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1.
Bioorg Med Chem ; 105: 117734, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38677112

RESUMO

Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the ß-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.


Assuntos
Antimaláricos , Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Harmina , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Harmina/farmacologia , Harmina/química , Harmina/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Plasmodium falciparum/efeitos dos fármacos , Estrutura Molecular , Descoberta de Drogas , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Testes de Sensibilidade Parasitária
2.
Molecules ; 29(13)2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38998949

RESUMO

Newly synthesized 7-chloro-4-aminoquinoline-benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC50 value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure-activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R2 = 0.886; Rext2 = 0.937; F = 41.589) and Dd2 strain (R2 = 0.859; Rext2 = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities.


Assuntos
Antimaláricos , Antineoplásicos , Benzimidazóis , Desenho de Fármacos , Plasmodium falciparum , Relação Quantitativa Estrutura-Atividade , Humanos , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Antimaláricos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Estrutura Molecular , Aminoquinolinas
3.
Angew Chem Int Ed Engl ; 63(19): e202319765, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38502093

RESUMO

The natural product chlorotonil displays high potency against multidrug-resistant Gram-positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late-stage functionalization, we aimed to further optimize the molecule. Previously unknown reactions including a sulfur-mediated dehalogenation were revealed. Dehalogenil, the product of this reaction, was identified as the most promising compound so far, as this new derivative displayed improved solubility and in vivo efficacy while retaining excellent antimicrobial activity. We confirmed superb activity against multidrug-resistant clinical isolates of Staphylococcus aureus and Enterococcus spp. and mature transmission stages of Plasmodium falciparum. We also demonstrated favorable in vivo toxicity, pharmacokinetics and efficacy in infection models with S. aureus. Taken together, these results identify dehalogenil as an advanced lead molecule.


Assuntos
Antibacterianos , Staphylococcus aureus , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Animais , Enterococcus/efeitos dos fármacos , Estrutura Molecular , Humanos , Camundongos
4.
Bioorg Med Chem ; 94: 117468, 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37696205

RESUMO

Malaria, one of the oldest parasitic diseases, remains a global health threat, and the increasing resistance of the malaria parasite to current antimalarials is forcing the discovery of new, effective drugs. Harmicines, hybrid compounds in which harmine/ß-carboline alkaloids and cinnamic acid derivatives are linked via an amide bond or a triazole ring, represent new antiplasmodial agents. In this work, we used a multiple linear regression technique to build a linear quantitative structure-activity relationship (QSAR) model, based on a group of 40 previously prepared amide-type (AT) harmicines and their antiplasmodial activities against erythrocytic stage of chloroquine-sensitive strain of P. falciparum (Pf3D7). After analysing the QSAR model, new harmicines were designed and synthesized: six amide-type, eleven carbamate-type and two ureido-type harmicines at the N-9 position of the ß-carboline core. Subsequently, we evaluated the antiplasmodial activity of the new harmicines against the erythrocytic and hepatic stages of the Plasmodium life cycle in vitro and their antiproliferative activity against HepG2 cells. UT harmicine (E)-1-(2-(7-methoxy-1-methyl-9H-pyrido[3,4-b]indol-9-yl)ethyl)-3-(3-(3-(trifluoromethyl)phenyl)allyl)urea at the N-9 position of the ß-carboline ring exhibited pronounced antiplasmodial activity against both the erythrocytic and the hepatic stages of the Plasmodium life cycle, accompanied by good selectivity towards Plasmodium.

5.
Adv Exp Med Biol ; 1439: 51-70, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37843805

RESUMO

Microorganisms are ubiquitous in diverse habitats and studying their chemical interactions with the environment and comprehend its complex relations with both hosts and environment, are crucial for the development of strategies to control microbial diseases. This chapter discusses the importance of studying microorganisms with agricultural benefits, using specialized metabolites as examples. Herein we highlight the challenges and opportunities in utilizing microorganisms as alternatives to synthetic pesticides and fertilizers in agriculture. Genome-guided investigations and improved analytical methodologies are necessary to characterize diverse and complex biomolecules produced by microorganisms. Predicting and isolating bioproducts based on genetic information have become a focus for researchers, aided by tools like antiSMASH, BiG-SCAPE, PRISM, and others. However, translating genomic data into practical applications can be complex. Therefore, integrating genomics, transcriptomics, and metabolomics enhances chemical characterization, aiding in discovering new metabolic pathways and specialized metabolites. Additionally, elicitation is one promising strategy to enhance beneficial metabolite production. Finally, identify and characterize microbial secondary metabolites remain challenging due to their low production, complex chemical structure characterization and different environmental factors necessary for metabolite in vitro production.


Assuntos
Metabolômica , Praguicidas , Metabolômica/métodos , Genômica/métodos , Redes e Vias Metabólicas , Perfilação da Expressão Gênica
6.
J Cancer Educ ; 38(3): 940-947, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36029416

RESUMO

AIM: In this study, we evaluated the impact of an integrated oral care protocol for pediatric patients undergoing antineoplastic treatment from the perspective of the multidisciplinary team, oral healthcare team, and caregivers. SUBJECT AND METHODS: This was a qualitative study carried out in the pediatric sector of a reference cancer hospital in Brazil. Focus group and individual semi-structured interview techniques were used, and the data were analyzed by the Discourse of the Collective Subject (DCS) method. RESULTS: A total of 44 professionals involved in providing care to children and adolescents with cancer and 38 caregivers were interviewed. All interviewees perceived an improvement in the patients' oral health condition. Health professionals reported a reduction in the occurrence and severity of oral mucositis (OM). Communicating with the medical team and understanding the importance of oral care to the patient's systemic condition were the greatest difficulties reported by the oral healthcare team. CONCLUSION: This implementation project contributed to establishing a complete multidisciplinary team to assist pediatric patients in all their needs during antineoplastic treatment. The integrated oral care protocol further contributed to reducing the occurrence and severity of OM by increasing its surveillance and diagnostic efficiency, which, altogether, improved the patients' quality of life.


Assuntos
Antineoplásicos , Neoplasias , Estomatite , Adolescente , Criança , Humanos , Qualidade de Vida , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Estomatite/prevenção & controle , Estomatite/induzido quimicamente , Pacientes
7.
Int J Mol Sci ; 23(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36012590

RESUMO

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/ß-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the ß-carboline ring and ferrocene, as well as its position on the ß-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.


Assuntos
Antineoplásicos , Malária Falciparum , Antineoplásicos/química , Apoptose , Carbolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular , Harmina , Humanos , Metalocenos/farmacologia , Relação Estrutura-Atividade
8.
Angew Chem Int Ed Engl ; 61(30): e202202816, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35485800

RESUMO

The rise of antimicrobial resistance poses a severe threat to public health. The natural product chlorotonil was identified as a new antibiotic targeting multidrug resistant Gram-positive pathogens and Plasmodium falciparum. Although chlorotonil shows promising activities, the scaffold is highly lipophilic and displays potential biological instabilities. Therefore, we strived towards improving its pharmaceutical properties by semisynthesis. We demonstrated stereoselective epoxidation of chlorotonils and epoxide ring opening in moderate to good yields providing derivatives with significantly enhanced solubility. Furthermore, in vivo stability of the derivatives was improved while retaining their nanomolar activity against critical human pathogens (e.g. methicillin-resistant Staphylococcus aureus and P. falciparum). Intriguingly, we showed further superb activity for the frontrunner molecule in a mouse model of S. aureus infection.


Assuntos
Antimaláricos , Malária Falciparum , Staphylococcus aureus Resistente à Meticilina , Animais , Antibacterianos/farmacologia , Antimaláricos/farmacologia , Compostos de Epóxi/farmacologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Staphylococcus aureus
9.
Cell Tissue Res ; 384(3): 721-734, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33977324

RESUMO

Bone marrow cells (BMCs) from obese Swiss mice fed with Western diet show mitochondrial dysfunction. Obesity interferes with BMCs disrupting energetic metabolism, stimulating apoptosis, and reducing cell proliferation since adipose tissue releases inflammatory adipokines into the medullar microenvironment. These changes lead to reduction of BMC differentiation capacity and hematopoiesis impairment, a process responsible for blood cell continuous production through hematopoietic stem cells (HSCs). This work aimed to analyze the effects of IGF-1 therapy on BMC viability in Western diet-induced obesity, in vivo. We observed that after only 1 week of treatment, obese Swiss mice presented reduced body weight and visceral fat and increased mitochondrial oxidative capacity and coupling, indicating mitochondrial function improvement. In addition, IGF-1 was able to reduce apoptosis of total BMCs, stem cell subpopulations (hematopoietic and mesenchymal), and leukocytes, restoring all progenitor hematopoietic lineages. The treatment also contributed to increase proliferative capacity of hematopoietic stem cells and leukocytes, keeping the hematopoietic and immune systems balanced. Therefore, we conclude that IGF-1 short period therapy improved BMC survival, proliferation, and differentiation capacity in obese Swiss mice.


Assuntos
Células da Medula Óssea , Fator de Crescimento Insulin-Like I/farmacologia , Obesidade , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Masculino , Camundongos , Camundongos Obesos , Mitocôndrias/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/patologia
10.
Molecules ; 26(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921170

RESUMO

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.


Assuntos
Antimaláricos/uso terapêutico , Reposicionamento de Medicamentos/métodos , Animais , Antibacterianos/uso terapêutico , Resistência a Medicamentos/genética , Humanos , Malária/fisiopatologia , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidade
11.
J Community Psychol ; 49(1): 95-117, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32840883

RESUMO

Disasters affect sociospatial links in a dynamic and unstable meshwork of aspects that are reconfigured. In this sense, accounting for this complexity is central to analyze the transformation of the sociospatial linkage of the affected people and communities. Addressing from community environmental psychology, we propose the concept of assemblage to guide a situated reading of subjective, material, and community aspects present in a reconstruction process after a disaster. Following a qualitative methodology, using spatially referenced narrative interviews (n = 16) and thematic analysis, it is described how these links are presented in a community that lived the mega-fire of a part of the city of Valparaíso in Chile. The results describe that the experience of being a community is a variable flow within a process defined by an ever-emerging configuration of spatial, technological, personal, social, and sensory characteristics. We conclude by pointing out the qualities of the communities when considered from an assemblage perspective.


Assuntos
Desastres , Chile , Cidades , Humanos
12.
Nutr Metab Cardiovasc Dis ; 30(1): 151-161, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31753790

RESUMO

BACKGROUND AND AIMS: Cardiovascular diseases are the main cause of mortality in obesity. Despite advanced understanding, the mechanisms that regulate cardiac progenitor cells (CPC) survival in pathological conditions are not clear. Low IGF-1 plasma levels are correlated to obesity, cardiomyopathy and CPC death, so this work aimed to investigate IGF-1 therapeutic potential on cardiomyopathy and its relationship with the survival, proliferation and differentiation of CPC in Western diet-induced obesity. METHODS AND RESULTS: Male Swiss mice were divided into control group (CG, n = 8), fed with standard diet; and obese group (OG, n = 16), fed with Western diet, for 12 weeks. At 11th week, OG was subdivided to receive a daily subcutaneous injection of human recombinant IGF-1 (100 µg.Kg-1) for seven consecutive days (OG + IGF1, n = 8). Results showed that IGF-1 therapy improved the metabolic parameters negatively impacted by western diet in OG, reaching levels similar to CG. OG + IGF-1 also demonstrated restored heart energetic metabolism, fibrosis resolution, decreased apoptosis level, restored cardiac gap junctions and intracellular calcium balance. Cardiomyopathy improvement was accompanied by increased CPC survival, proliferation and newly cardiomyocytes formation related to increased pAkt/Akt ratio. CONCLUSION: These results suggest that only one week of IGF-1 therapy has cardioprotective effects through Akt pathway upregulation, ensuring CPC survival and differentiation, contributing to heart failure rescue.


Assuntos
Cardiomiopatias/prevenção & controle , Fator de Crescimento Insulin-Like I/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Células-Tronco/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sinalização do Cálcio , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Injeções Subcutâneas , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Obesidade/complicações , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/administração & dosagem , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Tempo , Remodelação Ventricular/efeitos dos fármacos
13.
Exp Parasitol ; 209: 107826, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31881207

RESUMO

Protozoan parasites like Leishmania amazonensis are excellent models to test the effects of new drugs against a functional molecular arsenal used to establish successfully an infection in the vertebrate host, where they invade the cells of the monocytic system. However, little is known about the influence of metal ions on the cellular functionality of the infective forms of L. amazonensis. In the present work, we show that ZnCl2 (an essential metal to cellular metabolism) did not induce drastic effects on the survival of the promastigote under the conditions tested. However, incubation of ZnCl2 prior to subsequent treatment with CdCl2 and HgCl2 led to a drastic toxic effect on parasite survival in vitro. Nonessential metals such as CdCl2 and HgCl2 promoted a drastic effect on parasite survival progressively with increasing dose and time of exposure. Notably, HgCl2 produced an effective elimination of the parasite in doses/time smaller than the CdCl2. This toxic action induced in the parasite a high condensation of the nuclear heterochromatin, besides the absence or de-structuring of functional organelles such as glycosomes, acidocalcisomes, and mitochondria in the cytoplasm. Our results suggest that promastigotes of L. amazonensis are sensitive to the toxic activity of nonessential metals, and that this activity increases when parasites are previously exposed to Zn. To summarize, toxic effects of the tested metals are dose and time dependent and can be used as a study model to better understand the functionality of the molecular arsenal responsible for the parasitism.


Assuntos
Cloreto de Cádmio/farmacologia , Cloretos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Cloreto de Mercúrio/farmacologia , Compostos de Zinco/farmacologia , Humanos , Concentração Inibidora 50 , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/ultraestrutura , Microscopia Eletrônica de Transmissão
14.
Molecules ; 25(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977642

RESUMO

Harmicines represent hybrid compounds composed of ß-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a-f and O-harmicines 6a-h were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of P. falciparum, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of P. berghei. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of PfHsp90, while the calculated binding free energies confirmed higher activity of N-harmicines 5 over their O-substituted analogues 6. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.


Assuntos
Antimaláricos/farmacologia , Alcaloides Indólicos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Feminino , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Fígado/efeitos dos fármacos , Fígado/parasitologia , Simulação de Dinâmica Molecular , Plasmodium berghei/metabolismo , Plasmodium berghei/fisiologia , Plasmodium falciparum/metabolismo , Plasmodium falciparum/fisiologia , Conformação Proteica
15.
Artigo em Inglês | MEDLINE | ID: mdl-31109978

RESUMO

Ivermectin is the drug of choice for many parasitic infections, with more than one billion doses being distributed in onchocerciasis programs. The drug has been put into focus recently by the malaria community because of its potential to kill blood-sucking mosquitoes, thereby reducing malaria transmission. However, the activity of ivermectin against the malaria parasite itself has been only partly investigated. This study aimed to investigate the in vitro activity of ivermectin against asexual and sexual stages of Plasmodium falciparum Both asexual and late-stage gametocytes were incubated with ivermectin and control drugs in vitro The growth-inhibiting effects were assessed for asexual stages of different Plasmodium falciparum laboratory strains and culture-adapted clinical isolates using the histidine-rich protein 2 enzyme-linked immunosorbent assay technique. The effect against stage IV/V gametocytes was evaluated based on ATP quantification. Ivermectin showed activities at nanomolar concentrations against asexual stages (50% inhibitory concentration of ∼100 nM) and stage IV/V gametocytes (500 nM) of P. falciparum Stage-specific assays suggested that ivermectin arrests the parasite cycle at the trophozoite stage. Ivermectin might add a feature to its "wonder drug" properties with activity against asexual stages of the malaria parasite Plasmodium falciparum The observed activities might be difficult to reach with current regimens but will be more relevant with future high-dose regimens under investigation. Further studies should be performed to confirm these results in vitro and in vivo.


Assuntos
Antimaláricos/farmacologia , Ivermectina/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/fisiologia , Antimaláricos/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Ivermectina/administração & dosagem , Malária Falciparum/parasitologia , Plasmodium falciparum/isolamento & purificação , Reprodução Assexuada/efeitos dos fármacos , Trofozoítos/efeitos dos fármacos
16.
Exp Physiol ; 104(5): 740-754, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30790372

RESUMO

NEW FINDINGS: What is the central question of this study? Can a single bone marrow mononuclear cell (BMMC) transplant into the subcapsular region of kidney improve cellular communication and adhesion, while restoring renal tissue cytoarchitecture and function during renovascular hypertension? What is the main finding and its importance? The BMMC transplantation restored connexin 40 expression and led to recovery of N- and E-cadherin levels within 15 days. It was observed, for the first time, that BMMC transplantation restores expression of nephrin, a component of the glomerular filtration barrier related to podocytes and the glomerular basal membrane. ABSTRACT: Stem cell therapy has emerged as a potential treatment for renal diseases owing to the regenerative potential of stem cells. However, a better understanding of the morphological and functional changes of damaged renal cells in the presence of transplanted stem cells is needed. The aim of this study was to investigate cell-cell communication and adhesion in renal parenchyma, with analysis of fibrosis, to evaluate renal morphology and function after bone marrow mononuclear cell (BMMC) transplantation in two-kidney-one-clip rats. The BMMC therapy significantly decreased blood pressure and renin expression, improved renal morphology and restored the glomerular filtration barrier, with remodelling of podocytes. In addition, there was a reduction in fibrosis, and connexin 40 and nephrin expression were significantly increased after 7 and 15 days of transplantation. Plasma creatinine, urea and total protein levels were restored, and proteinuria was reduced. Furthermore, N- and E-cadherin expression was increased soon after BMMC therapy. Green fluorescent protein-positive BMMCs were found in the renal cortex 24 and 48 h after transplantation into the renal subcapsule, and at 7 and 15 days after transplantation, these cells were observed throughout the renal medulla, indicating cellular migration. Therefore, these data suggest that transplanted BMMCs improve cell-cell communication and adhesion between damaged cells, which is accompanied by a recovery of renal morphology and function.


Assuntos
Transplante de Medula Óssea/métodos , Barreira de Filtração Glomerular/patologia , Hipertensão Renovascular/patologia , Hipertensão Renovascular/terapia , Junções Intercelulares/patologia , Animais , Pressão Sanguínea , Caderinas/metabolismo , Comunicação Celular , Fibrose , Rim/patologia , Córtex Renal/patologia , Masculino , Monócitos/transplante , Podócitos/patologia , Ratos , Ratos Wistar , Renina/biossíntese
17.
Amino Acids ; 51(10-12): 1633-1648, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31654210

RESUMO

For medical use of proteins and peptide-based drugs, it is desirable to have small biologically active sequences because they improve stability, reduce side effects, and production costs. Several plant defensins have their biological activities imparted by a sequence named γ-core. Vu-Def, a Vigna unguiculata defensin, has activity against Leishmania amazonensis, which is one etiological agent of leishmaniasis and for which new drugs are needed. Our intention was to understand if the region comprising the Vu-Def γ-core is responsible for the biological activity against L. amazonensis and to unveil its mechanism of action. Different microbiological assays with L. amazonensis in the presence of the synthetic peptide A36,42,44γ32-46Vu-Def were done, as well as ultrastructural and fluorescent analyses. A36,42,44γ32-46Vu-Def showed biological activity similar to Vu-Def. A36,42,44γ32-46Vu-Def (74 µM) caused 97% inhibition of L. amazonensis culture and parasites were unable to regrow in fresh medium. The cells of the treated parasites showed morphological alterations by ultrastructural analysis and fluorescent labelings that corroborate with the data of the organelles alterations. The general significance of our work is based on the description of a small synthetic peptide, A36,42,44γ32-46Vu-Def, which has activity on L. amazonensis and that the interaction between A36,42,44γ32-46Vu-Def-L. amazonensis results in parasite inhibition by the activation of an apoptotic-like cell death pathway.


Assuntos
Apoptose/efeitos dos fármacos , Defensinas/química , Leishmania/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Vigna/química , Sequência de Aminoácidos , Defensinas/farmacologia , Leishmania/crescimento & desenvolvimento , Modelos Moleculares , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Estrutura Secundária de Proteína , Sementes/química
18.
Can J Microbiol ; 64(7): 455-464, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29586486

RESUMO

Plant defensins are plant antimicrobial peptides that present diverse biological activities in vitro, including the elimination of Leishmania amazonensis. Plant defensins are considered promising candidates for the development of new drugs. This protozoan genus has great epidemiological importance and the mechanism behind the protozoan death by defensins is unknown, thus, we chose L. amazonensis for this study. The aim of the work was to analyze the possible toxic mechanisms of Vu-Defr against L. amazonensis. For analyses, the antimicrobial assay was repeated as previously described, and after 24 h, an aliquot of the culture was tested for viability, membrane perturbation, mitochondrial membrane potential, reactive oxygen species (ROS) and nitric oxide (NO) inductions. The results of these analyses indicated that after interaction with L. amazonensis, the Vu-Defr causes elimination of promastigotes from culture, membrane perturbation, mitochondrial membrane collapse, and ROS induction. Our analysis demonstrated that NO is not produced after Vu-Defr and L. amazonensis interaction. In conclusion, our work strives to help to fill the gap relating to effects caused by plant defensins on protozoan and thus better understand the mechanism of action of this peptide against L. amazonensis.


Assuntos
Anti-Infecciosos/farmacologia , Defensinas/farmacologia , Leishmania/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vigna/química , Animais , Membrana Celular/metabolismo , Extratos Vegetais/toxicidade , Proteínas Recombinantes/farmacologia , Sementes/química
19.
Parasitol Res ; 117(4): 1245-1256, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29455419

RESUMO

Toxoplasma gondii, the etiological agent of toxoplasmosis, infects nucleated cells and then resides and multiplies within a parasitophorous vacuole. For this purpose, the parasite secretes many virulence factors for the purpose of invading and subverting the host microbicidal defenses in order to facilitate its survival in the intracellular milieu. Essential metals are structural components of proteins and enzymes or cofactors of enzymatic reactions responsible for these parasitic survival mechanisms. However, an excess of non-essential or essential metals can lead to parasite death. Thus, infected host cells were incubated with 20 µM ZnCl2 in conjunction with 3 µM CdCl2 or HgCl2 for 12 h in order to investigate cellular events and organelle damage related to intracellular parasite death and elimination. In the presence of these metals, the tachyzoites undergo lipid uptake and transport impairment, functional and structural mitochondrial disorders, DNA condensation, and acidification of the parasitophorous vacuole, thus leading to parasite death. Additional research has suggested that lysosome-vacuole fusion was involved in parasite elimination since acid phosphatases were found inside the parasitophorous vacuole, and vacuoles containing parasites were also positive for autophagy. In conclusion, low concentrations of CdCl2, HgCl2, and ZnCl2 can cause damage to Toxoplasma gondii organelles, leading to loss of viability, organelle death, and elimination without causing toxic effects to host cells.


Assuntos
Cloreto de Cádmio/farmacologia , Cloretos/farmacologia , Cloreto de Mercúrio/farmacologia , Toxoplasma/efeitos dos fármacos , Vacúolos/efeitos dos fármacos , Compostos de Zinco/farmacologia , Animais , Autofagia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Interações Hospedeiro-Parasita/efeitos dos fármacos , Lisossomos , Macaca mulatta , Mitocôndrias/patologia , Desnaturação de Ácido Nucleico/efeitos dos fármacos , Toxoplasma/patogenicidade , Vacúolos/parasitologia , Vacúolos/patologia , Fatores de Virulência
20.
Molecules ; 23(4)2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29597255

RESUMO

Most cinnamic acids, their esters, amides, aldehydes, and alcohols present several therapeutic actions through anti-inflammatory, antitumor, and inhibitory activity against a great variety of microorganisms. In this work, eight amines derived from cinnamic acid were synthesized and tested against host cells infected with Toxoplasma gondii and the bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and three strains of Staphylococcus aureus. Compounds 3 and 4 showed the best result against intracellular T. gondii, presenting antiparasitic activity at low concentrations (0.38 and 0.77 mM). The antibacterial activity of these compounds was also evaluated by the agar microdilution method, and amides 2 and 5 had a minimum inhibitory concentration of 250 µg mL-1 against two strains of S. aureus (ATCC 25923 and bovine strain LSA 88). These also showed synergistic action along with a variety of antibiotics, demonstrating that amines derived from cinnamic acid have potential as pharmacological agents.


Assuntos
Amidas , Antibacterianos , Antiprotozoários , Bactérias/crescimento & desenvolvimento , Cinamatos , Toxoplasma/crescimento & desenvolvimento , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Cinamatos/química , Cinamatos/farmacologia
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