdrawal, withdrawn, removed and redress. Documents were manually checked to identify those that actually referred to retractions, which were then analyzed and categorized according to the reasons alleged in the notices. Dates of publication/retraction and time to retraction were also recorded. Searching procedures were performed between June and December 2014. Thirty-one retraction notices were identified, fifteen of which were in JCR-indexed journals. Plagiarism was alleged in six retractions of this group. Among the non-JCR journals, retraction reasons were alleged in fourteen cases, twelve of which were attributed to plagiarism. The proportion of retracted articles for the SciELO database was approximately 0.005%. The reasons alleged in retraction notices may be used as signposts to inform discussions in Latin America on plagiarism and research integrity. At the international level, these results suggest that the correction of the literature is becoming global and is not limited to mainstream international publications.


PubMed | Institute Bioquimica Medica Leopoldo Of Meis and Federal University of Rio de Janeiro
Type: | Journal: Acta tropica | Year: 2016

The most commonly used drugs against visceral leishmaniasis are based on pentavalent antimonial compounds, which have played a fundamental role in therapy for over 70 years. However, the treatment is painful and has severe toxic side effects that can be fatal. Antimonial resistance is spreading and reaching alarming proportions. Linalool and eugenol have been shown to kill Leishmania (L.) amazonensis and Trypanosoma cruzi at low doses. In the present study, we demonstrate the effects of linalool and eugenol, components of essential oils, on Leishmania (L.) infantum chagasi, one of the causative agents of visceral leishmaniasis. We compared the effects of those compounds to the effects of glucantime, a positive control. In L. infantum chagasi killing assays, the LD


PubMed | Institute Bioquimica Medica Leopoldo Of Meis and Federal University of Rio de Janeiro
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2016

Protein misfolding results in devastating degenerative diseases and cancer. Among the culprits involved in these illnesses are prions and prion-like proteins, which can propagate by converting normal proteins to the wrong conformation. For spongiform encephalopathies, a real prion can be transmitted among individuals. In other disorders, the bona fide prion characteristics are still under investigation. Besides inducing misfolding of native proteins, prions bind nucleic acids and other polyanions. Here, we discuss how nucleic acid binding might influence protein misfolding for both disease-related and benign, functional prions and why the line between bad and good amyloids might be more subtle than previously thought.


PubMed | Institute Bioquimica Medica Leopoldo Of Meis, Federal University of Rio de Janeiro and Instituto Oswaldo Cruz
Type: Journal Article | Journal: Memorias do Instituto Oswaldo Cruz | Year: 2015

Phytomonas serpens are flagellates in the family Trypanosomatidae that parasitise the tomato plant (Solanum lycopersicum L.), which results in fruits with low commercial value. The tomato glycoalkaloid tomatine and its aglycone tomatidine inhibit the growth of P. serpens in axenic cultures. Tomatine, like many other saponins, induces permeabilisation of the cell membrane and a loss of cell content, including the cytosolic enzyme pyruvate kinase. In contrast, tomatidine does not cause permeabilisation of membranes, but instead provokes morphological changes, including vacuolisation. Phytomonas treated with tomatidine show an increased accumulation of labelled neutral lipids (BODYPY-palmitic), a notable decrease in the amount of C24-alkylated sterols and an increase in zymosterol content. These results are consistent with the inhibition of 24-sterol methyltransferase (SMT), which is an important enzyme that is responsible for the methylation of sterols at the 24 position. We propose that the main target of tomatidine is the sterols biosynthetic pathway, specifically, inhibition of the 24-SMT. Altogether, the results obtained in the present paper suggest a more general effect of alkaloids in trypanosomatids, which opens potential therapeutic possibilities for the treatment of the diseases caused by these pathogens.


PubMed | Institute Bioquimica Medica Leopoldo Of Meis, Federal University of Rio de Janeiro and Instituto Oswaldo Cruz
Type: | Journal: Memorias do Instituto Oswaldo Cruz | Year: 2015

Phytomonas serpens are flagellates in the family Trypanosomatidae that parasitise the tomato plant (Solanum lycopersicum L.), which results in fruits with low commercial value. The tomato glycoalkaloid tomatine and its aglycone tomatidine inhibit the growth of P. serpens in axenic cultures. Tomatine, like many other saponins, induces permeabilisation of the cell membrane and a loss of cell content, including the cytosolic enzyme pyruvate kinase. In contrast, tomatidine does not cause permeabilisation of membranes, but instead provokes morphological changes, including vacuolisation. Phytomonas treated with tomatidine show an increased accumulation of labelled neutral lipids (BODYPY-palmitic), a notable decrease in the amount of C24-alkylated sterols and an increase in zymosterol content. These results are consistent with the inhibition of 24-sterol methyltransferase (SMT), which is an important enzyme that is responsible for the methylation of sterols at the 24 position. We propose that the main target of tomatidine is the sterols biosynthetic pathway, specifically, inhibition of the 24-SMT. Altogether, the results obtained in the present paper suggest a more general effect of alkaloids in trypanosomatids, which opens potential therapeutic possibilities for the treatment of the diseases caused by these pathogens.

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