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1.
Exp Parasitol ; 208: 107793, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31711973

RESUMO

Praziquantel (PZQ) is the sole drug used to treat schistosomiasis, and the probability of developing resistance is growing the longer it is relied upon, justifying the search for alternatives. Phosphodiesterases (PDEs), particularly the PDE4 family, have attracted considerable attention as drug targets, including in Schistosoma mansoni, and especially SmPDE4A. This study investigates the potential antischistosomal activity of human PDE4 and potent SmPDE4A inhibitor roflumilast, either alone or combined with PZQ. In vitro, roflumilast resulted in a significant, concentration-dependent reduction in egg production but not of worm viability. In vitro exposure to roflumilast in combination with a low concentration of PZQ was less effective than PZQ alone, pointing to antagonism. S. mansoni-infected mice treated with roflumilast showed significant reductions in worm burden (27%) as well as hepatic and intestinal egg burdens (~28%) two weeks post treatment. Scanning EM of worms isolated from roflumilast-treated and untreated mice did not reveal noticeable changes to their tegument. S. mansoni-infected mice treated with a fixed dosage of roflumilast and a variable dosage of PZQ resulted in a higher reduction in worm burden, reduced hepatic egg counts, absence of immature eggs and a marked increase in dead eggs, compared to PZQ alone. However, the combination resulted in increased animal mortality, probably attributable to pharmacodynamic interactions between the two drugs. Although this study marks the first report of in vivo antischistosomal potential by a PDE inhibitor, an important proof of concept, we conclude that the antischistosomal effects of roflumilast are insufficient to warrant further development.


Assuntos
Aminopiridinas/farmacologia , Anti-Helmínticos/farmacologia , Benzamidas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/efeitos dos fármacos , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Oviposição/efeitos dos fármacos , Praziquantel/farmacologia , Schistosoma mansoni/enzimologia , Schistosoma mansoni/fisiologia , Schistosoma mansoni/ultraestrutura
2.
Acta Trop ; 201: 105159, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31491401

RESUMO

Currently, the control of schistosomiasis is based on a single drug, praziquantel, which is effective against all species of Schistosoma but only in the adult stage, presenting a schistosomicidal deficit at the other developmental stages of the parasites. Recently our research group has demonstrated that the potassium salt of usnic acid (PS-UA) presented schistosomicidal property against couples of adult worms of S. mansoni. Thus, the present study seeks to report for the first time the in vitro activity of PS-UA against different developmental stages of S. mansoni (schistosomules and young worms). As schistosomicide parameters, we evaluated motility, mortality, cell viability of the worms and tegument changes by scanning electron microscopy (SEM). After 3 h exposure, PS-UA was lethal to schistosomules at concentrations of 100 and 50 µM, whereas for concentrations 25 and 12.5 µM, 38 and 18% of mortality and 62 and 24% changes in motility, respectively, were reached. Yet for schistosomules, concentration of 25 µM caused 90 and 100% of death after 6 and 12 h, respectively. In the concentration of 12.5 µM at intervals of 12 and 24 h mortality was 68 and 100%, respectively. For young worms, after 3 h of exposure at concentrations of 200 and 100 µM caused 57 and 27% mortality, respectively. After 12 and 24 h, these concentrations caused mortality of 90 and 100% and 47 and 60% respectively. After 24 h, concentrations of 50 and 25 µM caused 80 and 30% change in motility, respectively. However, at the 12.5 µM concentration no change was observed. In addition, PS-UA reduced the cellular viability of young worms by 50.98% and 85.87% at concentrations of 100 and 200 µM, respectively. In both stages of worms and at different exposure intervals, PS-UA caused alterations such as: dorsoventral contraction, peeling, swelling, blisters, erosion, exposure of subtegumental tissue and disintegration of tegument. According to the results, changes in motility and mortality caused by PS-UA against schistosomules and young worms were concentration and time-dependents, also PS-UA even at low concentration, was able to cause profound ultrastructural changes in the integument of the worms. PS-UA is a promising candidate as prophylactic agent in the control of schistosomiasis mansoni.


Assuntos
Benzofuranos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Schistosoma mansoni/crescimento & desenvolvimento , Schistosoma mansoni/ultraestrutura
3.
Artigo em Inglês | MEDLINE | ID: mdl-31561039

RESUMO

Subversion of parasite neuromuscular function is a key strategy for anthelmintic drug development. Schistosome Ca2+ signaling has been an area of particular interest for decades, with a specific focus on L-type voltage-gated Ca2+ channels (Cavs). However, the study of these channels has been technically challenging. One barrier is the lack of pharmacological probes that are active on flatworms, since the dihydropyridine (DHP) based ligands typically used to study Cavs are relatively ineffective on schistosomes. Here, we have characterized the effect of a structurally distinct putative L-type Cav agonist, FPL-64176, on schistosomes cultured ex vivo and in an in vivo murine model of infection. Unlike DHPs, FPL-64176 evokes rapid and sustained contractile paralysis of adult Schistosoma mansoni reminiscent of the anthelmintic praziquantel. This is accompanied by tegument disruption and an arrest of mitotic activity in somatic stem cells and germ line tissues. Interestingly, this strong ex vivo phenotype was temperature dependent, with FPL-64176 treatment being less potent at 37 °C than 23 °C. However, FPL-64176 caused intra-tegument lesions at the basement membrane of worms cultured ex vivo under both conditions, as well as an in vivo hepatic shift of parasites from the mesenteric vasculature of infected mice to the liver. Gene expression profiling of worms harvested following in vivo FPL-64176 exposure reveals differences in transcripts associated with muscle and extracellular matrix function, as well as female reproduction, which is consistent with the worm phenotypes observed following ex vivo drug treatment. These data advance FPL-64176 as a useful tool to study schistosome Ca2+ signaling, and the benzoyl pyrrole core as a hit compound that may be optimized to develop new parasite-selective leads.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Pirróis/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Animais , Biotinilação , Agonistas dos Canais de Cálcio/química , Agonistas dos Canais de Cálcio/uso terapêutico , Feminino , Proteínas de Helminto/metabolismo , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Pirróis/química , Pirróis/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Schistosoma mansoni/citologia , Schistosoma mansoni/genética , Schistosoma mansoni/ultraestrutura , Esquistossomose mansoni/parasitologia
4.
Exp Parasitol ; 203: 30-35, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150655

RESUMO

Schistosoma mansoni adult worms are extensively challenged by reactive oxygen species from intrinsic sources. However, the effects of extrinsic sources such as ethanol have not been looked at in schistosomes. We examined adult worms recovered from ethanol-consuming mice by light (LM), confocal (CM) and scanning electron microscopy (SEM) to address this question. Schistosomiasis-infected mice were orally gavaged with 18% (v/v) ethanol from 35 to 63 days post-infection, when they were euthanized. CM examination revealed reduced germ cells density (-36%, p = 0.0001) and sperm density (-58%, p = 0.0001) in testicular lobes, and immature cells in seminal vesicle compared to unexposed control worms. Female worms showed reduced density of vitellin glands (-71%, p = 0.0001), maturation of oocytes (-7%, p = 0.0071) and reduced spermatozoa density (-23%, p = 0.0002) within the seminal receptacle. SEM revealed remarkable damages in male's tegument, including tubercles flattening, tegumental peeling and erosive lesions. Given that lipids are present in reproductive system and tegument, our results suggest that phenotypic changes are due to ethanol-induced lipid peroxidation. To the best of our knowledge, this is the first report revealing the biological action of ethanol intake on adult schistosomes in vivo.


Assuntos
Etanol/administração & dosagem , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/parasitologia , Administração Oral , Animais , Etanol/toxicidade , Feminino , Genitália/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Veias Mesentéricas/parasitologia , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Varredura , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Sistema Porta/parasitologia , Reprodução/efeitos dos fármacos , Schistosoma mansoni/fisiologia , Schistosoma mansoni/ultraestrutura
5.
Eur J Pharm Sci ; 133: 15-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30877068

RESUMO

Schistosomiasis is a major public health problem worldwide, especially in poor communities. Praziquantel is currently the only drug available to treat schistosomiasis and it shows low efficacy against schistosomula and juveniles stages of Schistosoma mansoni, allowing lower cure rate in areas with high endemicity. There is an urgent need to identify new antischistosomal drugs. Previous works identified phthalimido-thiazoles as privileged structures acting as schistossomicidal agent. In this way, a phthalimido-thiosemicarbazide intermediate and eight phthalimido-thiazoles derivatives were evaluated concerning the in vitro antischistosomal activity compounds in adult phase of Schistosoma mansoni and examined alterations on the tegumental surface. The results revealed that compounds 2f, 2 l and 2 m caused significant mortality in adult worms at concentrations range of 20 µg/mL to 100 µg/mL. These compounds were also selected in view to verify the activity against the schistosomula. Compound 2 m promoted 100% of mortality of larval forms until doses of 2.5 µg/mL within 48 h. In addition, when compound 2 m was administered orally at dose of 200 mg/kg for 5 consecutive days to the infected mouse with adult schistosomes, a reduction in the parasite burden was observed. Furthermore, scanning electron microscopy revealed that compound 2 m kill the parasite by tegumental damage and bubbles generation.


Assuntos
Ftalimidas/uso terapêutico , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/uso terapêutico , Tiazóis/uso terapêutico , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cercárias/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Carga Parasitária , Ftalimidas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Esquistossomose mansoni/parasitologia , Esquistossomicidas/farmacologia , Tiazóis/farmacologia
6.
Exp Parasitol ; 199: 1-8, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790572

RESUMO

Schistosomiasis remains a severe problem of public health in developing countries. The development of resistance to praziquantel (PZQ) has justified the search for new alternative chemotherapies with new formulations, more effective, and without adverse effects. Curcumin (CUR), the major phenolic compound present in rhizome of turmeric (Curcuma longa L.), has been traditionally used against various diseases including parasitic infections. Here, the antischistosomal activity of CUR (50-500 µM), evaluated in parallel against S. mansoni and S. haematobium adult worms, appeared significant (P < 0.05 to < 0.0001) in a time- and dose-dependent manner. Two h incubation with CUR (500 µM) caused 100% irreversible killing of both schistosomal species. CUR (250 µM) caused the death of S. haematobium and S. mansoni worms after 2 h and 4 h, respectively. As CUR concentration decreases (50 µM), all coupled adult worms were separated into individual male and female but the worms remained viable up to 4 h. Scanning and transmission electron microscopy revealed that S. haematobium are more sensitive than S. mansoni to CUR schistosomicidal effects. In support, CUR was found to affect the antigenicity of surface membrane molecules of S. haematobium, but not S. mansoni. Of importance, CUR significantly (P < 0.05 to < 0.0001) affected S. mansoni eggs hatchability and viability, a ground for its use in chemotherapy of schistosomiasis mansoni and japonicum because of its increased bioavailability in the gastrointestinal tract. The data together emphasize that CUR is a promising potential schistosomicidal drug.


Assuntos
Curcumina/farmacologia , Schistosoma haematobium/efeitos dos fármacos , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Antígenos de Helmintos/imunologia , Antígenos de Helmintos/isolamento & purificação , Antígenos de Superfície/imunologia , Antígenos de Superfície/isolamento & purificação , Cricetinae , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Intestino Delgado/parasitologia , Fígado/parasitologia , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Óvulo/efeitos dos fármacos , Óvulo/fisiologia , Schistosoma haematobium/imunologia , Schistosoma haematobium/fisiologia , Schistosoma haematobium/ultraestrutura , Schistosoma mansoni/imunologia , Schistosoma mansoni/fisiologia , Schistosoma mansoni/ultraestrutura , Fatores de Tempo
7.
Parasitol Res ; 118(2): 505-516, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30617587

RESUMO

Schistosomiasis is a tropical neglected disease whose socioeconomic impact is surpassed only by malaria. Until recently, praziquantel (PZQ) has been the only available drug, raising concerns that tolerant/resistant strains may appear. Since the discovery of the schistosomicidal potential of artemisinin (ART), new derivatives have been produced and evaluated. In this work, we evaluated the activity of ART derivatives against Schistosoma mansoni, both in vitro and in vivo. In the in vitro assay, worm survival, oviposition, and morphological alterations were evaluated. Further analysis of morphological alterations and membrane integrity was conducted using scanning electron microscopy and a cell-permeable, benzimidazole dye (Hoescht 33258) that binds to the minor groove of double stranded DNA. For the in vivo assay, artesunic acid (AcART) and dihydroartemisinin acetate (AcDQHS) were selected, since they showed the best in vitro results. Infected mice treated 21, 45, or 60 days post-infection (dpi), with a concentration of 100 mg/kg of either AcART or AcDQHS, showed a significant worm reduction (particularly in females), fewer eggs eliminated in feces, and a decrease of immature eggs in the intestinal tissues. Our results indicate that AcART and AcDQHS have some schistosomicidal activity against juvenile and adult stages of S. mansoni.


Assuntos
Artemisininas/farmacologia , Artemisininas/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Esquistossomicidas/uso terapêutico , Animais , Linhagem Celular , Fezes/parasitologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oviposição/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Esquistossomose mansoni/tratamento farmacológico
8.
Parasit Vectors ; 11(1): 580, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400935

RESUMO

BACKGROUND: Schistosomiasis is one of the most harmful parasitic diseases worldwide, praziquantel being the only drug in widespread use to treat it. We recently demonstrated that ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine (Fc-OXA, Rc-OXA and Bn-OXA) are promising antischistosomal drug candidates. METHODS: In this study we assessed the tegumental damage of these three derivatives of oxamniquine using scanning electron microscopy. Adult Schistosoma mansoni and S. haematobium were exposed to a concentration of 100 µM of each drug and incubated for 4-120 h, according to their onset of action and activity. RESULTS: While on S. mansoni the fastest acting compound was Fc-OXA, which revealed high activity after 4 h of incubation, on S. haematobium, Rc-OXA revealed the quickest onset, being lethal on all males within 24 h. In both species studied, the three derivatives showed the same patterns of tegumental damage consisting of blebs, sloughing and tegument rupturing all over the body. Additionally, on S. mansoni distinct patterns of tegumental damage were observed for each of the compounds: tissue ruptures in the gynaecophoric canal for Fc-OXA, loss of spines for Rc-OXA and oral sucker rupture for Bn-OXA. CONCLUSIONS: Our study confirmed that Fc-OXA, Rc-OXA and Bn-OXA are promising broad spectrum antischistosomal drug candidates. All derivatives show fast in vitro activity against S. mansoni and S. haematobium while validating the previous finding that the parent drug oxamniquine is less active in vitro under the conditions described. This work sets the base for further studies on the identification of a lead oxamniquine derivative, with the aim of identifying a molecule with the potential to become a new drug for human use.


Assuntos
Compostos Organometálicos/farmacologia , Oxamniquine/farmacologia , Schistosoma haematobium/anatomia & histologia , Schistosoma haematobium/efeitos dos fármacos , Schistosoma mansoni/anatomia & histologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Feminino , Concentração Inibidora 50 , Camundongos , Microscopia Eletrônica de Varredura , Compostos Organometálicos/química , Oxamniquine/química , Schistosoma mansoni/ultraestrutura , Esquistossomose/parasitologia , Esquistossomicidas/farmacologia
9.
PLoS Negl Trop Dis ; 12(10): e0006873, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30365505

RESUMO

BACKGROUND: The possibility of emergence of praziquantel-resistant Schistosoma parasites and the lack of other effective drugs demand the discovery of new schistosomicidal agents. In this context the study of compounds that target histone-modifying enzymes is extremely promising. Our aim was to investigate the effect of inhibition of EZH2, a histone methyltransferase that is involved in chromatin remodeling processes and gene expression control; we tested different developmental forms of Schistosoma mansoni using GKS343, a selective inhibitor of EZH2 in human cells. METHODOLOGY/PRINCIPAL FINDINGS: Adult male and female worms and schistosomula were treated with different concentrations of GSK343 for up to two days in vitro. Western blotting showed a decrease in the H3K27me3 histone mark in all three developmental forms. Motility, mortality, pairing and egg laying were employed as schistosomicidal parameters for adult worms. Schistosomula viability was evaluated with propidium iodide staining and ATP quantification. Adult worms showed decreased motility when exposed to GSK343. Also, an approximate 40% reduction of egg laying by GSK343-treated females was observed when compared with controls (0.1% DMSO). Scanning electron microscopy showed the formation of bulges and bubbles throughout the dorsal region of GSK343-treated adult worms. In schistosomula the body was extremely contracted with the presence of numerous folds, and growth was markedly slowed. RNA-seq was applied to identify the metabolic pathways affected by GSK343 sublethal doses. GSK343-treated adult worms showed significantly altered expression of genes related to transmembrane transport, cellular homeostasis and egg development. In females, genes related to DNA replication and noncoding RNA metabolism processes were downregulated. Schistosomula showed altered expression of genes related to cell adhesion and membrane synthesis pathways. CONCLUSIONS/SIGNIFICANCE: The results indicated that GSK343 presents in vitro activities against S. mansoni, and the characterization of EZH2 as a new potential molecular target establishes EZH2 inhibitors as part of a promising new group of compounds that could be used for the development of schistosomicidal agents.


Assuntos
Replicação do DNA/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Oviposição/efeitos dos fármacos , Piridonas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/fisiologia , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Microscopia Eletrônica de Varredura , RNA não Traduzido/metabolismo , Schistosoma mansoni/enzimologia , Schistosoma mansoni/ultraestrutura , Análise de Sobrevida
10.
Int J Nanomedicine ; 13: 4493-4505, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30122922

RESUMO

Purpose: Lipid nanocapsules (LNCs) have shown potential to increase the bioavailability and efficacy of orally administered drugs. However, their intestinal translocation to distal target sites and their implication in pharmacokinetic (PK)-pharmacodynamic (PD) relationships are yet to be elucidated. In this study, the effect of LNCs on the PD activity and pharmacokinetics of praziquantel (PZQ), the mainstay of schistosomiasis chemotherapy, was investigated. Materials and methods: The composition of LNCs was modified to increase PZQ payload and to enhance membrane permeability. PZQ-LNCs were characterized in vitro for colloidal properties, entrapment efficiency (EE%), and drug release. PD activity of the test formulations was assessed in Schistosoma mansoni-infected mice 7 days post-oral administration of a single 250 mg/kg oral dose. Pharmacokinetics of the test formulations and their stability in simulated gastrointestinal (GI) fluids were investigated to substantiate in vivo data. Results: PZQ-LNCs exhibited good pharmaceutical attributes in terms of size (46-62 nm), polydispersity index (0.01-0.08), EE% (>95%), and sustained release profiles. Results indicated significant efficacy enhancement by reduction in worm burden, amelioration of liver pathology, and extensive damage to the fluke suckers and tegument. This was partly explained by PK data determined in rats. In addition, oral targeting of the worms was supported by the stability of PZQ-LNCs in simulated GI fluids and scanning electron microscopy (SEM) visualization of nanostructures on the tegument of worms recovered from mesenteric/hepatic veins. Cytotoxicity data indicated tolerability of PZQ-LNCs. Conclusion: Data obtained provide evidence for the ability of oral LNCs to target distal post-absorption sites, leading to enhanced drug efficacy. From a practical standpoint, PZQ-LNCs could be suggested as a potential tolerable single lower dose oral nanomedicine for more effective PZQ mass chemotherapy.


Assuntos
Lipídeos/química , Nanocápsulas/uso terapêutico , Praziquantel/administração & dosagem , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/parasitologia , Masculino , Camundongos , Praziquantel/farmacocinética , Praziquantel/uso terapêutico , Ratos Wistar , Schistosoma mansoni/ultraestrutura , Esquistossomose mansoni/sangue , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/patologia
11.
Parasitol Res ; 117(7): 2105-2115, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29736731

RESUMO

Phthalimide, 1,3-thiazole, and thiazolidinone cores are considered privileged scaffolds and represent an attractive starting point to design new bioactive compounds for neglected tropical disease (NTD). Schistosomiasis is a NTD, caused by Schistosoma worms which praziquantel (PZQ) is the only drug used to treat humans, but the decrease in the effect after treatment has been reported. Recently, some phthalimide-thiazole derivatives exhibited in vitro antischistosomal activity against adult worms with significant ultrastructural changes and a lower cytotoxic effect on splenocytes. This new biological phthalimido-thiazole profile has motivated us to evaluate a new generation of such molecules in immature and adult worms. Thus, a phthalimido-thiazolidinone derivative, (3c), and three phthalimido-thiazoles (6c, 7a, and 7h) were evaluated concerning their in vitro activity on schistosomulae and adult worms. The results showed that these compounds brought a significant reduction on the mortality, inhibited oviposition, and then induced mortality in immature and adult worms alike. According to scanning electron microscopy, the tegument was the principal target for 7a and 7h and revealed gradual damage to the tegument surface, inducing destruction and decomposition of the tegument in the same areas and exposition of subtegumental tissue and of muscle tissue. Furthermore, they caused less toxicity in splenocytes than PZQ. Compounds 7a and 7h revealed to possess promising activity against larval forms. According to the present study, the privileged structure phthalimido-thiazoles act as a molecular framework that has antischistosomal activity and most form the basis to the next pre-clinical tests. Graphical abstract.


Assuntos
Ftalimidas , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Tiazóis , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Técnicas In Vitro , Microscopia Eletrônica de Varredura , Ftalimidas/química , Ftalimidas/farmacologia , Ftalimidas/uso terapêutico , Schistosoma mansoni/ultraestrutura , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêutico
12.
Chem Biol Interact ; 283: 20-29, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29366735

RESUMO

Schistosomiasis is considered a serious public health problem in 78 countries and territories located in Africa, Asia and America and it is estimated in more than 249 million people infected by any of the species of Schistosoma. The exclusive use of praziquantel (PZQ), effective drug against all species of Schistosoma, has been the basis of the development of a possible resistance against the strains of this parasite. In addition, PZQ is not effective against young forms of worms. Thus, there is a need for the development of new drugs with schistosomicidal activity. The objective of this work was to synthesize and to evaluate the therapeutic potential of new benzodioxole derivatives (3-14) candidates for schistosomicidal drugs. All compounds synthesized showed in vitro schistosomicidal activity. The derivative 12 was considered the best compound, since it took 100% of worms to mortality in the first 72 h of exposure at the concentration of 100 µM and 83.3% at the concentration of 50 µM. Furthermore, male and female adult worms, incubated for 24 h with the compound 12 showed tegument damages characterized by extensive desquamation and edema, tuber destruction, bubble formation and exposure of the muscle layer. This compound has a restricted structure, where the thiazolidinone is attached to the 4-position of the 1,3-benzodioxol ring. The structural conformation of derivative 12 was probably responsible for the promising schistosomicidal activity, where the presence of an electron/conformational restriction of the thiazolidine ring, as well as the action of bromine as a bulk substitute, favored an increase in biological activity. In addition, tegumentary changes caused by derivative 12 may also have been responsible for the death of adult worms of Schistosoma mansoni. Therefore, we verified that the results obtained in this study make benzodioxole derivatives possible candidates for prototypes of new schistosomicidal drugs.


Assuntos
Dioxóis/química , Dioxóis/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/síntese química , Esquistossomicidas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Dioxóis/uso terapêutico , Células HeLa , Humanos , Microscopia Eletrônica de Varredura , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Schistosoma mansoni/ultraestrutura , Esquistossomose/tratamento farmacológico , Esquistossomose/patologia , Esquistossomicidas/uso terapêutico
13.
PLoS One ; 12(9): e0184192, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898250

RESUMO

Proteasome is a proteolytic complex responsible for intracellular protein turnover in eukaryotes, archaea and in some actinobacteria species. Previous work has demonstrated that in Schistosoma mansoni parasites, the proteasome inhibitor MG-132 affects parasite development. However, the molecular targets affected by MG-132 in S. mansoni are not entirely known. Here, we used expression microarrays to measure the genome-wide changes in gene expression of S. mansoni adult worms exposed in vitro to MG-132, followed by in silico functional analyses of the affected genes using Ingenuity Pathway Analysis (IPA). Scanning electron microscopy was used to document changes in the parasites' tegument. We identified 1,919 genes with a statistically significant (q-value ≤ 0.025) differential expression in parasites treated for 24 h with MG-132, when compared with control. Of these, a total of 1,130 genes were up-regulated and 790 genes were down-regulated. A functional gene interaction network comprised of MG-132 and its target genes, known from the literature to be affected by the compound in humans, was identified here as affected by MG-132. While MG-132 activated the expression of the 26S proteasome genes, it also decreased the expression of 19S chaperones assembly, 20S proteasome maturation, ubiquitin-like NEDD8 and its partner cullin-3 ubiquitin ligase genes. Interestingly, genes that encode proteins related to potassium ion binding, integral membrane component, ATPase and potassium channel activities were significantly down-regulated, whereas genes encoding proteins related to actin binding and microtubule motor activity were significantly up-regulated. MG-132 caused important changes in the worm tegument; peeling, outbreaks and swelling in the tegument tubercles could be observed, which is consistent with interference on the ionic homeostasis in S. mansoni. Finally, we showed the down-regulation of Bax pro-apoptotic gene, as well as up-regulation of two apoptosis inhibitor genes, IAP1 and BRE1, and in contrast, down-regulation of Apaf-1 apoptotic activator, thus suggesting that apoptosis is deregulated in S. mansoni exposed to MG-132. A considerable insight has been gained concerning the potential of MG-132 as a gene expression modulator, and overall the data suggest that the proteasome might be an important molecular target for the design of new drugs against schistosomiasis.


Assuntos
Leupeptinas/farmacologia , Inibidores de Proteassoma/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Reprodutibilidade dos Testes , Schistosoma mansoni/genética , Schistosoma mansoni/ultraestrutura , Transcriptoma
14.
PLoS Negl Trop Dis ; 11(7): e0005789, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28753630

RESUMO

BACKGROUND: Schistosomiasis has been reported in 78 endemic countries and affects 240 million people worldwide. The digenetic parasite Schistosoma mansoni needs fresh water to compete its life cycle. There, it is susceptible to soluble compounds that can affect directly and/or indirectly the parasite's biology. The cercariae stage is one of the key points in which the parasite is vulnerable to different soluble compounds that can significantly alter the parasite's life cycle. Molluscicides are recommended by the World Health Organization for the control of schistosomiasis transmission and Euphorbia milii latex is effective against snails intermediate hosts. METHODOLOGY/PRINCIPAL FINDINGS: We used parasitological tools and electron microscopy to verify the effects of cercariae exposure to natural molluscicide (Euphorbia milii latex) on morphology, physiology and fitness of adult parasite worms. In order to generate insights into key metabolic pathways that lead to the observed phenotypes we used comparative transcriptomics and proteomics. CONCLUSIONS/SIGNIFICANCE: We describe here that the effect of latex on the adult is not due to direct toxicity but it triggers an early change in developmental trajectory and perturbs cell memory, mobility, energy metabolism and other key pathways. We conclude that latex has not only an effect on the vector but applies also long lasting schistosomastatic action. We believe that these results are of interest not only to parasitologists since it shows that natural compounds, presumably without side effects, can have an impact that occurred unexpectedly on developmental processes. Such collateral damage is in this case positive, since it impacts the true target of the treatment campaign. This type of treatment could also provide a rational for the control of other pests. Our results will contribute to enforce the use of E. milii latex in Brazil and other endemic countries as cheap alternative or complement to mass drug treatment with Praziquantel, the only available drug to cure the patients (without preventing re-infection).


Assuntos
Cercárias/crescimento & desenvolvimento , Látex/administração & dosagem , Moluscocidas/administração & dosagem , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Animais , Biomphalaria/parasitologia , Brasil , Cercárias/efeitos dos fármacos , Feminino , Modelos Lineares , Fígado/patologia , Masculino , Camundongos , Microscopia Eletrônica , Carga Parasitária , Extratos Vegetais/administração & dosagem , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/prevenção & controle , Análise de Sequência de RNA
15.
Toxicol In Vitro ; 44: 273-279, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28755871

RESUMO

Oxazine derivatives, a class of heterocyclic compounds, exhibit a variety of biological properties, such as anticonvulsant and antitumor activities. In this study, we evaluated the effect of two cyclohexene-fused 1,3-oxazines (cis­1-benzyl-N-phenyl-1,4,4a,5,8,8a-hexahydro-3,1-benzoxazin-2-imine (1) and trans­N-phenyl-1,4,4a,5,8,8a-hexahydro-3,1-benzoxazin-2-imine (2)) in cultures of Bacillus cereus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Serratia marcescens, Shigella flexneri and Staphylococcus aureus by the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC). Additionally, the ex vivo antiparasitic activity of oxazines was assessed against Schistosoma mansoni, a helminth that is one of the major agents of the disease schistosomiasis Also, oxazines were evaluated on three tumor cell lines, NCI-H292 (human lung carcinoma), MCF-7 (human breast adenocarcinoma) and HEp-2 (human cervix carcinoma), and two normal cell lines (Vero and red blood cells). Bioassays revealed that oxazine 2 is more effective against bacteria than oxazine 1, with the lowest MIC and MBC values of 3.91 and 32.5µg/mL, respectively. Similarly, compound 2 demonstrated higher antiparasitic activity than 1, and scanning electron microscopy analysis showed several morphological alterations in the tegument of worms in a concentration-dependent manner. In contrast, both oxazines exhibited low cytotoxic effects on cancer and normal cell lines. These results indicated that oxazines exerted direct effects on bacteria and parasite schistosomes. More importantly, since schistosomiasis control programs rely on one drug, praziquantel, oxazines may have the potential to become new antischistosomal agents.


Assuntos
Antibacterianos/farmacologia , Cicloexenos/farmacologia , Oxazinas/farmacologia , Esquistossomicidas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Ovinos
16.
Int J Antimicrob Agents ; 50(3): 467-472, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28666754

RESUMO

Schistosomiasis is a major public health problem worldwide, especially in poor communities. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new antischistosomal drugs. Nerolidol is a sesquiterpene present as an essential oil in several plants that has been approved by the FDA. This study evaluated the in vivo antischistosomal activity of nerolidol in a mouse model of schistosomiasis infected with either adult or juvenile stages of Schistosoma mansoni. A single dose of nerolidol (100, 200 or 400 mg/kg) administered orally to mice infected with adult schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest nerolidol dose (400 mg/kg) caused significant reduction in a total worm burden of 70.06% (P < 0.001). Additionally, the technique of quantitative and qualitative oograms showed that a single 400 mg/kg nerolidol dose achieved an immature egg reduction of 84.6% (P < 0.001). In faecal samples, the Kato-Katz method also revealed a reduction of 75.2% in eggs/g at a dose of 400 mg/kg (P < 0.001). Furthermore, scanning electron microscopy revealed that nerolidol-mediated worm killing was associated with tegumental damage. In contrast to activity against adult S. mansoni infection, oral treatment with nerolidol 400 mg/kg had low efficacy in mice harbouring juvenile schistosomes. Since nerolidol is already in use globally as a food additive and has a proven safety record, evaluation of this natural compound's potential for treatment of schistosomiasis could be entirely cost effective in the near future.


Assuntos
Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacologia , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fezes/parasitologia , Feminino , Masculino , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Contagem de Ovos de Parasitas , Carga Parasitária , Schistosoma mansoni/ultraestrutura , Resultado do Tratamento
17.
Rev Inst Med Trop Sao Paulo ; 59: e8, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28380119

RESUMO

Introduction:: Schistosomiasis is an infectious parasitic disease caused by trematodes of the genus Schistosoma, which threatens at least 258 million people worldwide and its control is dependent on a single drug, praziquantel. The aim of this study was to evaluate the anti-Schistosoma mansoni activity in vitro of novel imidazolidine derivatives. Material and methods: : We synthesized two novel imidazolidine derivatives: (LPSF/PTS10) (Z)-1-(2-chloro-6-fluorobenzyl)-4-(4-dimethylaminobenzylidene)-5-thioxoimidazolidin-2-one and (LPSF/PTS23) (Z)-1-(2-chloro-6-fluoro-benzyl)-5-thioxo-4-(2,4,6-trimethoxy-benzylidene)-imidazolidin-2-one. The structures of two compounds were determined by spectroscopic methods. During the biological assays, parameters such as motility, oviposition, mortality and analysis by Scanning Electron Microscopy were performed. Results: : LPSF/PTS10 and LPSF/PTS23 were considered to be active in the separation of coupled pairs, mortality and to decrease the motor activity. In addition, LPSF/PTS23 induced ultrastructural alterations in worms, after 24 h of contact, causing extensive erosion over the entire body of the worms. Conclusion: : The imidazolidine derivatives containing the trimetoxy and benzylidene halogens showed promising in vitro schistosomicidal activity.


Assuntos
Imidazolidinas/farmacologia , Células-Tronco de Sangue Periférico/efeitos dos fármacos , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Humanos , Imidazolidinas/síntese química , Imidazolidinas/toxicidade , Camundongos , Microscopia Eletrônica de Varredura , Testes de Sensibilidade Parasitária , Schistosoma mansoni/ultraestrutura , Esquistossomicidas/síntese química , Esquistossomicidas/toxicidade , Fatores de Tempo
18.
Mem. Inst. Oswaldo Cruz ; 112(4): 247-254, Apr. 2017. graf
Artigo em Inglês | LILACS | ID: biblio-841783

RESUMO

BACKGROUND Praziquantel has been cited as the only drug for treating schistosomiasis. However, concerns over drug resistance have encouraged the search for novel drug leads. The antimalarial drug primaquine possesses interesting anti-schistosmal properties. OBJECTIVES This study is the first to document the potential role of primaquine as a schistosomicide and the ultrastructural changes induced by primaquine on juvenile or adult male worms of Schistosoma mansoni. METHODS Ultrastructural alterations in the tegumental surface of 21-day-old juvenile and adult male worms of S. mansoni were demonstrated following primaquine treatment at different concentrations (2, 5, 10, 15, and 20 µg/mL) and incubation periods (1, 3, 6, 24, and 48 h) in vitro, using both scanning and transmission electron microscopy. FINDINGS At low concentrations (2, 5, and 10 µg/mL) both juvenile and adult male worms were alive after 24 h of incubation, whereas contraction, paralysis, and death of all worms were observed after 24 h of drug exposure at 20 µg/mL. The tegument of juvenile and adult male worms treated with primaquine exhibited erosion, peeling, and sloughing. Furthermore, extensive damage of both tegumental and subtegumental layers included embedded spines, and shrinkage of muscles with vacuoles. The in vitro results confirmed that primaquine has dose-dependent effects with 20 µg/mL as the most effective concentration in a short incubation period. MAIN CONCLUSIONS The schistosomicidal activity of primaquine indicates that this drug possesses moderate in vitro activity against juvenile and adult male worms, since it caused high mortality and tegumental alterations. This study confirmed that the antimalarial drug primaquine possesses anti-schistosomal activity. Further investigation is needed to elucidate its mechanism of action.


Assuntos
Animais , Masculino , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Anti-Helmínticos/farmacologia , Fatores de Tempo , Microscopia Eletrônica de Varredura , Cricetinae , Relação Dose-Resposta a Droga
19.
Mem Inst Oswaldo Cruz ; 112(4): 247-254, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28327785

RESUMO

BACKGROUND: Praziquantel has been cited as the only drug for treating schistosomiasis. However, concerns over drug resistance have encouraged the search for novel drug leads. The antimalarial drug primaquine possesses interesting anti-schistosmal properties. OBJECTIVES: This study is the first to document the potential role of primaquine as a schistosomicide and the ultrastructural changes induced by primaquine on juvenile or adult male worms of Schistosoma mansoni. METHODS: Ultrastructural alterations in the tegumental surface of 21-day-old juvenile and adult male worms of S. mansoni were demonstrated following primaquine treatment at different concentrations (2, 5, 10, 15, and 20 µg/mL) and incubation periods (1, 3, 6, 24, and 48 h) in vitro, using both scanning and transmission electron microscopy. FINDINGS: At low concentrations (2, 5, and 10 µg/mL) both juvenile and adult male worms were alive after 24 h of incubation, whereas contraction, paralysis, and death of all worms were observed after 24 h of drug exposure at 20 µg/mL. The tegument of juvenile and adult male worms treated with primaquine exhibited erosion, peeling, and sloughing. Furthermore, extensive damage of both tegumental and subtegumental layers included embedded spines, and shrinkage of muscles with vacuoles. The in vitro results confirmed that primaquine has dose-dependent effects with 20 µg/mL as the most effective concentration in a short incubation period. MAIN CONCLUSIONS: The schistosomicidal activity of primaquine indicates that this drug possesses moderate in vitro activity against juvenile and adult male worms, since it caused high mortality and tegumental alterations. This study confirmed that the antimalarial drug primaquine possesses anti-schistosomal activity. Further investigation is needed to elucidate its mechanism of action.


Assuntos
Anti-Helmínticos/farmacologia , Praziquantel/farmacologia , Primaquina/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Animais , Cricetinae , Relação Dose-Resposta a Droga , Masculino , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Fatores de Tempo
20.
Rev Soc Bras Med Trop ; 50(1): 86-91, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28327807

RESUMO

INTRODUCTION:: Schistosomiasis, a parasitic disease caused by trematode flatworms of the genus Schistosoma, affects more than 200 million people worldwide, and its control is dependent on a single drug, praziquantel. Here, we report the in vitro effect of rotundifolone, a monoterpene isolated from Mentha x villosa (Lamiaceae), on Schistosoma mansoni adult worms. METHODS:: The in vitro effect of rotundifolone on adult Schistosoma mansoni was evaluated by analysis of behavior and mortality and through a scanning electron microscopic analysis of ultrastructural changes in the tegument of the worms. RESULTS:: At concentrations of 3.54 and 7.09µg/mL-1 rotundifolone, no worm mortality was observed at any of the sampling intervals. A minor reduction in movement of the tail, suckers, and gynecophoral canal membrane was observed after 96 h of exposure to 7.09µg/mL-1 rotundifolone. At 70.96µg/mL-1, a lack of movement was observed from 72h onwards and all worms were deemed dead; similar effects were observed at 48h with 177.4µg/mL-1, and at 24h with 354.8µg/mL-1 and 700.96µg/mL-1. Rotundifolone also caused death of all parasites and separation of coupled pairs into individual males and females after 24h at 354.8µg/mL-1. CONCLUSIONS:: The main changes in the tegument induced by the different ROT treatments were: after 24h incubation, bubble lesions spread over the entire body and loss of tubercles occurred in some regions of the ventral region.


Assuntos
Mentha/química , Monoterpenos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Feminino , Masculino , Microscopia Eletrônica de Varredura , Monoterpenos/isolamento & purificação , Testes de Sensibilidade Parasitária , Schistosoma mansoni/ultraestrutura
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