135 results on '"Fagundes EM"'
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2. A EXPRESSÃO DIFERENCIAL DE CÉLULAS PROGENITORAS LEUCÊMICAS DEFINIDAS POR CD99/CD123 ESTÁ ASSOCIADA À MUTAÇÃO FLT3-ITD E RECAÍDA NA LEUCEMIA MIELOIDE AGUDA
- Author
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Marani, LO, primary, Costa, AFO, additional, Kuznetsova, V, additional, Faria, JTB, additional, Garcia, CAB, additional, Scheucher, PS, additional, Schiavinato, J, additional, Lima, ASG, additional, Welner, R, additional, Madeira, MIA, additional, Gloria, ABF, additional, Fagundes, EM, additional, Nunes, EC, additional, Higashi, M, additional, Duarte, BK, additional, Pagnano, KB, additional, Traina, F, additional, Rego, EM, additional, and Figueiredo-Pontes, LL, additional
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- 2022
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3. Formation of ion pairing as an alternative to improve encapsulation and anticancer activity of all-trans retinoic acid loaded in solid lipid nanoparticles
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Carneiro G, Silva EL, Pacheco LA, Souza-Fagundes EM, Corrêa NC, Goes AM, Oliveira MC, and Ferreira LA
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Medicine (General) ,R5-920 - Abstract
Guilherme Carneiro,1 Elton Luiz Silva,1 Layssa Alves Pacheco,1 Elaine Maria de Souza-Fagundes,2 Natássia Caroline Resende Corrêa,3 Alfredo Miranda de Goes,3 Mônica Cristina de Oliveira,1 Lucas Antônio Miranda Ferreira11Department of Pharmaceutics, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil; 2Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; 3Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, BrazilAbstract: This work aims to develop solid lipid nanoparticles (SLNs) loaded with retinoic acid (RA) to evaluate the influence of two lipophilic amines, stearylamine (SA) and benethamine (BA), and one hydrophilic, triethylamine (TA), on drug-encapsulation efficiency (EE) and cytotoxicity in cancer cell lines. The SLNs were characterized for EE, size, and zeta potential. The mean particle size decreased from 155 ± 1 nm (SLNs without amine) to 104 ± 4, 95 ± 1, and 96 ± 1 nm for SLNs prepared with SA, BA, and TA, respectively. SA-RA-loaded SLNs resulted in positively charged particles, whereas those with TA and BA were negatively charged. The EEs were significantly improved with the addition of the amines, and they increased from 36% ± 6% (without amine) to 97% ± 2%, 90% ± 2%, and 100% ± 1% for SA, TA, and BA, respectively. However, stability studies showed higher EE for BA-RA-loaded SLNs than TA-RA-loaded SLNs after 30 days. The formulations containing SA loaded or unloaded (blank SLNs) with RA were cytotoxic in normal and cancer cell lines. In contrast, the blank SLNs containing TA or BA did not show cytotoxicity in human breast adenocarcinoma cells (MCF-7), while RA-loaded SLNs with the respective amines were significantly more cytotoxic than free RA. Furthermore, the cytotoxicity of BA-RA-loaded SLNs was significantly higher than TA-RA-loaded SLNs. These findings are in agreement with the data obtained in the evaluation of subdiploid DNA content and cell-cycle analysis, which showed better anticancer activity for BA-RA-loaded SLNs than TA-RA-loaded SLNs and free RA. Taken together, these findings suggest that the BA-RA-loaded SLN formulation is a promising alternative for the intravenous administration of RA in the treatment of cancer.Keywords: solid lipid nanoparticles, all-trans retinoic acid, cancer, treatment, antitumor activity, ion pairing
- Published
- 2012
4. MORTALITY BY COVID-19 IN ADULTS WITH ACUTE MYELOID LEUKEMIA: A SURVEY WITH HEMATOLOGISTS IN BRAZIL
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Martins, NNN, primary, Fagundes, OG, additional, and Fagundes, EM, additional
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- 2021
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5. Improved In Vitro Antileukemic Activity of All-Trans Retinoic Acid Loaded in Cholesteryl Butyrate Solid Lipid Nanoparticles
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de Souza-Fagundes Em, Guilherme Carneiro, Elton Luiz Silva, Dawidson Assis Gomes, Ramos Jonas Periera, Lucas Antônio Miranda Ferreira, and Lima Fa
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Acute promyelocytic leukemia ,medicine.drug_class ,Biomedical Engineering ,Retinoic acid ,HL-60 Cells ,Tretinoin ,Bioengineering ,02 engineering and technology ,Butyrate ,030226 pharmacology & pharmacy ,Butyric acid ,Jurkat Cells ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Solid lipid nanoparticle ,medicine ,Humans ,General Materials Science ,Viability assay ,Retinoid ,Cytotoxicity ,Leukemia ,General Chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,chemistry ,Biochemistry ,Nanoparticles ,lipids (amino acids, peptides, and proteins) ,Cholesterol Esters ,Drug Screening Assays, Antitumor ,0210 nano-technology - Abstract
All-trans retinoic acid, a hydrophobic drug, has become one of the most successful examples of differentiation agents used for treatment of acute promyelocytic leukemia. On the other hand, histone deacetylase inhibitors, such as cholesteryl butyrate, present differentiating activity and.can potentiate action of drugs such as all-trans retinoic acid. Solid lipid nanoparticles represent a promising alternative for administration of hydrophobic drugs such as ATRA. This study aimed to develop, characterize, and evaluate the cytotoxicity of all-trans retinoic acid-loaded solid lipid nanoparticles for leukemia treatment. The influence of in situ formation of an ion pairing between all-trans retinoic acid and lipophilic amines on the characteristics of the particles (size, zeta potential, encapsulation efficiency) was evaluated. Cholesteryl butyrate, a butyric acid donor, was used as a component of the lipid matrix. In vitro activity on cell viability and distribution of cell cycle phases were evaluated for HL-60, Jurkat, and THP-1 cell lines. The encapsulation efficiency of all-trans retinoic acid in cholesteryl butyrate-solid lipid nanoparticles was significantly increased by the presence of the amine. Inhibition of cell viability by all-trans retinoic acid-loaded solid lipid nanoparticles was more pronounced than the free drug. Analysis of the distribution of cell cycle phases also showed increased activity for all-trans retinoic acid-loaded cholesteryl butyrate-solid lipid nanoparticles, with a clear increase in subdiploid DNA content. The ion pair formation in SLN containing cholesteryl butyrate can be explored as a simple and inexpensive strategy to improve the efficacy and bioavail-ability of ATRA in the treatment of the cancer and metabolic diseases in which this retinoid plays an important role.
- Published
- 2016
6. Indium(III) complexes with lapachol: cytotoxic effects against human breast tumor cells and interactions with DNA.
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de Carvalho AB, Souza AMS, Bento LP, de Oliveira Silva M, Souza-Fagundes EM, Diniz R, and Beraldo H
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- Humans, Coordination Complexes pharmacology, Coordination Complexes chemistry, Coordination Complexes chemical synthesis, Cell Line, Tumor, Female, Drug Screening Assays, Antitumor, Crystallography, X-Ray, MCF-7 Cells, Models, Molecular, Molecular Structure, Naphthoquinones chemistry, Naphthoquinones pharmacology, Indium chemistry, Indium pharmacology, DNA chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Breast Neoplasms drug therapy, Breast Neoplasms pathology
- Abstract
Lapachol (2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione) is a 1,4-naphthoquinone-derived natural product that presents numerous bioactivities and was shown to have cytotoxic effects against several human tumor cells. Indium(III) complexes with a variety of ligands also exhibit antineoplastic activity. Indium(III) complexes [In(lap)Cl
2 ].4H2 O (1), [In(lap)2 Cl(Et3 N)] (2), [In(lap)3 ]·2H2 O (3) [In(lap)(bipy)Cl2 ] bipy = 2,2'-bipyridine (4) and [In(lap)(phen)Cl2 ] phen = 1,10-phenanthroline (5) were obtained with 2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione (lapachol). Crystal structure determinations for (4) and (5) revealed that the indium(III) center is coordinated to two O atoms from lapachol, two N atoms from 1,10-phenanthroline or 2,2'-bipyridine, and two chloride anions, in a distorted octahedral geometry. Although both complexes (4) and (5) interacted with CT-DNA in vitro by an intercalative mode, only 5 exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being threefold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. The foregoing results suggest that further studies on the cytotoxic effects and cellular targets of complex (5) are of utmost relevance., (© 2024. The Author(s), under exclusive licence to Society for Biological Inorganic Chemistry (SBIC).)- Published
- 2024
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7. Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia.
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Koury LCA, Kim HT, Undurraga MS, Navarro-Cabrera JR, Salinas V, Muxi P, Melo RAM, Gloria ABF, Pagnano KBB, Nunes EC, Bittencourt RI, Rojas N, Quintana Truyenque SM, Ayala-Lugo AI Dr, Oliver AC, de Figueiredo-Pontes LL, Traina F, Moreira F, Fagundes EM, Duarte BKL, Mora-Alferez AP, Ortiz P, Untama JL, Tallman MS, Ribeiro RC, Ganser A, Dillon RJ, Valk PJM, Sanz MA, Löwenberg B, Berliner N, and Rego EM
- Abstract
The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC., (Copyright © 2024 American Society of Hematology.)
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- 2024
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8. Chemotherapy-Induced Peripheral Neuropathy Impacts Quality of Life and Activities of Daily Living of Brazilian Multiple Myeloma Patients.
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de Miranda Drummond PL, Dos Santos RMM, Silveira LP, Malta JS, Moreira Reis AM, Costa NL, de Paula E Silva RO, Fagundes EM, and de Pádua CAM
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- Humans, Female, Male, Cross-Sectional Studies, Aged, Middle Aged, Brazil epidemiology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Agents adverse effects, Aged, 80 and over, Adult, Multiple Myeloma drug therapy, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases epidemiology, Quality of Life, Activities of Daily Living
- Abstract
Background: Survival in multiple myeloma (MM) has improved in the past years with the introduction of immunomodulators and proteasome inhibitors. However, chemotherapyinduced peripheral neuropathy (CIPN) is associated with both drug classes affecting Health- Related Quality of Life (HRQoL) and activities of daily living (ADL)., Objective: We evaluated CIPN in MM patients to identify associated factors and impacts on HRQoL and ADL., Methods: This is a cross-sectional study with Brazilian patients from public and private health services. Patients were interviewed using validated tools to measure CIPN and HRQoL, along with sociodemographic and clinical questions. Logistic regression was used to assess the association of CIPN with sociodemographic, clinical, and HRQoL variables., Results: In total, 217 patients were eligible for the study. The median age was 67, 50.9% were women, 51.6% had low income, 47.5% had low education, and 55.3% attended private health services. The chemotherapy regimen most used was the combination of cyclophosphamide, thalidomide, and dexamethasone (17.5%) among the 24 types of regimens found. Most patients (90.3%) had at least one CIPN symptom: 62.7% were severe, and 51.62% were extremely bothered ADL. Numbness was the most common symptom (40.6%). CIPN was independently associated with education, hospitalization, chemotherapy, side effects, disease symptoms, and global health status in HRQoL., Conclusion: MM patients showed a high frequency of CIPN, which affected ADL and impaired HRQoL. Early and accurate detection of CIPN and dose management in patients with thalidomide and bortezomib-based regimens should be performed to provide better treatment outcomes and avoid permanent disabilities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2024
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9. Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia.
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Carvalho GA, Chiareli RA, Pedrazzi JFC, Silva-Amaral D, da Rocha ALB, Oliveira-Lima OC, Lião LM, de Souza-Fagundes EM, Schildknecht S, Leist M, Del-Bel EA, Gomez RS, Birbrair A, Menegatti R, and Pinto MCX
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- Humans, Receptors, N-Methyl-D-Aspartate, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Schizophrenia chemically induced, Schizophrenia drug therapy, Schizophrenia metabolism, Ketamine pharmacology, Ketamine therapeutic use, Amino Acid Transport Systems, Neutral therapeutic use
- Abstract
The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as L-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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10. Telomeric repeat-containing RNA is dysregulated in acute myeloid leukemia.
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Catto LFB, Zanelatto LC, Donaires FS, de Carvalho VS, Santana BA, Pinto AL, Fantacini D, de Souza LEB, Fonseca NP, Telho BS, Ayrosa Madeira MI, Barbosa Pagnano KB, Firmato AB, Fagundes EM, Higashi M, Nunes EC, Traina F, Lobo de F Pontes L, Rego EM, and Calado RT
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- Humans, Cell Line, DNA, Telomerase, Leukemia, Myeloid, Acute genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma, RNA, Long Noncoding
- Abstract
TERRA (telomeric repeat-containing RNA) is a class of long noncoding RNAs transcribed from subtelomeric and telomeric regions. TERRA binds to the subtelomeric and telomeric DNA-forming R-loops (DNA-RNA hybrids), which are involved in telomere maintenance and telomerase function, but the role of TERRA in human cells is not well characterized. Here, we comprehensively investigated for the first time TERRA expression in primary human hematopoietic cells from an exploratory cohort of patients with acute myeloid leukemia (AML), patients with acute lymphoblastic leukemia (ALL), patients with telomere biology disorder (TBD), and healthy subjects. TERRA expression was repressed in primary human hematopoietic cells, including healthy donors, patients with ALL, and patients with TBD, irrespective of their telomere length, except for AML. A second cohort comprising 88 patients with AML showed that TERRA was overexpressed in an AML subgroup also characterized by higher R-loop formation, low TERT and RNAseH2 expression, and a paucity of somatic splicing factor mutations. Telomere length did not correlate with TERRA expression levels. To assess the role of TERRA R-loops in AML, we induced R-loop depletion by increasing RNAseH1 expression in 2 AML cell lines. Decreased TERRA R-loops in AML cell lines resulted in increased chemosensitivity to cytarabine. Our findings indicate that TERRA is uniformly repressed in primary human hematopoietic cells but abnormally expressed in an AML subset with low telomerase., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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11. Rhythmic profile of memory T and B-cells along childhood and adolescence.
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Brito-de-Sousa JP, Lima-Silva ML, Costa-Rocha IAD, Júnior LRAO, Campi-Azevedo AC, Peruhype-Magalhães V, Quetz JDS, Coelho-Dos-Reis JGA, Costa-Pereira C, Garcia CC, Antonelli LRDV, Fonseca CT, Lemos JAC, Mambrini JVM, Souza-Fagundes EM, Teixeira-Carvalho A, Faria AMC, Gomes AO, Torres KCL, and Martins-Filho OA
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- Male, Female, Humans, Adolescent, Child, B-Lymphocytes, Immunophenotyping, Flow Cytometry, Immunologic Memory, T-Lymphocyte Subsets, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes
- Abstract
Immunobiography describes the life-long effects of exogenous or endogenous stimuli on remodeling of immune cell biology, including the development of memory T and B-cells. The present study aimed at investigating the rhythms of changes in phenotypic features of memory T and B-cells along childhood and adolescence. A descriptive-observational investigation was conducted including 812 healthy volunteers, clustered into six consecutive age groups (9
Mths -1Yr ; 2Yrs ; 3-4Yrs ; 5-7Yrs ; 8-10Yrs ; 11-18Yrs ). Immunophenotypic analysis of memory T-cell (CD4+ and CD8+ ) and B-cell subsets were performed by flow cytometry. The results pointed out that memory-related biomarkers of T and B-cells displayed a bimodal profile along healthy childhood and adolescence, regardless of sex. The first stage of changes occurs around 2Yrs , with predominance of naive cells, while the second and more prominent wave occurs around the age 8-10Yrs , with the prevalence of memory phenotypes. The neighborhood connectivity profile analysis demonstrated that the number of correlations reaches a peak at 11-18Yrs and lower values along the childhood. Males presented higher and conserved number of correlations when compared to females. Altogether, our results provide new insights into immunobiography and a better understanding of interactions among the cellular subsets studied here during childhood and adolescence., (© 2023. The Author(s).)- Published
- 2023
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12. A functional assay using human whole blood and flow cytometry analysis to evaluate cytotoxicity and immunomodulatory effect of anti-Trypanosoma cruzi drugs.
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Lopes MEASA, Ribeiro JM, Teixeira-Carvalho A, Murta SMF, and Souza-Fagundes EM
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- Humans, Interleukin-10, Interleukin-8, Flow Cytometry, Cytokines, Trypanosoma cruzi, Nitroimidazoles pharmacology, Nitroimidazoles therapeutic use, Chagas Disease drug therapy, Trypanocidal Agents pharmacology, Trypanocidal Agents therapeutic use
- Abstract
The discovery and development of new drugs for the treatment of Chagas disease is urgent due to the high toxicity and low cure efficacy, mainly during the chronic phase of this disease. Other chemotherapeutic approaches for Chagas disease treatment are being researched and require screening assays suitable for evaluating the effectivity of new biologically active compounds. This study aims to evaluate a functional assay using the internalization of epimastigotes forms of Trypanosoma cruzi by human peripheral blood leukocytes from healthy volunteers and analyses by flow cytometry of cytotoxicity, anti-T. cruzi activity, and immunomodulatory effect of benznidazole, ravuconazole, and posaconazole. The culture supernatant was used to measure cytokines (IL-1-β, IL-6, INF-γ, TNF and IL-10) and chemokines (MCP-1/CCL2, CCL5/RANTES and CXCL8/IL-8). The data showed a reduction in the internalization of T. cruzi epimastigote forms treated with ravuconazole, demonstrating its potential anti-T. cruzi activity. In addition, an increased amount of IL-10 and TNF cytokines was observed in the supernatant of cultures upon the addition of the drug, mainly IL-10 in the presence of benznidazole, ravuconazole and posaconazole, and TNF in the presence of ravuconazole and posaconazole. Moreover, the results revealed a decrease in the MCP-1/CCL2 index in cultures in the presence of benznidazole, ravuconazole, and posaconazole. A decrease in the CCL5/RANTES and CXCL8/IL-8 index in cultures with BZ, when compared to the culture without drugs, was also observed. In conclusion, the innovative functional test proposed in this study may be a valuable tool as a confirmatory test for selecting promising compounds identified in prospecting programs for new drugs for Chagas disease treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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13. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.
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Pereira-Martins DA, Coelho-Silva JL, Weinhäuser I, Franca-Neto PL, Silveira DR, Ortiz C, Moreira-Aguiar A, Lima MM, Koury LC, de Melo RA, Glória AB, Fagundes EM, Lino BK, Pagnano K, Bittencourt R, Nunes E, Traina F, Figueiredo-Pontes L, Keating A, Tallman MS, Ribeiro RC, Dilon R, Ganser A, Sanz MA, Berliner N, Valk P, Löwenberg B, Ottone T, Noguera NI, Voso MT, Paoloni F, Fazi P, Ammatuna E, Huls G, Schuringa JJ, Rego EM, and Lucena-Araujo AR
- Subjects
- Humans, Tretinoin therapeutic use, DNA, Mitochondrial genetics, Clinical Relevance, Neoplasm Recurrence, Local drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Treatment Outcome, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute genetics
- Abstract
Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
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14. Bioengineered Carboxymethylcellulose-Peptide Hybrid Nanozyme Cascade for Targeted Intracellular Biocatalytic-Magnetothermal Therapy of Brain Cancer Cells.
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Mansur AAP, Carvalho SM, Oliveira LCA, Souza-Fagundes EM, Lobato ZIP, Leite MF, and Mansur HS
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Glioblastoma remains the most lethal form of brain cancer, where hybrid nanomaterials biofunctionalized with polysaccharide peptides offer disruptive strategies relying on passive/active targeting and multimodal therapy for killing cancer cells. Thus, in this research, we report for the first time the rational design and synthesis of novel hybrid colloidal nanostructures composed of gold nanoparticles stabilized by trisodium citrate (AuNP@TSC) as the oxidase-like nanozyme, coupled with cobalt-doped superparamagnetic iron oxide nanoparticles stabilized by carboxymethylcellulose ligands (Co-MION@CMC) as the peroxidase-like nanozyme. They formed inorganic-inorganic dual-nanozyme systems functionalized by a carboxymethylcellulose biopolymer organic shell, which can trigger a biocatalytic cascade reaction in the cancer tumor microenvironment for the combination of magnetothermal-chemodynamic therapy. These nanoassemblies were produced through a green aqueous process under mild conditions and chemically biofunctionalized with integrin-targeting peptide (iRDG), creating bioengineered nanocarriers. The results demonstrated that the oxidase-like nanozyme (AuNP) was produced with a crystalline face-centered cubic nanostructure, spherical morphology (diameter = 16 ± 3 nm), zeta potential (ZP) of -50 ± 5 mV, and hydrodynamic diameter (D
H ) of 15 ± 1 nm. The peroxide-like nanostructure (POD, Co-MION@CMC) contained an inorganic crystalline core of magnetite and had a uniform spherical shape (2R = 7 ± 1 nm) which, summed to the contribution of the CMC shell, rendered a hydrodynamic diameter of 45 ± 4 nm and a negative surface charge (ZP = -41 ± 5 mV). Upon coupling both nanozymes, water-dispersible colloidal supramolecular vesicle-like organic-inorganic nanostructures were produced (AuNP//Co-MION@CMC, ZP = -45 ± 4 mV and DH = 28 ± 3 nm). They confirmed dual-nanozyme cascade biocatalytic activity targeted by polymer-peptide conjugates (AuNP//Co-MION@CMC_iRGD, ZP = -29 ± 3 mV and DH = 60 ± 4 nm) to kill brain cancer cells (i.e., bioenergy " starvation " by glucose deprivation and oxidative stress through reactive oxygen species generation), which was boosted by the magneto-hyperthermotherapy effect when submitted to the alternating magnetic field (i.e., induced local thermal stress by " nanoheaters "). This groundwork offers a wide avenue of opportunities to develop innovative theranostic nanoplatforms with multiple integrated functionalities for fighting cancer and reducing the harsh side effects of conventional chemotherapy.- Published
- 2022
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15. Transcription factor SOX3 upregulated pro-apoptotic genes expression in human breast cancer.
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Silva FHS, Underwood A, Almeida CP, Ribeiro TS, Souza-Fagundes EM, Martins AS, Eliezeck M, Guatimosim S, Andrade LO, Rezende L, Gomes HW, Oliveira CA, Rodrigues RC, Borges IT, Cassali GD, Ferreira E, and Del Puerto HL
- Subjects
- Caspase 3, Female, Fluorescein-5-isothiocyanate, Humans, RNA, Messenger, SOXB1 Transcription Factors, Tumor Suppressor Proteins, Up-Regulation, bcl-2-Associated X Protein, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics
- Abstract
Background: Sex-determining region Y-box 3 (SOX3) protein, a SOX transcriptions factors group, has been identified as a key regulator in several diseases, including cancer. Downregulation of transcriptions factors in invasive ductal carcinoma (IDC) can interfere in neoplasia development, increasing its aggressiveness. We investigated SOX3 protein expression and its correlation with apoptosis in the MDA-MB-231 cell line, as SOX3 and Pro-Caspase-3 immunoexpression in paraffin-embedded invasive ductal carcinoma tissue samples from patients (n = 27). Breast cancer cell line MDA-MD-231 transfected with pEF1-SOX3 + and pEF1-Empty vector followed by cytotoxicity assay (MTT), Annexin-V FITC PI for apoptosis percentage assessment by flow cytometry, qPCR for apoptotic-related gene expression, immunofluorescence, and immunohistochemistry to SOX3 immunolocalization in culture cells, and paraffin-embedded invasive ductal carcinoma tissue samples., Results: Apoptotic rate was higher in cells transfected with pEF1-SOX3 + (56%) than controls (10%). MDA-MB-231 transfected with pEF1-SOX3 + presented upregulation of pro-apoptotic mRNA from CASP3, CASP8, CASP9, and BAX genes, contrasting with downregulation antiapoptotic mRNA from BCL2, compared to non-transfected cells and cells transfected with pEF1-empty vector (p < 0.005). SOX3 protein nuclear expression was detected in 14% (4/27 cases) of ductal carcinoma cases, and pro-Caspase-3 expression was positive in 50% of the cases., Conclusion: Data suggest that SOX3 transcription factor upregulates apoptosis in breast cancer cell line MDA-MB-231, and has a down nuclear expression in ductal carcinoma cases, and need to be investigated as a tumor suppressor protein, and its loss of expression and non-nuclear action turn the cells resistant to apoptosis. Further studies are necessary to understand how SOX3 protein regulates the promoter regions of genes involved in apoptosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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16. Pamidronate, a promising repositioning drug to treat leishmaniasis, displays antileishmanial and immunomodulatory potential.
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Ribeiro JM, Rodrigues-Alves ML, Oliveira E, Guimarães PPG, Maria Murta Santi A, Teixeira-Carvalho A, Murta SMF, Peruhype-Magalhães V, and Souza-Fagundes EM
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- Animals, Drug Repositioning, Humans, Interleukin-10 therapeutic use, Mice, Mice, Inbred BALB C, Pamidronate, Antiprotozoal Agents pharmacology, Antiprotozoal Agents therapeutic use, Leishmania infantum, Leishmaniasis drug therapy, Leishmaniasis, Visceral drug therapy
- Abstract
Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania infantum (L. infantum). Currently, there are no vaccines and/or prophylactic therapies against VL, and the recentpharmacological approaches come from the drug repositioning strategy. Here, we evaluated the anticancer drug pamidronate (PAM) to identify a new therapeutic option for the treatment of human VL. We assessed its in vitro antileishmanial activity against the promastigote and amastigote forms of L. infantum by evaluating cell cytotoxicity. The antileishmanial and immunomodulatory activities were assessed using human peripheral blood leukocytes ex vivo. PAM induced the formation of vacuoles in the cytoplasm of the promastigotes and alterations in the morphology of the kinetoplast and mitochondria in vitro, which indicates anti-promastigote activity. PAM also reduced the number of infected macrophages and intracellular amastigotes in a concentration-dependent manner, with cell viability above 70%. In ex vivo, PAM reduced the internalized forms of L. infantum in the classical monocyte subpopulation. Furthermore, it enhanced IL-12 and decreased IL-10 and TGF-β by monocytes and neutrophils. Increased IFN-γ and TNF levels for CD8
- and CD8+ T lymphocytes and B lymphocytes, respectively, were observed after the treatment with PAM, as well as a reduction in IL-10 by the lymphocyte subpopulations evaluated. Taken together, our results suggest that PAM may be eligible as a potential therapeutic alternative for drug repurposing to treat human visceral leishmaniasis., (Copyright © 2022. Published by Elsevier B.V.)- Published
- 2022
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17. Acute toxicity and antitumor potential of 1,3,4-trisubstituted-1,2,3-triazole dhmtAc-loaded liposomes on a triple-negative breast cancer model.
- Author
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Ramos JP, Abdel-Salam MAL, Nobre DAB, Glanzmann N, de Souza CP, Leite EA, de Abreu Teles PP, Barbosa AS, Barcelos LS, Dos Reis DC, Cassali GD, de Lima ME, de Castro QJT, Grabe-Guimarães A, da Silva AD, and de Souza-Fagundes EM
- Subjects
- Animals, Cell Line, Tumor, Humans, Leukocytes, Mononuclear, Mice, Mice, Inbred BALB C, Structure-Activity Relationship, Triazoles pharmacology, Liposomes, Triple Negative Breast Neoplasms drug therapy
- Abstract
For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC., (© 2022 Deutsche Pharmazeutische Gesellschaft.)
- Published
- 2022
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18. Morita-Baylis-Hillman adducts derived from thymol: synthesis, in silico studies and biological activity against Giardia lamblia.
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Xavier FJS, Lira AB, Verissimo GC, de S Saraiva FS, de Oliveira Filho AA, de Souza-Fagundes EM, de F F M Diniz M, Gomes MA, Castro AC, Silva FPL, Lima-Junior CG, and Vasconcellos MLAA
- Subjects
- Aldehydes, Catalysis, HEK293 Cells, Humans, Giardia lamblia, Thymol pharmacology
- Abstract
Giardiasis is a neglected disease, and there is a need for new molecules with less side effects and better activity against resistant strains. This work describes the evaluation of the giardicidal activity of thymol derivatives produced from the Morita-Baylis-Hillman reaction. Thymol acrylate was reacted with different aromatic aldehydes, using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst. Eleven adducts (8 of them unpublished) with yields between 58 and 80% were obtained from this reaction, which were adequately characterized. The in silico prediction showed theoretical bioavailability after oral administration as well as antiparasitic activity against Giardia lamblia. Compound 4 showed better biological activity against G. lamblia. In addition to presenting antigiardial activity 24 times better than thymol, this MBHA was obtained in a short reaction time (3 h) with a yield (80%) superior to the other investigated molecules. The molecule was more active than the precursors (thymol and MBHA 12) and did not show cytotoxicity against HEK-293 or HT-29 cells. In conclusion, this study presents a new class of drugs with better antigiardial activity in relation to thymol, acting as a basis for the synthesis of new bioactive molecules. Molecular hybridization technique combined with the Morita-Baylis-Hillman reaction provided new thymol derivatives with giardicidal activity superior to the precursor molecules., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2022
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19. LyeTxI-b, a Synthetic Peptide Derived From a Spider Venom, Is Highly Active in Triple-Negative Breast Cancer Cells and Acts Synergistically With Cisplatin.
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de Avelar Júnior JT, Lima-Batista E, Castro Junior CJ, Pimenta AMC, Dos Santos RG, Souza-Fagundes EM, and De Lima ME
- Abstract
Breast cancer is the most common cancer that affects women globally and is among the leading cause of women's death. Triple-negative breast cancer is more difficult to treat because hormone therapy is not available for this subset of cancer. The well-established therapy against triple-negative breast cancer is mainly based on surgery, chemotherapy, and immunotherapy. Among the drugs used in the therapy are cisplatin and carboplatin. However, they cause severe toxicity to the kidneys and brain and cause nausea. Therefore, it is urgent to propose new chemotherapy techniques that provide new treatment options to patients affected by this disease. Nowadays, peptide drugs are emerging as a class of promising new anticancer agents due to their lytic nature and, apparently, a minor drug resistance compared to other conventional drugs (reviewed in Jafari et al., 2022). We have recently reported the cytotoxic effect of the antimicrobial peptide LyeTx I-b against glioblastoma cells (Abdel-Salam et al., 2019). In this research, we demonstrated the cytotoxic effect of the peptide LyeTx I-b, alone and combined with cisplatin, against triple-negative cell lines (MDA-MD-231). LyeTx-I-b showed a selectivity index 70-fold higher than cisplatin. The peptide:cisplatin combination (P:C) 1:1 presented a synergistic effect on the cell death and a selective index value 16 times greater than the cisplatin alone treatment. Therefore, an equi-effective reduction of cisplatin can be reached in the presence of LyeTx I-b. Cells treated with P:C combinations were arrested in the G2/M cell cycle phase and showed positive staining for acridine orange, which was inhibited by bafilomycin A1, indicating autophagic cell death (ACD) as a probable cell death mechanism. Furthermore, Western blot experiments indicated a decrease in P21 expression and AKT phosphorylation. The decrease in AKT phosphorylation is indicative of ACD. However, other studies are still necessary to better elucidate the pathways involved in the cell death mechanism induced by the peptide and the drug combinations. These findings confirmed that the peptide LyeTx I-b seems to be a good candidate for combined chemotherapy to treat breast cancer. In addition, in vivo studies are essential to validate the use of LyeTx I-b as a therapeutic drug candidate, alone and/or combined with cisplatin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Avelar Júnior, Lima-Batista, Castro Junior, Pimenta, Dos Santos, Souza-Fagundes and De Lima.)
- Published
- 2022
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20. Mortality by COVID-19 in adults with acute myeloid leukemia: a survey with hematologists in Brazil.
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Fagundes EM, Neto NN, Caldas LM, Aragão JR, Gloria ABF, Leite LG, Bastos P, Fernandes CM, Chalup M, Arcuri R, and Fagundes OG
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- Adult, Brazil epidemiology, Humans, SARS-CoV-2, Surveys and Questionnaires, COVID-19, Leukemia, Myeloid, Acute
- Published
- 2022
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21. STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells.
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Vicari HP, Coelho-Silva JL, Pereira-Martins DA, Lucena-Araujo AR, Lima K, Lipreri da Silva JC, Scheucher PS, Koury LC, de Melo RA, Bittencourt R, Pagnano K, Nunes E, Fagundes EM, Kerbauy F, de Figueiredo-Pontes LL, Costa-Lotufo LV, Rego EM, Traina F, and Machado-Neto JA
- Subjects
- Cell Differentiation, Cell Proliferation, Humans, Mitosis, Oncogene Proteins, Fusion genetics, Paclitaxel, Stathmin genetics, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute pathology
- Abstract
Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML-RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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22. Evaluation of Toxicity and Oxidative Stress of 2-Acetylpyridine- N (4)-orthochlorophenyl Thiosemicarbazone.
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Lira AB, Parrilha GL, Dias GT, de Sousa Saraiva FS, Veríssimo GC, de Sousa RS, da Silva TG, de Oliveira Filho AA, Alves AF, de Souza-Fagundes EM, Beraldo H, Gomes MA, and Diniz MFFM
- Subjects
- Animals, Lipid Peroxidation, Oxidative Stress, Pyridines, Thiosemicarbazones chemistry, Thiosemicarbazones toxicity
- Abstract
Thiosemicarbazones are well known for their broad spectrum of action, including antitumoral and antiparasitic activities. Thiosemicarbazones work as chelating binders, reacting with metal ions. The objective of this work was to investigate the in silico , in vitro , and in vivo toxicity and oxidative stress of 2-acetylpyridine- N (4)-orthochlorophenyl thiosemicarbazone (TSC01). The in silico prediction showed good absorption by biological membranes and no theoretical toxicity. Also, the compound did not show cytotoxicity against Hep-G2 and HT-29 cells. In the acute nonclinical toxicological test, the animals treated with TSC01 showed behavioral changes of stimulus of the central nervous system (CNS) at 300 mg/kg. One hour after administration, a dose of 2000 mg/kg caused depressive signs. All changes disappeared after 24 h, with no deaths, which suggest an estimated LD50 of 5000 mg/kg and GSH 5. The group treated with 2000 mg/kg had an increase of water consumption and weight gain in the second week. The biochemical parameters presented no toxicity relevance, and the analysis of oxidative stress in the liver found an increase of lipid peroxidation and nitric oxide. However, histopathological analysis showed organ integrity was maintained without any changes. In conclusion, the results show the low toxicological potential of thiosemicarbazone derivative, indicating future safe use., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Andressa Brito Lira et al.)
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- 2022
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23. LyeTx I-b Peptide Attenuates Tumor Burden and Metastasis in a Mouse 4T1 Breast Cancer Model.
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Abdel-Salam MAL, Pinto B, Cassali G, Bueno L, Pêgas G, Oliveira F, Silva I, Klein A, Souza-Fagundes EM, de Lima ME, and Carvalho-Tavares J
- Abstract
Cationic anticancer peptides have exhibited potent anti-proliferative and anti-inflammatory effects in neoplastic illness conditions. LyeTx I-b is a synthetic peptide derived from Lycosa erythrognatha spider venom that previously showed antibiotic activity in vitro and in vivo. This study focused on the effects of LyeTxI-b on a 4T1 mouse mammary carcinoma model. Mice with a palpable tumor in the left flank were subcutaneously or intratumorally injected with LyeTx I-b (5 mg/kg), which significantly decreased the tumor volume and metastatic nodules. Histological analyses showed a large necrotic area in treated primary tumors compared to the control. LyeTxI-b reduced tumor growth and lung metastasis in the 4T1 mouse mammary carcinoma model with no signs of toxicity in healthy or cancerous mice. The mechanism of action of LyeTx I-b on the 4T1 mouse mammary carcinoma model was evaluated in vitro and is associated with induction of apoptosis and cell proliferation inhibition. Furthermore, LyeTx I-b seems to be an efficient regulator of the 4T1 tumor microenvironment by modulating several cytokines, such as TGF-β, TNF-α, IL-1β, IL-6, and IL-10, in primary tumor and lung, spleen, and brain. LyeTx I-b also plays a role in leukocytes rolling and adhesion into spinal cord microcirculation and in the number of circulating leukocytes. These data suggest a potent antineoplastic efficacy ofLyeTx I-b.
- Published
- 2021
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24. Rare and intractable fibrodysplasia ossificans progressiva shows different PBMC phenotype possibly modulated by ascorbic acid and propranolol treatment.
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Nascimento DR, Balaniuc SLB, Palhares DB, Underwood A, Palhares MG, Alves F, Vieira FO, Souza-Fagundes EM, Giuliani LR, Xavier PCN, Puerto HLD, Santos RAS, Milsted A, Brum JM, Silva IS, and Martins AS
- Abstract
Fibrodysplasia Ossificans Progressiva (FOP) is a rare congenital intractable disease associated with a mutation in ACVR1 gene, characterized by skeleton malformations. Ascorbic acid (AA) and propranolol (PP) in combination is reported to minimize flare-ups in patients. FOP leukocyte phenotype may possibly be modulated by AA and PP treatment. In this study, expression of 22 potential target genes was analyzed by RT-PCR in peripheral blood mononuclear cells culture (PBMC) from FOP patients and controls to determine effectiveness of the combination therapy. PBMC were treated with AA, PP and AA+PP combination. Basal expression of 12 of the 22 genes in FOP PBMC was statistically different from controls. ACVR1 , ADCY2 , ADCY9 and COL3 were downregulated while COL1 was upregulated. ADRB1 , ADRB2 , RUNX2 , TNF-α and ACTB , were all overexpressed in FOP PBMC. In control, AA upregulated COL1, SVCT1, ACTB, AGTR2 and downregulated ADCY2 . In FOP cells, AA upregulated ACVR1, BMP4, COL1, COL3, TNF-α , ADCY2, ADCY9, AGTR2 and MAS , while downregulated ADBR2, RUNX2, ADCY1, SVCT1 and ACTB . PP increased ADBR1 and decreased RUNX2, TNF-α, AGTR1, ACTB and CHRNA7 genes in treated control PBMC compared to untreated. PP upregulated ADBR1, ADBR2 and MAS , and downregulated TNF-α and ACTB in treated FOP PBMC versus untreated. AA+PP augmented ADRB1 and ADRB2 expressions in control PBMC. In FOP PBMC, AA+PP augmented ACVR1, COL1, COL3, ADBR1, AGTR2 and MAS expression and downregulated ADBR2, RUNX2, ACTB and MRGD . These data show distinct gene expression modulation in leukocytes from FOP patients when treated with AA and or PP., Competing Interests: The authors have no conflicts of interest to disclose., (2021, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)
- Published
- 2021
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25. Shortened derivatives from native antimicrobial peptide LyeTx I: In vitro and in vivo biological activity assessment.
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Fuscaldi LL, de Avelar Júnior JT, Dos Santos DM, Boff D, de Oliveira VLS, Gomes KAGG, Cruz RC, de Oliveira PL, Magalhães PP, Cisalpino PS, Farias LM, de Souza-Fagundes EM, Delp J, Leist M, Resende JM, Amaral FA, Pimenta AMC, Fernandes SOA, Cardoso VN, and de Lima ME
- Subjects
- Animals, Antimicrobial Cationic Peptides chemical synthesis, Antimicrobial Cationic Peptides isolation & purification, Bacteria drug effects, Cell Death drug effects, Circular Dichroism, Erythrocytes drug effects, Erythrocytes metabolism, Fungi drug effects, Humans, Inflammation pathology, Mice, Microbial Sensitivity Tests, Nociception drug effects, Rabbits, Antimicrobial Cationic Peptides pharmacology
- Abstract
In the continuing search for novel antibiotics, antimicrobial peptides are promising molecules, due to different mechanisms of action compared to classic antibiotics and to their selectivity for interaction with microorganism cells rather than with mammalian cells. Previously, our research group has isolated the antimicrobial peptide LyeTx I from the venom of the spider Lycosa erythrognatha . Here, we proposed to synthesize three novel shortened derivatives from LyeTx I (LyeTx I mn; LyeTx I mnΔK; LyeTx I mnΔKAc) and to evaluate their toxicity and biological activity as potential antimicrobial agents. Peptides were synthetized by Fmoc strategy and circular dichroism analysis was performed, showing that the three novel shortened derivatives may present membranolytic activity, like the original LyeTx I, once they folded as an alpha helix in 2.2.2-trifluorethanol and sodium dodecyl sulfate. In vitro assays revealed that the shortened derivative LyeTx I mnΔK presents the best score between antimicrobial (↓ MIC) and hemolytic (↑ EC
50 ) activities among the synthetized shortened derivatives, and LUHMES cell-based NeuriTox test showed that it is less neurotoxic than the original LyeTx I (EC50 [LyeTx I mnΔK] ⋙ EC50 [LyeTx I]). In vivo data, obtained in a mouse model of septic arthritis induced by Staphylococcus aureus , showed that LyeTx I mnΔK is able to reduce infection, as demonstrated by bacterial recovery assay (∼10-fold reduction) and scintigraphic imaging (less technetium-99m labeled-Ceftizoxime uptake by infectious site). Infection reduction led to inflammatory process and pain decreases, as shown by immune cells recruitment reduction and threshold nociception increment, when compared to positive control group. Therefore, among the three shortened peptide derivatives, LyeTx I mnΔK is the best candidate as antimicrobial agent, due to its smaller amino acid sequence and toxicity, and its greater biological activity.- Published
- 2021
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26. Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.
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Weinhäuser I, Pereira-Martins DA, Ortiz C, Silveira DR, Simões LAA, Bianco TM, Araujo CL, Koury LC, Melo RAM, Bittencourt RI, Pagnano K, Pasquini R, Nunes EC, Fagundes EM, Gloria AB, Kerbauy F, Chauffaille ML, Keating A, Tallman MS, Ribeiro RC, Dillon R, Ganser A, Löwenberg B, Valk P, Lo-Coco F, Sanz MA, Berliner N, Ammatuna E, Lucena-Araujo AR, Schuringa JJ, and Rego EM
- Abstract
The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2
high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count ( p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p < 0.001). Functionally, SLIT2 -knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count ( p = 0.001) and decreased overall survival ( p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.- Published
- 2020
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27. Evaluation of cobalt(III) complexes as potential hypoxia-responsive carriers of esculetin.
- Author
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Palmeira-Mello MV, Caballero AB, Ribeiro JM, de Souza-Fagundes EM, Gamez P, and Lanznaster M
- Subjects
- Antioxidants chemistry, Antioxidants pharmacology, Cell Hypoxia drug effects, Cell Line, Tumor, Coordination Complexes chemistry, Drug Delivery Systems, HEK293 Cells, HT29 Cells, Humans, Neoplasms pathology, Umbelliferones chemistry, Cobalt chemistry, Coordination Complexes pharmacology, Neoplasms drug therapy, Umbelliferones pharmacology
- Abstract
Differentiation between hypoxic and normoxic tissues have been exploited for the development of selective chemotherapeutic agents. In this context, cobalt(III)-based coordination compounds have been designed and investigated as prospective hypoxia-responsive drug delivery systems. Three cobalt(III) complexes, namely [Co
III (esc)(py2 en)]ClO4 ·(CH3 OH)2 (1) [CoIII (esc)(TPA)]ClO4 ·3H2 O (2) and [CoIII (bipy)2 (esc)]ClO4 ·2.5H2 O (3) (py2 en = N,N'-bis(pyridin-2-ylmethyl)ethylenediamine, TPA = tris(2-pyridylmethyl)amine, bipy = 2,2'-bipyridine and esc = 6,7-dihydroxycoumarin or esculetin), were prepared and investigated as potential carriers of esculetin. The spectroscopic and electrochemical properties of 1-3 were investigated and compared. Reactions of the complexes with biologically relevant reducing agents, viz. ascorbic acid, cysteine and glutathione, were monitored spectroscopically for 24 h, in pH 6.2 and 7.4 PBS phosphate buffer saline (PBS) solutions at 37 °C, under air, argon and dioxygen atmospheres. Dissociation of esculetin was observed upon Co3+ /Co2+ reduction preferably under hypoxic conditions, with more effective conversion rates for 3 > 2 > 1. These results illustrate the importance to modulate the Co3+ /Co2+ redox potential through the donor-acceptor properties of the ancillary ligands. Complex 3 is cytotoxic against HCT-116 but not against HT-29 and HEK-293 cells. In addition, DNA-binding studies indicate that interactions of 1 and 3 with the biomolecule are electrostatic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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28. An ex vivo multiparametric flow cytometry assay using human whole blood to simultaneously measure cytotoxicity and leishmanicidal activities.
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Ribeiro JM, Bandeira CC, de Faria BG, Alves MLR, Vieira FO, Giunchetti RC, Uzonna JE, Teixeira-Carvalho A, Peruhype-Magalhães V, and Souza-Fagundes EM
- Subjects
- Adult, Amphotericin B pharmacology, Amphotericin B toxicity, Animals, Antiprotozoal Agents pharmacology, Antiprotozoal Agents therapeutic use, Drug Discovery methods, Drug Evaluation, Preclinical methods, Fluorescein-5-isothiocyanate, Fluorescent Dyes, Humans, Leishmania braziliensis drug effects, Leishmaniasis drug therapy, Leukocytes drug effects, Leukocytes parasitology, Meglumine Antimoniate pharmacology, Meglumine Antimoniate therapeutic use, Meglumine Antimoniate toxicity, Microscopy, Confocal, Middle Aged, Monocytes drug effects, Monocytes parasitology, Time Factors, Young Adult, Animal Testing Alternatives methods, Antiprotozoal Agents toxicity, Flow Cytometry methods, Leishmania drug effects, Neglected Diseases drug therapy
- Abstract
Therapeutic options for the treatment of leishmaniasis are insufficient and need improvements owing to their low efficiency and high toxicity as well as the emergence of resistant strains. The limited number of new drugs for neglected diseases and lack of innovation in your development are still challenges. In this context, the process of discovery and development of biological assays play a pivotal role for the identification of bioactive compounds. The assays currently used for screening of drugs with cytotoxic activity against Leishmania parasites, include different processes that utilize intact parasite (free or intracellular) or specific enzymes of metabolism as a target cell. These assays allow the screening of large numbers of samples followed by more detailed secondary confirmatory assays to confirm the observed activity and assess their toxicity. In the present study, we described the development of a new functional and more complete assay that enables simultaneous assessment of potential anti-Leishmania compounds through evaluation of internalization of fluorescein-labeled L. braziliensis promastigotes by human peripheral blood monocytes and their cytotoxicity by flow cytometry. We standardized the conditions for parasite labeling to achieve better phagocytosis analysis by setting the ratio of number of parasites per cell as 1 to 2, at incubation time of 6h. The cytotoxicity assessment was performed by the quantification of cells undergoing early/late apoptosis and necrosis using a double labelling platform employing 7AAD for late apoptosis and necrosis analysis and Annexin-V for early apoptosis evaluation. Hemolysis analysis was an additional parameter to test cytotoxicity. Two drugs used on clinic (Amphotericin B and Glucantime®) were used to validate the proposed methodology, and the assay was able to detect their known leishmanicidal activity and immunotoxicity properties. This new predictive assay will contribute to the development of translational medicine strategies in drug discovery for neglected diseases such as leishmaniasis., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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29. NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia.
- Author
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Thomé CH, Ferreira GA, Pereira-Martins DA, Dos Santos GA, Ortiz CA, de Souza LEB, Sobral LM, Silva CLA, Scheucher PS, Gil CD, Leopoldino AM, Silveira DRA, Coelho-Silva JL, Traina F, Koury LC, Melo RAM, Bittencourt R, Pagnano K, Pasquini R, Nunes EC, Fagundes EM, Gloria ABF, Kerbauy FR, Chauffaille ML, Keating A, Tallman MS, Ribeiro RC, Dillon R, Ganser A, Löwenberg B, Valk P, Lo-Coco F, Sanz MA, Berliner N, Faça VM, and Rego EM
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adolescent, Adult, Aged, Animals, Anthracyclines pharmacology, Anthracyclines therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow pathology, Cell Differentiation drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Disease-Free Survival, Female, Gene Knockdown Techniques, Humans, Leukemia, Promyelocytic, Acute blood, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute mortality, Leukocyte Count, Male, Membrane Microdomains metabolism, Mice, Middle Aged, Retrospective Studies, Survival Analysis, Tretinoin pharmacology, Tretinoin therapeutic use, Xenograft Model Antitumor Assays, Young Adult, Adaptor Proteins, Signal Transducing metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Leukemia, Promyelocytic, Acute pathology
- Abstract
Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
- Published
- 2020
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30. Lapachol acetylglycosylation enhances its cytotoxic and pro-apoptotic activities in HL60 cells.
- Author
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Marques LB, Ottoni FM, Pinto MCX, Ribeiro JM, de Sousa FS, Weinlich R, de Victo NC, Kisitu J, Holzer AK, Leist M, Alves RJ, and Souza-Fagundes EM
- Subjects
- Apoptosis drug effects, Cell Cycle drug effects, Cell Survival drug effects, Glycosylation drug effects, HL-60 Cells, Humans, Antineoplastic Agents toxicity, Naphthoquinones toxicity
- Abstract
Lapachol is a plant-derived naphthoquinone that kills several types of cancer cells. Derivatives of this molecule may therefore prove to be useful chemotherapeutic agents. In this study, we explored whether glycosylation increases the cytotoxic potency of lapachol towards HL-60 human leukemia cells. Two beta-glycosides were synthesized and characterized: LA4A (lapachol-β-glucoside) and LA4C (lapachol-N-acetylglucosamine-β-glucoside). The sugar moieties of both novel molecules were per-acetylated to facilitate cellular uptake. The IC
50 values (in μM) for LA4A (5.7) and LA4C (5.3) were lower than those for lapachol (25). LA4A and LA4C triggered typical signs of apoptosis, such as the exposure of phosphatidylserine on the outside of cells, chromatin condensation, DNA fragmentation and a decrease of the mitochondrial transmembrane potential (ΔΨm) prior to cell lysis. Moreover, DNA fragmentation triggered by the lapachol-glycosides was reduced by pre-treatment with the caspase inhibitor, z-VAD-fmk. While LA4A and LA4C activated caspases-3, -8 and -9, lapachol failed to activate these apoptotic proteases, even when used at high concentrations. Finally, the toxicity of lapachol and its derivatives was also tested on non-tumor cells. We used human peripheral neurons (PeriTox test) to evaluate the side effect potential of these compounds. LA4C was clearly less toxic than LA4A. We conclude that LA4C had the most favorable profile as drug candidate (high tumor cell toxicity, reduced neurotoxicity). In general, this study shows that the cytotoxicity of lapachol towards HL-60 can be enhanced by glycosylation, and that the therapeutic ratio may be modified by the type of sugar added., Competing Interests: Declaration of Competing Interest The authors declare that they do not have any conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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31. Novel self-nanoemulsifying drug-delivery system enhances antileukemic properties of all- trans retinoic acid.
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Marques Borges GS, Oliveira Ferencs M, Mello Gomide Loures C, Abdel-Salam MA, Gontijo Evangelista FC, Sales CC, Reis da Silva PH, de Oliveira RB, Malachias Â, Yoshida MI, de Souza-Fagundes EM, Paula Sabino A, Fernandes C, and Miranda Ferreira LA
- Subjects
- Administration, Oral, Animals, Biological Availability, Emulsions, Mice, Drug Delivery Systems, Tretinoin
- Abstract
Aim: All- trans retinoic acid (ATRA) shows erratic oral bioavailability when administered orally against leukemia, which can be solved through its incorporation in self-nanoemulsifying drug-delivery systems (SEDDS). The SEDDS developed contained a hydrophobic ion pair between benzathine (BZT) and ATRA and was enriched with tocotrienols by the input of a palm oil tocotrienol rich fraction (TRF) in its composition. Results: SEDDS-TRF-ATRA-BZT allowed the formation of emulsions with nanometric size that retained ATRA within their core after dispersion. Pharmacokinetic parameters after oral administration of SEDDS-TRF-ATRA-BZT in mice were improved compared with what was seen for an ATRA solution. Moreover, SEDDS-TRF-ATRA-BZT had improved activity against HL-60 cells compared with SEDDS without TRF. Conclusion: SEDDS-TRF-ATRA-BZT is a promising therapeutic choice over ATRA conventional medicine.
- Published
- 2020
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32. Triethylphosphinegold(I) Complexes with Secnidazole-Derived Thiosemicarbazones: Cytotoxic Activity against HCT-116 Colorectal Cancer Cells under Hypoxia Conditions.
- Author
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Oliveira APA, Freitas JTJ, Diniz R, Pessoa C, Maranhão SS, Ribeiro JM, Souza-Fagundes EM, and Beraldo H
- Abstract
Triethylphosphinegold(I) complexes [Au(HL1)P(CH
2 CH3 )3 ]PF6 ( 1 ), [Au(HL2)P(CH2 CH3 )3 ]PF6 ( 2 ), and [Au(HL3)P(CH2 CH3 )3 ]PF6 ( 3 ) were obtained with ( E )-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)hydrazinecarbothioamide ( HL1 ), ( E )- N -methyl-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)hydrazinecarbothioamide ( HL2 ), and ( E )-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)- N -phenylhydrazinecarbothioamide ( HL3 ). All compounds were assayed for their cytotoxic activities against HCT-116 colorectal carcinoma cells under normoxia and hypoxia conditions and against nonmalignant HEK-293 human embryonic kidney cells under normoxia conditions. The thiosemicarbazone ligands HL1 - HL3 were inactive against HCT-116 cells under hypoxia but while HL3 was inactive, HL1 and HL2 proved to be cytotoxic to both cell lineages under normoxia conditions. Complexes ( 1 - 3 ) and the triethylphosphinegod(I) precursor proved to be active against both cell lineages in normoxia as well as in hypoxia. While 1 and 3 revealed to be active against HEK-293 and HCT-116 cells, being approximately as active against HCT-116 cells in normoxia as under hypoxia, complex ( 2 ) proved to be more active against HCT-116 cells under hypoxia than under normoxia conditions, and more active against HCT-116 cells than against the nonmalignant HEK-293 cells, with the selectivity index, calculated as SI = IC50HEK-293 /IC50HCT-116hypoxia , equal to 3.7, similar to the value obtained for the control drug tirapazamine (tirapazamine (TPZ), SI = 4). Although the compounds showed distinct cytotoxic activities, the electrochemical behaviors of HL1 - HL3 were very similar, as were the behaviors of complexes ( 1 - 3 ). Complex ( 2 ) deserves special interest since it was significantly more active under hypoxia than under normoxia conditions. Hence, in this case, selective reduction of the nitro group in a low oxygen pressure environment, resulting in toxic reactive oxygen species (ROS) and damage to DNA or other biomolecules, might operate, while for the remaining compounds, other modes of action probably occur., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)- Published
- 2020
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33. Systemic mastocytosis associated with acute myeloid leukemia.
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Nogueira FL, Martins NNN, Cardoso PSR, Murao M, de Melo FHC, Glória ABF, and Fagundes EM
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- Adult, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Male, Mastocytosis, Systemic genetics, Mastocytosis, Systemic metabolism, Mastocytosis, Systemic pathology, Mutation, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Leukemia, Myeloid, Acute diagnosis, Mastocytosis, Systemic diagnosis
- Published
- 2020
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34. Anti-inflammatory and cytotoxic activities of the extracts, fractions, and chemical constituents isolated from Luehea ochrophylla Mart.
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Araújo CRR, de Melo Silva T, Dos Santos MG, Ottoni MHF, de Souza Fagundes EM, de Sousa Fontoura H, de Melo GEBA, and de Carvalho Alcântara AF
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- Animals, Anti-Inflammatory Agents isolation & purification, Cell Line, Cell Proliferation drug effects, Humans, Lymphocytes cytology, Lymphocytes drug effects, Lymphocytes immunology, Plant Extracts isolation & purification, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacology, Malvaceae chemistry, Plant Extracts chemistry, Plant Extracts pharmacology
- Abstract
Background: Stem bark of Luehea ochrophylla (L. ochrophylla) is used by the traditional Brazilian medicine for treatment of rheumatic diseases and tumors. This study aimed to investigate inhibition of acute and chronic inflammations and cytotoxic activity of extracts, fractions, and isolated compounds from L. ochrophylla., Methods: Hexane (HE) and ethanol (EE) extracts obtained from stem bark of L. ochrophylla were submitted to chromatographic fractionation. In order to test acute inflammation, experimental model of impact injury was used, followed by transdermal application of gels using phonophoresis. Histological analysis was based on scores assigned by the capacity of decreasing the lesion. To evaluate the effect EE and fractions on cell proliferation, human lymphocytes were stimulated with phytohemagglutinin and analyzed using flow cytometry. Proliferation was measured using VPD 450 staining and the calculated proliferative index (PI). The cytotoxic activity was evaluated using MTT colorimetric method against MDA-MB-231, MCF-7, HCT-116, and Vero cells. GraphPad Prism Version 5 was used for statistical analysis., Results: HE and EE provided friedelin, β-friedelinol, lupeol, mixture of lupeol and pseudotaraxasterol, β-sitosterol, betulinic acid, mixture of lupeol and taraxasterol, (-)-epicatechin, β-sitosterol-3-O-β-D-glucopyranoside, and (+)-epicatechin-(4β-8)-epicatechin. HE, ethyl acetate fraction (AF), betulinic acid, and β-sitosterol promoted regeneration of muscle fibers caused by muscle injury. AF significantly (p < 0.05) reduced the lymphocyte proliferation index (1.36 for cultures stimulated with PHA, 0.7 for untreated cultures and 0.12 for cultures stimulated with PHA and treated with AF 25 μg/mL and AF 50 μg/mL, respectively). β-Sitosterol-3-O-β-D-glucopyranoside exhibited high cytotoxic activity (IC
50 = 1.279 μg/mL) against HCT-116 cell line., Conclusion: These results suggest that extracts, fractions, and chemical constituents from L. ochrophylla decreases inflammatory processes generated by muscle injury. The anti-inflammatory activity may be justified by high inhibition of T cell proliferation. These extracts, fractions, and chemical constituents from L. ochrophylla may be useful as a therapeutic agent against rheumatic diseases. Moreover, chemical constituents from L. ochrophylla show potent cytotoxic activity against colon and rectal carcinomas.- Published
- 2019
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35. Efficient atrazine degradation catalyzed by manganese porphyrins: Determination of atrazine degradation products and their toxicity evaluation by human blood cells test models.
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Almeida Lage AL, Ribeiro JM, de Souza-Fagundes EM, Brugnera MF, and Martins DCDS
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- Acetonitriles chemistry, Biomimetics, Brazil, Catalysis, Cell Survival drug effects, Herbicides, Humans, Iodobenzenes chemistry, Manganese chemistry, Oxidants chemistry, Peroxides chemistry, Pesticides chemistry, Toxicity Tests, Atrazine chemistry, Biodegradation, Environmental, Leukocytes, Mononuclear drug effects, Porphyrins chemistry, Water Pollutants, Chemical chemistry, Water Purification methods
- Abstract
Atrazine (ATZ) is an herbicide that has been considered an environmental pollutant worldwide. ATZ contaminates groundwaters and can persist in soils for up to a year causing several environmental and health problems. This study aimed to investigate ATZ degradation catalyzed by manganese porphyrins as biomimetic cytochrome P450 models. We used PhIO, PhI(OAc)
2 , H2 O2 , t-BuOOH, m-CPBA, or Oxone® as oxidant under mild conditions and evaluated a range of manganese porphyrins as catalyst. Concerning oxidant, iodosylbenzene provided the best result-ATZ degradation catalyzed by one of the studied manganese porphyrins in acetonitrile was as high as 47%. We studied the same catalyst/oxidant systems in natural water from a Brazilian river as solvent and obtained up to 100% ATZ degradation when iodobenzene diacetate was the oxidant, regardless of the manganese porphyrin. Besides the already known ATZ degradation products, we also identified unexpected degradation compounds (ring-opening products). Toxicity tests showed that the latter products were capable of proliferate blood cells because they did not show toxicity under the evaluated conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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36. Evaluation of 5-hydroxy-1,4-naphthoquinone-cobalt(III) complexes for hypoxia-activated drug delivery.
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de Mello MVP, Cebrián-Torrejón G, Pereira JR, Dos Santos Moreira C, Gomes CBSMR, da Rocha DR, de Souza Fagundes EM, Ferreira GB, and Lanznaster M
- Subjects
- Ascorbic Acid chemistry, Cell Survival drug effects, Coordination Complexes chemistry, Electrochemistry, HCT116 Cells, HT29 Cells, Humans, Molecular Structure, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Hypoxia physiology, Cobalt chemistry, Naphthoquinones chemistry
- Abstract
Three novel Py
2 N2- cobalt(III) complexes with the 5-hydroxy-1,4-naphthoquinone nuclei (NQ) were evaluated as potential hypoxia-activated anticancer prodrugs. The complexes were synthesized and fully characterized by IR and UV-Visible spectroscopies, ESI mass spectrometry and CHN elemental analysis. Structural information was obtained from density functional theory (DFT) calculations. Cyclic voltammetry analysis in acetonitrile indicates that the ligand substituents (H, CH3 and p-tolylthio) do not have a relevant effect on the Co3+ /Co2+ redox potential. Reactions with ascorbic acid in phosphate buffers were performed to simulate redox activation of the complexes in biological media. Fast and irreversible dissociation of the NQ ligands was observed for all complexes upon Co3+ /Co2+ reduction. Cytotoxic activity of complexes 1 and 3 was evaluated in tumor cells (HT-29 and HCT-116) under hypoxic and normoxic conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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37. Synthetic Mn(III) porphyrins as biomimetic catalysts of CYP450: Degradation of antibiotic norfloxacin in aqueous medium.
- Author
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Meireles AM, Almeida Lage AL, Ribeiro JM, Silva MAND, Souza-Fagundes EM, and Martins DCDS
- Subjects
- Biomimetics, Catalysis, Hydrogen Peroxide, Oxidation-Reduction, Anti-Bacterial Agents chemistry, Cytochrome P-450 Enzyme System metabolism, Manganese chemistry, Norfloxacin chemistry, Porphyrins analysis, Water Pollutants, Chemical chemistry
- Abstract
Norfloxacin (NOR) is a synthetic broad-spectrum fluoroquinolone antibiotic classified as an emerging contaminant. Here, we investigate Mn(III) porphyrin-catalyzed NOR degradation using peroxides or peracids (H
2 O2 , t-BuOOH, or Oxone®) as oxidants. We evaluate three Mn(III) porphyrins: the 1st -generation tetraphenylporphyrin and 2nd -generation porphyrins bearing halogen atoms at the ortho-positions of the porphyrin macrocycle meso-aryl groups. Experiments were carried out in aqueous medium under mild conditions. NOR degradation was 67%. Products were proposed by mass spectrometry (MS) analysis. Oxone® was the best oxidant for NOR degradation despite its possible decomposition in the reaction medium. The second-generation Mn(III) porphyrins were more resistant than the first-generation Mn(III) porphyrin, indicating that the bulky groups introduced into the porphyrin macrocycle meso-aryl groups led to more robust catalysts. The degradation products did not present cytotoxic behavior under the employed conditions. In conclusion, Mn(III) porphyrin-catalyzed NOR degradation is a promising strategy to degrade fluoroquinolones and other pollutants., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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38. Short-Lived Immunity After 17DD Yellow Fever Single Dose Indicates That Booster Vaccination May Be Required to Guarantee Protective Immunity in Children.
- Author
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Campi-Azevedo AC, Reis LR, Peruhype-Magalhães V, Coelho-Dos-Reis JG, Antonelli LR, Fonseca CT, Costa-Pereira C, Souza-Fagundes EM, da Costa-Rocha IA, Mambrini JVM, Lemos JAC, Ribeiro JGL, Caldas IR, Camacho LAB, Maia MLS, de Noronha TG, de Lima SMB, Simões M, Freire MDS, Martins RM, Homma A, Tauil PL, Vasconcelos PFC, Romano APM, Domingues CM, Teixeira-Carvalho A, and Martins-Filho OA
- Subjects
- Antibodies, Neutralizing immunology, Antibodies, Viral immunology, B-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Immunization, Secondary methods, Infant, Male, Vaccination methods, Immunity immunology, Yellow Fever immunology, Yellow Fever prevention & control, Yellow Fever Vaccine immunology, Yellow fever virus immunology
- Abstract
The Yellow Fever (YF) vaccination is recommended for people living in endemic areas and represents the most effective strategy to reduce the risk of infection. Previous studies have warned that booster regimens should be considered to guarantee the long-term persistence of 17DD-YF-specific memory components in adults living in areas with YF-virus circulation. Considering the lower seroconversion rates observed in children (9-12 months of age) as compared to adults, this study was designed in order to access the duration of immunity in single-dose vaccinated children in a 10-years cross-sectional time-span. The levels of neutralizing antibodies (PRNT) and the phenotypic/functional memory status of T and B-cells were measured at a baseline, 30-45 days, 1, 2, 4, 7, and 10 years following primary vaccination. The results revealed that a single dose induced 85% of seropositivity at 30-45 days and a progressive time-dependent decrease was observed as early as 2 years and declines toward critical values (below 60%) at time-spans of ≥4-years. Moreover, short-lived YF-specific cellular immunity, mediated by memory T and B-cells was also observed after 4-years. Predicted probability and resultant memory analysis emphasize that correlates of protection (PRNT; effector memory CD8
+ T-cells; non-classical memory B-cells) wane to critical values within ≥4-years after primary vaccination. Together, these results clearly demonstrate the decline of 17DD-YF-specific memory response along time in children primarily vaccinated at 9-12 months of age and support the need of booster regimen to guarantee the long-term persistence of memory components for children living in areas with high risk of YF transmission., (Copyright © 2019 Campi-Azevedo, Reis, Peruhype-Magalhães, Coelho-dos-Reis, Antonelli, Fonseca, Costa-Pereira, Souza-Fagundes, Costa-Rocha, Mambrini, Lemos, Ribeiro, Caldas, Camacho, Maia, de Noronha, de Lima, Simões, Freire, Martins, Homma, Tauil, Vasconcelos, Romano, Domingues, Teixeira-Carvalho and Martins-Filho.)- Published
- 2019
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39. Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia.
- Author
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Lucena-Araujo AR, Coelho-Silva JL, Pereira-Martins DA, Silveira DR, Koury LC, Melo RAM, Bittencourt R, Pagnano K, Pasquini R, Nunes EC, Fagundes EM, Gloria AB, Kerbauy F, de Lourdes Chauffaille M, Bendit I, Rocha V, Keating A, Tallman MS, Ribeiro RC, Dillon R, Ganser A, Löwenberg B, Valk PJM, Lo-Coco F, Sanz MA, Berliner N, and Rego EM
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Pharmacological analysis, Biomarkers, Tumor analysis, Cohort Studies, Female, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute pathology, Male, Middle Aged, Molecular Diagnostic Techniques methods, Mutation, Prognosis, Tandem Repeat Sequences genetics, Transcriptome, Treatment Outcome, Tretinoin administration & dosage, Young Adult, fms-Like Tyrosine Kinase 3 genetics, Biomarkers, Tumor genetics, DNA Mutational Analysis methods, Gene Expression Profiling methods, Leukemia, Promyelocytic, Acute diagnosis, Leukemia, Promyelocytic, Acute genetics
- Abstract
By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all- trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and ID1 , BAALC , ERG , and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality ( P < .001), remission ( P = .004), overall survival ( P < .001), cumulative incidence of relapse ( P = .028), disease-free survival ( P = .03), and event-free survival ( P < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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40. Cecropia pachystachya Leaves Present Potential to Be Used as New Ingredient for Antiaging Dermocosmetics.
- Author
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Fernandes MF, Conegundes JLM, Pinto NCC, de Oliveira LG, de Aguiar JAK, Souza-Fagundes EM, and Scio E
- Abstract
Several biological activities have been reported for leaf extracts of Cecropia pachystachya species, including antioxidant and wound healing activities. This study aims to report, for the first time, the antiaging potential of the hydroethanolic (HE) and the ethanolic (EE) extracts obtained from the leaves of C. pachystachya using different in vitro assays. Both HE and EE presented relevant antioxidant capacity in different models, including phosphomolybdenum, 1,1-diphenyl-2-picryl-hydrazyl (DPPH), carotene/linoleic acid bleaching, and thiobarbituric acid reactive substances (TBARS) assays. Their ability to prevent the production of advanced glycation end products (AGEs) was also evaluated, and both extracts showed important activity, especially HE. The extracts also stimulated the fibroblasts proliferation in vitro , specialized cells that produce several mediators which maintain the skin integrity and youthfulness. Cytotoxicity of the extracts was not observed for this lineage or HEK-293, human embryonic kidney cells widely used to evaluate cytotoxicity of chemical compounds. HE also exhibited the ability to inhibit the collagenase (metalloproteinase MMP-2) and elastase activities. The total phenolic and flavonoids contents were also determined. HPLC analysis revealed the presence of the flavonoids orientin and iso-orientin, which were quantified to be used as chemical markers. The results suggested that the extracts of C. pachystachya leaves present the potential to be used in dermocosmetic formulations to prevent the skin aging process, which attracts the attention of pharmaceutical companies and researchers interested in the development of novel ingredients likely to be used as active principles in antiaging products.
- Published
- 2019
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41. The synthetic peptide LyeTxI-b derived from Lycosa erythrognatha spider venom is cytotoxic to U-87 MG glioblastoma cells.
- Author
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Abdel-Salam MAL, Carvalho-Tavares J, Gomes KS, Teixeira-Carvalho A, Kitten GT, Nyffeler J, Dias FF, Dos Reis PVM, Pimenta AMC, Leist M, de Lima ME, and de Souza-Fagundes EM
- Subjects
- Animals, Autophagy, Cell Membrane Permeability, Cells, Cultured, Fibroblasts drug effects, Glioblastoma drug therapy, Hemolysis drug effects, Humans, Necrosis, Neuroblastoma drug therapy, Antimicrobial Cationic Peptides pharmacology, Apoptosis drug effects, Fibroblasts pathology, Glioblastoma pathology, Neuroblastoma pathology, Spider Venoms pharmacology, Spiders chemistry
- Abstract
Antimicrobial peptides present a broad spectrum of therapeutic applications, including their use as anticancer peptides. These peptides have as target microbial, normal, and cancerous cells. The oncological properties of these peptides may occur by membranolytic mechanisms or non-membranolytics. In this work, we demonstrate for the first time the cytotoxic effects of the cationic alpha-helical antimicrobial peptide LyeTx I-b on glioblastoma lineage U87-MG. The anticancer property of this peptide was associated with a membranolytic mechanism. Loss of membrane integrity occurred after incubation with the peptide for 15 min, as shown by trypan blue uptake, reduction of calcein-AM conversion, and LDH release. Morphological studies using scanning electron microscopy demonstrated disruption of the plasma membrane from cells treated with LyeTx I-b, including the formation of holes or pores. Transmission electron microscopy analyses showed swollen nuclei with mild DNA condensation, cell volume increase with an electron-lucent cytoplasm and organelle vacuolization, but without the rupture of nuclear or plasmatic membranes. Morphometric analyses revealed a high percentage of cells in necroptosis stages, followed by necrosis and apoptosis at lower levels. Necrostatin-1, a known inhibitor of necroptosis, partially protected the cells from the toxicity of the peptide in a concentration-dependent manner. Imaging flow cytometry confirmed that 59% of the cells underwent necroptosis after 3-h incubation with the peptide. It is noteworthy that LyeTx I-b showed only mild cytotoxicity against normal fibroblasts of human and monkey cell lines and low hemolytic activity in human erythrocytes. All data together point out the anticancer potential of this peptide.
- Published
- 2019
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42. Propranolol and ascorbic acid in control of fibrodysplasia ossificans progressiva flare-ups due to accidental falls.
- Author
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Palhares DB, Nascimento DR, Palhares MG, Lopes S, de L, Cristhina P, Mauro J, Alves F, Vieira RO, Souza-Fagundes EM, Underwood A, Milsted A, Augusto R, and Martins AS
- Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare, intractable and devastating genetic connective tissue disorder characterized by progressive ectopic ossification in the soft tissues and skeleton. Three patients, one teenage girl (P1), one male adult (P2) and one male child (P3), were studied and treated with FOPCON (combined formulation of 14 mg of propranolol and 250 mg of ascorbic acid), given three times per day. P1 started treatment in March 2012, P2 in October 2012 and P3 in July 2015. The clinical follow-up of these three patients, before initiating treatment with FOPCON, showed that FOP flare-ups used to occur frequently and that under FOPCON therapy, none of these patients had flare-ups. The striking feature of this treatment with FOPCON, is that, all three cases suffered accidental falls with documented injures until complete healing and that where major flare-ups should occur, injures or sequels, there was none. The present clinical observation shows that ascorbic acid plus the nonspecific beta blocker propranolol can be effectively useful, when administered previously and continually, in the prophylaxis of FOP flare-ups, especially for accidental falls. In this regard, FOPCON could be a prophylactic aid in cases of surgery of patients with FOP, hoping that it may benefit patients from having the severe sequels, characteristic of heterotopic bone formation. All three patients reported, to date, they no longer had flare-ups nor heterotopic ossification and showed normal scar healing.
- Published
- 2019
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43. Effects of cytochalasin E on Paracoccidioides brasiliensis.
- Author
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Mendes G, Baltazar LM, Souza DG, Sá NP, Rosa LH, Rosa CA, Souza-Fagundes EM, Ramos JP, Alves-Silva J, Cota BB, and Johann S
- Subjects
- Antifungal Agents isolation & purification, Aspergillus chemistry, Cytochalasins isolation & purification, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Cytochalasins pharmacology, Paracoccidioides drug effects
- Abstract
Aims: To determine the effects of cytochalasin E, isolated from the extremophile fungus Aspergillus felis, on the cells of Paracoccidioides brasiliensis Pb18., Methods and Results: Cytochalasin E showed a minimal inhibitory concentration of 3·6 μmol l
-1 and minimum fungicidal concentration of 7·2 μmol l-1 on P. brasiliensis by in vitro microdilution and IC50 >964·0 μmol l-1 on murine macrophages. Its selectivity index (>263) indicated that this compound has selectivity for fungal cells. Morphological alterations were determined by optical and fluorescence microscopy, as well as scanning and transmission electron microscopy. Cytochalasin E affected P. brasiliensis bud-forming pseudohyphae, cell morphology, cell walls and cell membranes; caused the release of cellular material; and resulted in the production of reactive oxygen species. In murine macrophages, it affected cytoskeletal actin and inhibited phagocytosis., Conclusion: Cytochalasin E may be useful as an antifungal prototype against P. brasiliensis and in studies on phagocytosis., Significance and Impact of the Study: Paracoccidioides spp. are the etiological agents of paracoccidioidomycosis (PCM). Treatment is prolonged to control the clinical manifestations and prevent relapse. The study on the effects of cytochalasin E in P. brasiliensis is important because it can be used as a prototype for new antifungal drugs and consequently, broadens the treatment options for PCM., (© 2018 The Society for Applied Microbiology.)- Published
- 2018
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44. Ciprofloxacin degradation by first-, second-, and third-generation manganese porphyrins.
- Author
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Almeida Lage AL, Moreira Meireles A, Capelão Marciano A, Martins Ribeiro J, de Souza-Fagundes EM, and Carvalho da Silva Martins D
- Subjects
- Anti-Bacterial Agents toxicity, Catalysis, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Ciprofloxacin toxicity, Humans, Manganese toxicity, Oxidation-Reduction, Porphyrins toxicity, Anti-Bacterial Agents chemistry, Ciprofloxacin chemistry, Manganese chemistry, Porphyrins chemistry
- Abstract
A range of hydrophobic first-, second-, and third-generation manganese porphyrins (MnPs) was investigated as cytochrome P450 models for degradation of the antibiotic ciprofloxacin (CIP). The experiments were carried out under mild conditions; oxidants such as iodosylbenzene (PhIO), H
2 O2 , and meta-chloroperbenzoic acid were employed. The PhIO system yielded the best results: CIP degradation ranged between 56% and 76%. CIP degradation was not directly related to MnP generation. The second-generation MnP afforded the best result with the advantage that it required less preparation effort as compared to the third-generation MnP. Some new degradation products in MnP-mediated ciprofloxacin degradation were proposed, and the products of the reaction are not cytotoxic under the conditions evaluated., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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45. In vivo and in vitro activity of a bis-arylidenecyclo-alkanone against fluconazole-susceptible and -resistant isolates of Candida albicans.
- Author
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de Sá NP, de Paula LFJ, Lopes LFF, Cruz LIB, Matos TTS, Lino CI, de Oliveira RB, de Souza-Fagundes EM, Fuchs BB, Mylonakis E, and Johann S
- Subjects
- Animals, Antifungal Agents chemistry, Antifungal Agents pharmacology, Caenorhabditis elegans, Cyclohexanones chemistry, Cyclohexanones pharmacology, Disease Models, Animal, Drug Resistance, Fungal drug effects, Female, Fluconazole pharmacology, Humans, Mice, Microbial Sensitivity Tests, Antifungal Agents chemical synthesis, Candida albicans drug effects, Candidiasis drug therapy, Cyclohexanones chemical synthesis
- Abstract
Objectives: Candida albicans is a commensal organism and opportunistic pathogen associated both with superficial (mucosal and cutaneous) and systemic infections. Extensive use of antifungal agents has led to reduced susceptibility to the few existing drugs, which has encouraged the search for novel antifungal agents. Therefore, the present study investigated the antifungal activity of 2,6-bis[(E)-(4-pyridyl)methylidene]cyclohexanone (PMC) against C. albicans., Methods: The in vitro activity of PMC was evaluated against C. albicans. Additionally, an invertebrate infection model in Caenorhabditis elegans as well as two infected murine models of oral and systemic candidiasis were used to determine the antifungal efficacy of PMC in vivo., Results: Minimum inhibitory concentrations (MICs) of PMC ranged from 4-32μg/mL against nine clinical and two reference C. albicans isolates. Interestingly, PMC inhibited filamentation in vitro at subinhibitory concentrations similar to fluconazole. PMC also showed low toxicity against murine macrophages and human erythrocytes. In the invertebrate infection model, PMC was efficient in prolonging survival of C. elegans infected with C. albicans SC5314. Treatment with PMC was efficient both in murine models of systemic and oral candidiasis and was similar to that observed with conventional drug treatments (nystatin and fluconazole)., Conclusions: The results of this study indicate the therapeutic potential of PMC as it was able to inhibit filamentation of C. albicans in vitro. These alterations to the fungi by PMC resulted in a reduction of oral and systemic infection in mice. In conclusion, we present promising evidence of the anticandidal activity of PMC in vitro and in vivo., (Copyright © 2018. Published by Elsevier Ltd.)
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- 2018
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46. Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties.
- Author
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de Souza-Fagundes EM, Delp J, Prazeres PDM, Marques LB, Carmo AML, Stroppa PHF, Glanzmann N, Kisitu J, Szamosvàri D, Böttcher T, Leist M, and da Silva AD
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Clone Cells, Dopaminergic Neurons drug effects, Dopaminergic Neurons metabolism, Humans, Neurites drug effects, Neurites metabolism, Triazoles chemical synthesis, Neoplasms pathology, Neurotoxins toxicity, Triazoles chemistry, Triazoles toxicity
- Abstract
Triazoles are interesting templates for novel chemotherapeutic drugs. We synthesized here 17 1,3,4-substituted-1,2,3-triazoles that differed in their 1'-substituent (variable alkyl chain lengths C3-C12), the 3'-substituent (no substituent, -methyl or -propyl) or the salt form obtained. Several of the compounds were cytotoxic (μM range) for tumor cells (HL-60, Jurkat, MCF-7, HCT-116), and when the effect was compared to non-transformed cells (Vero), selectivity ratios of up to 23-fold were obtained. To estimate the liability of these potential drug candidates for triggering neurotoxicity, we used the LUHMES cell-based NeuriTox assay. This test quantifies damage to the neurites of human neurons. The four most potent tumoricidal compounds were found to be neurotoxic in a concentration range similar to the one showing tumor cell toxicity. As the neurites of the LUHMES neurons were affected at >4-fold lower concentrations than the overall cell viability, the novel triazoles were classified as specific neurotoxicants. The structure-activity relationship (SAR) for neurotoxicity was sharply defined and correlated with the one for anti-neoplastic activity. Based on this SAR, two non-neurotoxic compounds were predicted, and testing in the NeuriTox assay confirmed this prediction. In summary, the panel of novel triazoles generated and characterized here, allowed to define structural features associated with cytotoxicity and neurotoxicity. Moreover, the study shows that potential neurotoxic side effects may be predicted early in drug development if highly sensitive test methods for neurite integrity are applied., (Copyright © 2018 Elsevier B.V. All rights reserved.)
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- 2018
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47. Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity.
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Otta DA, de Araújo FF, de Rezende VB, Souza-Fagundes EM, Elói-Santos SM, Costa-Silva MF, Santos RA, Costa HA, Siqueira-Neto JL, Martins-Filho OA, and Teixeira-Carvalho A
- Subjects
- Apoptosis drug effects, Chagas Disease prevention & control, Furazolidone pharmacology, Leukocytes drug effects, Naphthyridines pharmacology, Phytohemagglutinins pharmacology, Immunologic Factors pharmacology, Trypanosoma cruzi drug effects
- Abstract
In seeking substitutions for the current Chagas disease treatment, which has several relevant side effects, new therapeutic candidates have been extensively investigated. In this context, a balanced interaction between mediators of the host immune response seems to be a key element for therapeutic success, as a proinflammatory microenvironment modulated by interleukin-10 (IL-10) is shown to be relevant to potentiate anti- Trypanosoma cruzi drug activity. This study aimed to identify the potential immunomodulatory activities of the anti- T. cruzi K777, pyronaridine (PYR), and furazolidone (FUR) compounds in peripheral blood mononuclear cells (PBMC) from noninfected (NI) subjects and chronic Chagas disease (CD) patients. Our results showed low cytotoxicity to PBMC populations, with 50% cytotoxic concentrations (CC
50 ) of 71.0 μM (K777), 9.0 μM (PYR), and greater than 20 μM (FUR). In addition, K777 showed no impact on the exposure index (EI) of phytohemagglutinin-stimulated leukocytes (PHA), while PYR and FUR treatments induced increased EI of monocytes and T lymphocytes at late stages of apoptosis in NI subjects. Moreover, K777 induced a more prominent proinflammatory response (tumor necrosis factor alpha-positive [TNF-α+ ] CD8+ /CD4+ , gamma interferon-positive [IFN-γ+ ] CD4+ /CD8+ modulated by interleukin-10-positive [IL-10+ ] CD4+ T/CD8+ T) than did PYR (TNF-α+ CD8+ , IL-10+ CD8+ ) and FUR (TNF-α+ CD8+ , IL-10+ CD8+ ). Signature analysis of intracytoplasmic cytokines corroborated the proinflammatory/modulated (K777) and proinflammatory (PYR and FUR) profiles previously found. In conclusion, the lead compound K777 may induce beneficial changes in the immunological profile of patients presenting the chronic phase of Chagas disease and may contribute to a more effective therapy against the disease., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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48. The experience of the International Consortium on Acute Promyelocytic Leukemia in monitoring minimal residual disease in acute promyelocytic leukaemia.
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Lange AP, Lima AS, Lucena-Araujo AR, Jácomo RH, Melo RA, Bittencourt RI, Pasquini R, Pagnano K, Fagundes EM, Chauffaille ML, Chiattone CS, Sanz MA, Lo-Coco F, Grimwade D, and Rego EM
- Subjects
- Adolescent, Adult, Aged, Child, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Promyelocytic, Acute therapy, Male, Middle Aged, Monitoring, Physiologic, Neoplasm, Residual, Survival Rate, Leukemia, Promyelocytic, Acute blood, Leukemia, Promyelocytic, Acute mortality
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- 2018
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49. Novel nitroaromatic compound activates autophagy and apoptosis pathways in HL60 cells.
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Perdigão GMC, Lopes MS, Marques LB, Prazeres PHDM, Gomes KS, de Oliveira RB, Pinto MCX, and de Souza-Fagundes EM
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- Amino Acid Chloromethyl Ketones pharmacology, Benzamidines chemistry, Caspase Inhibitors pharmacology, Caspases metabolism, Cells, Cultured, DNA Fragmentation drug effects, G2 Phase Cell Cycle Checkpoints drug effects, HL-60 Cells, Humans, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, M Phase Cell Cycle Checkpoints drug effects, Macrolides pharmacology, Membrane Potential, Mitochondrial drug effects, Reactive Oxygen Species metabolism, Apoptosis drug effects, Autophagy drug effects, Benzamidines toxicity
- Abstract
N-(2-butanoyloxyethyl)-4-(chloromethyl)-3-nitrobenzamide (NBCN) is a nitroaromatic bioreducible compound with cytotoxic effects in cancer cell lines. The aim of this work was to investigate the molecular mechanisms involved in cell death promoted by NBCN in HL60 cells. We observed that NBCN treatment increased intracellular ROS and reduced mitochondria membrane potential (ΔΨm). NBCN treatment also induced morphological changes, phosphatidylserine exposure, cell cycle arrest in G2/M-phase, DNA condensation and fragmentation, but it did not show cytotoxic effects on normal human peripheral blood mononuclear cells (PBMCs). NBCN-induced caspase 3- and 9-dependent DNA fragmentation, which was blocked by pretreatment with the broad-spectrum caspase inhibitor, z-VAD-fmk. Flow cytometry analysis demonstrated that NBCN also increased of the number of autophagic vesicles in HL60 cells, which was not observed when cells were pre-treated with bafilomycin A1. Taken together, these results indicate that NBCN triggered the mitochondrial apoptotic pathway and led to the onset of autophagic cell death, which contributed to its cytotoxic effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)
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- 2018
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50. Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood).
- Author
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Cota BB, Tunes LG, Maia DNB, Ramos JP, Oliveira DM, Kohlhoff M, Alves TMA, Souza-Fagundes EM, Campos FF, and Zani CL
- Subjects
- Animals, Cell Survival, Chlorocebus aethiops, Chromatography, High Pressure Liquid, Inhibitory Concentration 50, Parasitic Sensitivity Tests, Toxicity Tests, Trypanocidal Agents isolation & purification, Trypanocidal Agents toxicity, Vero Cells, Caesalpinia microbiology, Leishmania braziliensis drug effects, Nectria chemistry, Trypanocidal Agents pharmacology
- Abstract
BACKGROUND In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6'-acetoxy-piliformic acid (2), 5',6'-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 µM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells.
- Published
- 2018
- Full Text
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