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1.
Toxicol In Vitro ; : 105158, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33823240

RESUMO

BACKGROUND: Leishmaniasis is a parasitosis with a wide incidence in developing countries. The drugs which are indicated for the treatment of this infection usually are able to promote high toxicity. PURPOSE: A combination of limonene and carvacrol, monoterpenes present in plants with antiparasitic activity may constitute an alternative for the treatment of these diseases. METHODS: In this study, the antileishmania activity against Leishmania major, cytotoxicity tests, assessment of synergism, parasite membrane damage tests as well as molecular docking and immunomodulatory activity of limonene-carvacrol (Lim-Car) combination were evaluated. RESULTS: The Lim-Car combination (5:0; 1:1; 1:4; 2:3; 3:2; 4:1 and 0:5) showed potential antileishmania activity, with mean inhibitory concentration (IC50) ranging from 5.8 to 19.0 µg.mL-1. They demonstrated mean cytotoxic concentration (CC50) ranging from 94.1 to 176.0 µg.mL-1, and did not show significant hemolytic effect. In the investigation of synergistic interaction, the 4:1 Lim-Car combination showed better fractional inhibitory concentration (FIC) index as well as better activity on amastigotes and IS. The samples caused considerable damage to the parasite membrane this monoterpene activity seems to be more related to Trypanothione Reductase (TryR) enzyme interaction, demonstrated in the molecular docking assay. In addition, the 4:1 Lim-Car combination stimulated macrophage activation, and showed at was the best association, with reduction of infection and infectivity of parasitized macrophages. CONCLUSION: The 4:1 Lim-Car combination appears to be a promising candidate as a monotherapeutic antileishmania agent.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33660490

RESUMO

Species of Piperaceae are known by biological properties, including antiparasitic such as leishmanicidal, antimalarial and in the treatment of schistosomiasis. The aim of this work was to evaluate the antileishmania activity, cytotoxic effect, and macrophage activation patterns of the methanol (MeOH), hexane (HEX), dichloromethane (DCM) and ethyl acetate (EtOAc) extract fractions from the leaves of Piper cabralanum C.DC. The MeOH, HEX and DCM fractions inhibited Leishmanina amazonensis promastigote-like forms growth with a half maximal inhibitory concentration (IC50) of 144.54, 59.92, and 64.87 µg/mL, respectively. The EtOAc fraction did not show any relevant activity. The half maximal cytotoxic concentration (CC50) for macrophages were determined as 370.70, 83.99, 113.68 and 607 µg/mL for the MeOH, HEX and DCM fractions, respectively. The macrophage infectivity was concentration-dependent, especially for HEX and DCM. MeOH, HEX and DCM fractions showed activity against L. amazonensis with low cytotoxicity to murine macrophages and lowering infectivity by the parasite. Our results provide support for in vivo studies related to a potential application of P. cabralanum extract and fractions as a promising natural resource in the treatment of leishmaniasis.

3.
Antimicrob Agents Chemother ; 64(12)2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-32928735

RESUMO

In this study, we demonstrated the potential associative effect of combining conventional amphotericin B (Amph B) with gallic acid (GA) and with ellagic acid (EA) in topical formulations for the treatment of cutaneous leishmaniasis in BALB/c mice. Preliminary stability tests of the formulations and in vitro drug release studies with Amph B, GA, Amph B plus GA, EA, and Amph B plus EA were carried out, as well as assessment of the in vivo treatment of BALB/c mice infected with Leishmania major After 40 days of infection, the animals were divided into 6 groups and treated twice a day for 21 days with a gel containing Amph B, GA, Amph B plus GA, EA, or Amph B plus EA, and the negative-control group was treated with the vehicle. In the animals that received treatment, there was reduction of the lesion size and reduction of the parasitic load. Histopathological analysis of the treatments with GA, EA, and combinations with Amph B showed circumscribed lesions with the presence of fibroblasts, granulation tissue, and collagen deposition, as well as the presence of activated macrophages. The formulations containing GA and EA activated macrophages in all evaluated parameters, resulting in the activation of cells of the innate immune response, which can generate healing and protection. GA and EA produced an associative effect with Amph B, which makes them promising for use with conventional Amph B in the treatment of cutaneous leishmaniasis.

4.
Life Sci ; 256: 117915, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504752

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico
5.
Artigo em Inglês | MEDLINE | ID: mdl-32442090

RESUMO

BACKGROUND: Pharmaceutical nanotechnology represents an efficient alternative for the delivery of pharmacologically active plantderived compounds, considering their protective capacity, oral bioavailability and drug vectorization capacity. In this context, butters obtained from plant seeds have emerged as promising products for development of pharmacologically active nanostructures. They possess a complex lipid composition, allowing the formation of different emulsion systems with solid cores, since this mixture of the different triglycerides is solid at room temperature and body temperature. Therefore, the systematic mapping around the technological development of nanostructures produced from plant-derived butters is potentially valuable for researchers interested in novel alternative formulations for pharmacological therapy, with potential industrial, economic, health and societal impacts. METHODS: Systematic review was carried out by the search of scientific papers and patents deposited in official databases concerning the development of nanostructured pharmaceutical products using plant-derived butters as starting material. The publications obtained were subjected to sorting and analysis by applying the following inclusion/exclusion criteria. RESULTS: The Solid Lipid Nanoparticle (SLN) was the type of nanostructure produced in all the analyzed scientific papers, due to the physicochemical characteristics of the lipid constituents of plant-derived butters. In this sense, 54% of the articles have reported the use of Cocoa Butter for the production of nanostructures; 28% for Shea Butter; 6% for Cupuacu Butter, 6% for Murumuru Butter and 6% for Bacuri Butter. In the technological prospection, only two patents exhibited SLN as an invention based on cocoa butter and on shea butter, respectively. The production methods employed have included: phase inversion temperature, microemulsion, hot high pressure homogenization, high shear homogenization and ultrasonication. CONCLUSION: In light of this prospective review, the encouragement of novel studies in lipids-based nanotechnology is evident, considering the small number of findings so far, in order to stimulate new research involving plant-derived butters from easily cultivated fruits in tropical regions, then stimulating the pharmaceutical development of new therapeutic alternatives using biocompatible and sustainable raw materials.

6.
Toxicol In Vitro ; 63: 104750, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31862617

RESUMO

The present study was directed to the in vitro antileishmanial, cytotoxic and immunomodulatory effects of Garcinielliptone FC (GFC) against promastigote and macrophage-internalized amastigote forms of Leishmania amazonensis. GFC showed in vitro cytotoxicity against BALB/c peritoneal macrophages with CC50 of 74.90 µM. The hemolytic activity against sheep erythrocytes only demonstrated a decrease of 20.42% in cell viability at the highest tested concentration tested (1326.0 µM). GFC promoted in vitro growth inhibition of both promastigote and intracellular amastigotes with IC50 values of 14.06 and 1.91 µM, respectively, with 7.3-fold higher Selectivity Index (SI) for intracellular amastigotes (SI = 39.21) than for promastigotes (SI = 5.33). Interestingly, the pre-treatment of macrophages or promastigotes with GFC promoted decrease of infected macrophages and number of recovered amastigotes, respectively. Also, GFC was able to markedly promote macrophages activation by increase of phagocytic capability and nitrite production at concentrations able to solve infection of macrophages by L. amazonensis, suggesting the possible involvement of immunomodulatory modulation of macrophages leading to solve the infection. GFC is an emerging and promising chemical compound for the studies focused on the assessment of its therapeutic potential on in vivo experimental models of leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Fatores Imunológicos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Leishmania , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Nitritos/metabolismo , Fagocitose/efeitos dos fármacos , Ovinos
7.
Int J Biol Macromol ; 135: 808-814, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158421

RESUMO

In synthesis of silver nanoparticles (AgNPs), the composition of the stabilizer used can be closely related to the effectiveness of the synthesis and to the shape of the final nanoparticles. Recently, the use of collagen as an effective nanoparticle stabilization agent was reported. In this work, synthesis of silver nanoparticles using mixed capping agents is reported. The capping agents used were cashew gum-hydrolyzed collagen; kappa carrageenan-hydrolyzed collagen, and agar-hydrolyzed collagen. We evaluated antibacterial action against Gram-positive and Gram-negative bacteria, as well as antifungal activity and cytotoxicity. Homogenized mixtures of collagen and aqueous cashew gum, carrageenan or agar respectively were used to produce the nanoparticles AgNPcolCashew, AgNPcolCarr and AgNPcolAgar. AgNP characterization was performed using Uv-vis, XRD, TEM and DLS and the biological activities were assayed using MIC and MBC analyses for both antibacterial and antifungal application. Results showed that the AgNPcollcar sample showed the strongest bacterial inhibition with MIC values of 62.5 and 31.25 µM/mL Ag against E. coli and P. aeruginosa respectively. Interestingly, AgNPcollAgar also presented the lowest cytotoxicity when compared with other AgNPs and AgNO3.


Assuntos
Colágeno/química , Nanopartículas Metálicas/química , Polímeros/química , Prata/química , Prata/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Candida albicans/efeitos dos fármacos , Técnicas de Química Sintética , Escherichia coli/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Hidrólise , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Nanotecnologia , Pseudomonas aeruginosa/efeitos dos fármacos , Ovinos , Prata/toxicidade
8.
Nutrients ; 11(2)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781884

RESUMO

This work assessed the effects of a 28-day treatment with lycopene-rich extract (LRE) from red guava fruit (Psidium guajava L.) on the lipid profile and oxidative stress in an experimental model of dyslipidemia. Male hamsters (116.5 ± 2.16 g) were fed with the AIN 93G diet containing casein (20%), coconut fat (13.5%) and cholesterol (0.1%). The animals were divided into four groups: normolipidemic control (standard feed; NC, n = 7); hypercholesterolemic control (HC, n = 7); LRE 25 mg/kg/day (LRE-25, n = 7) and LRE 50 mg/kg/day (LRE-50, n = 9). After treatment, plasma concentrations of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-c), high-density lipoprotein (HDL) cholesterol (HDL-c), malondialdehyde (MDA-p) and myeloperoxidase (MPO), as well as erythrocytic superoxide dismutase (SOD-e) and the atherogenic index, were determined. Malondialdehyde (MDA-h), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD-h) levels were assessed. Feed intake (FI) and weight gain (WG) were also determined. The LRE-25 group presented significantly lower TG levels and atherogenic index than did the HC group (p < 0.05). Both LRE-25 and LRE-50 groups presented lower levels of MDA-p and MPO than did the HC group (p < 0.05). LRE demonstrated a promising effect against dyslipidemia and oxidative stress.


Assuntos
Dislipidemias/induzido quimicamente , Licopeno/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Psidium , Triglicerídeos/sangue , Animais , Biomarcadores/sangue , Cricetinae , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Dislipidemias/tratamento farmacológico , Masculino , Extratos Vegetais/química
9.
Br J Pharmacol ; 176(3): 386-399, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30403290

RESUMO

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner and has been reported to induce vasodilatation. Here, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms. EXPERIMENTAL APPROACH: Rat mesenteric arteries (diameter ≈ 200-400 µm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations. KEY RESULTS: In rat mesenteric arteries and human s.c. arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39), in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose. CONCLUSIONS AND IMPLICATIONS: GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/farmacologia , Liraglutida/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Superóxidos/análise , Superóxidos/metabolismo
10.
Braz. J. Pharm. Sci. (Online) ; 54(2): e17226, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-951940

RESUMO

ABSTRACT Lippia origanoides is a honey shrub which has showed hypotensive potential assessed by in vivo studies. The aim of this work is the development of a pharmaceutical formulation composed by an optimized extract obtained from aerial parts of L. origanoides. The quantification of the naringenin marker in the dry extract and tablets developed was performed, as well as the assessment of the oral acute toxicity in rats. The hydroalcoholic extract of L. origanoides was spray-dried with the addition of colloidal silicon dioxide (Lo-HAE/CSD), and then applied in the preparation of eight different lots of tablets. The influence of the diluent (cellulose or babassu mesocarp), the presence of binder, and the percentage of lubricant, as well as organoleptic and physicochemical characteristics were screened. For the quantification of the marker content both in Lo-HAE/CSD and in the tablets, an analytical curve of the naringenin standard was fitted, and the samples were then analyzed in UFLC. The toxicological assessment was performed in female Wistar rats according to the Acute Toxic Class Method from OECD. The developed tablets produced meet acceptable macroscopic characteristics, and the presence of babassu as diluent provided improved physicochemical properties. The best content of Lo-HAE/CSD in the tablet (100.27%) was identified for the lot containing babassu, composed by 1.0% magnesium stearate, without PVP binder in its formulation. Moreover, Lo-HAE/CSD showed no signs of toxicity. Therefore, the babassu mesocarp powder is a promising pharmaceutical excipient for the development of herbal tablets containing the Lippia origanoides extract.


Assuntos
Animais , Feminino , Ratos , Comprimidos/farmacologia , Lippia , Composição de Medicamentos/estatística & dados numéricos , Extratos Vegetais , Verbenaceae/classificação
11.
Artigo em Inglês | MEDLINE | ID: mdl-28852412

RESUMO

Platonia insignis Mart., popularly known as "bacurizeiro," is used in traditional medical practices based on its diverse biological properties. This study was aimed at evaluating the antileishmanial effects of the ethanol extract (EtOH-Ext), hexane fraction (Hex-F), and its main isolated Lupeol obtained from stem barks of P. insignis against Leishmania (Leishmania) amazonensis, as well as their cytotoxicity and possible mechanisms of action. The EtOH-Ext, Hex-F, and Lupeol inhibited the growth of L. amazonensis promastigote forms at IC50 of 174.24, 45.23, and 39.06 µg/mL, respectively, as well as L. amazonensis axenic amastigote forms at IC50 of 40.58, 35.87, and 44.10 µg/mL, respectively. The mean cytotoxic concentrations for macrophages (CC50) were higher than those for amastigotes (341.95, 71.65, and 144.0 µg/mL, resp.), indicating a selective cytotoxicity towards the parasite rather than the macrophages. Interestingly, all treatments promoted antileishmanial effect against macrophage-internalized amastigotes at concentrations lower than CC50. Furthermore, increases of lysosomal volume of macrophages treated with EtOH-Ext, Hex-F, and Lupeol were observed. On the other hand, only Lupeol stimulated increase of phagocytic capability of macrophages, suggesting this compound might be characterized as the biomarker for the antileishmanial effect of P. insignis stem bark, as well as the involvement of immunomodulatory mechanisms in this effect.

12.
Naunyn Schmiedebergs Arch Pharmacol ; 390(9): 893-903, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28643086

RESUMO

Leishmaniasis is a complex of parasitic protozoan diseases caused by more than 20 different species of parasites from Leishmania genus. Conventional treatments are high costly, and promote a sort of side effects. Besides, protozoan resistance to treatments has been reported. Natural products have been investigated as a source of new therapeutic alternatives, not only acting directly against the parasite but also being able to synergistically act on the host immune system in order to control parasitemia. Gallic acid (GA) and ellagic acid (EA) are plant-derived phenolic compounds which are able to induce antiinflammatory, gastroprotective, and anticarcinogenic activities. Therefore, the antileishmania, cytotoxic, and immunomodulatory activities of GA and EA were evaluated in this study. Both GA and EA were able to inhibit the growth of Leishmania major promastigotes (effective concentration (EC50) values 16.4 and 9.8 µg/mL, respectively). The cytotoxicity against BALB/c murine macrophages for GA and EA was also assessed (CC50 values 126.6 and 23.8 µg/mL, respectively). Interestingly, GA and EA also significantly reduced the infection and infectivity of macrophages infected by L. major (EC50 values 5.0 and 0.9 µg/mL, respectively), with selectivity index higher than 20. Furthermore, both GA and EA induced high immunomodulatory activity evidenced by the increase of phagocytic capability, lysosomal volume, nitrite release, and intracellular calcium [Ca2+i] in macrophages. Further investigations are reinforced in order to evaluate the therapeutic effects of GA and EA in in vivo experimental infection model of leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Ácido Elágico/farmacologia , Ácido Gálico/farmacologia , Leishmaniose Cutânea/tratamento farmacológico , Animais , Antiprotozoários/administração & dosagem , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Ácido Elágico/administração & dosagem , Feminino , Ácido Gálico/administração & dosagem , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Leishmania major/efeitos dos fármacos , Leishmania major/isolamento & purificação , Leishmaniose Cutânea/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
13.
Biomed Pharmacother ; 88: 488-499, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28126674

RESUMO

Schistosomiasis is a world health problem, and praziquantel is the only drug currently used for the treatment. There is some evidence that extensive monotherapy of praziquantel may be leading to drug resistance in the parasite. In order to find alternative treatments, the effects of the combination of epiisopiloturine (EPI), piplartine (PPT) and praziquantel (PZQ) were evaluated. Similarity analysis of these compounds was performed using optimized molecular structures to compare the shape and the charge modeling of combinations between PZQ and EPI or PPT. Supported by this data, in vitro association of PZQ-PPT, PZQ-EPI, and EPI-PPT was carried out, and the activity of these combinations against Schistosoma mansoni was assessed. The results showed synergistic activity with a combination index (CI) of 0.42 for the treatment with PZQ-PPT. Both PZQ-EPI and EPI-PPT combinations also showed synergistic effects, with CI values of 0.86 and 0.61, respectively. Surface alterations in the tegument of adult schistosomes after the treatments were observed using laser confocal microscopy and scanning electron microscopy. Additionally, the association of EPI-PPT decreased the cytotoxicity when compared with both isolated compounds in three different lines of mammalian cells. Thus, synergistic combinations of PZQ-PPT, PZQ-EPI, and EPI-PPT create the possibility of reduced doses to be used against Schistosoma mansoni.


Assuntos
4-Butirolactona/análogos & derivados , Imidazóis/farmacologia , Piperidonas/farmacologia , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Animais , Antiprotozoários/farmacologia , Forma Celular/efeitos dos fármacos , Chlorocebus aethiops , Cricetinae , Cães , Sinergismo Farmacológico , Quimioterapia Combinada , Imidazóis/química , Células Madin Darby de Rim Canino , Masculino , Camundongos , Microscopia Confocal , Piperidonas/química , Praziquantel/química , Schistosoma mansoni/ultraestrutura , Células Vero
14.
Basic Clin Pharmacol Toxicol ; 120(1): 52-58, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27398818

RESUMO

Leishmaniasis is an infectious disease complex caused by protozoa from the Leishmania genus, which presents a broad spectrum of clinical manifestations: cutaneous, mucocutaneous and visceral forms. The current treatments are unsatisfactory considering that few drugs are available and present some level of toxicity. Many lignans and neolignans have been used for the development of new antileishmania drugs. The capability in vitro of the neolignan 2,3-dihydrobenzofuran (2,3-DBF), a commonly found constituent of propolis and other plants, to inhibit the growth of promastigote and macrophage-internalized amastigote forms of Leishmania amazonensis was investigated. The cytotoxicity of this compound was assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test in BALB/c murine macrophages and human erythrocyte lysis assay. The 2,3-DBF was active against promastigote (IC50 =1.042 µM) and amastigote (IC50 =1.43 µM) forms, indicating a potent antileishmanial effect. There was no evidence of cytotoxicity to macrophages or erythrocytes at concentrations ranging from 13 to 0.5 µM, after 48 hr of exposure. The antileishmanial activity is probably mediated by the activation of macrophages, because treatment with 2,3-DBF increases both phagocytic and lysosomal activities, as well as the nitrite (NO2- ) levels. These results suggest that 2,3-DBF may be a potential candidate for the development of a new promising antileishmanial drug. Further studies are needed to determine its potential in vivo effect as well as additional mechanisms underlying the antileishmanial and immunomodulatory activities.


Assuntos
Antiprotozoários/farmacologia , Benzofuranos/farmacologia , Leishmania/efeitos dos fármacos , Lignanas/farmacologia , Animais , Antiprotozoários/efeitos adversos , Benzofuranos/efeitos adversos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Hidroxilação , Concentração Inibidora 50 , Leishmania/crescimento & desenvolvimento , Leishmania/fisiologia , Lignanas/efeitos adversos , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Óxido Nítrico/agonistas , Óxido Nítrico/metabolismo , Concentração Osmolar , Fagocitose/efeitos dos fármacos
15.
Front Genet ; 8: 236, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29503660

RESUMO

Molecular epidemiological studies have identified several risk factors linking to the genes and external factors in the pathogenesis of breast cancer. In this sense, genetic instability caused by DNA damage and DNA repair inefficiencies are important molecular events for the diagnosis and prognosis of therapies. Therefore, the objective of this study was to analyze correlation between sociocultural, occupational, and lifestyle risk factors with levels of genetic instability in non-neoplastic cells of breast cancer patients. Total 150 individuals were included in the study that included 50 breast cancer patients submitted to chemotherapy (QT), 50 breast cancer patients submitted to radiotherapy (RT), and 50 healthy women without any cancer. Cytogenetic biomarkers for apoptosis and DNA damage were evaluated in samples of buccal epithelial and peripheral blood cells through micronuclei and comet assay tests. Elder age patients (61-80 years) had higher levels of apoptosis (catriolysis by karyolysis) and DNA damage at the diagnosis (baseline damage) with increased cell damage during QT and especially during RT. We also reported the increased frequencies of cytogenetic biomarkers in patients who were exposed to ionizing radiation as well as for alcoholism and smoking. QT and RT induced high levels of fragmentation (karyorrhexis) and nuclear dissolution (karyolysis) and DNA damage. Correlations were observed between age and karyorrhexis at diagnosis; smoking and karyolysis during RT; and radiation and karyolysis during QT. These correlations indicate that risk factors may also influence the genetic instability in non-neoplastic cells caused to the patients during cancer therapies.

16.
Biomed. Pharmacother. ; 88: 488-499, 2017.
Artigo | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib15373

RESUMO

Schistosomiasis is a world health problem, and praziquantel is the only drug currently used for the treatment. There is some evidence that extensive monotherapy of praziquantel may be leading to drug resistance in the parasite. In order to find alternative treatments, the effects of the combination of epiisopiloturine (EPI), piplartine (PPT) and praziquantel (PZQ) were evaluated. Similarity analysis of these compounds was performed using optimized molecular structures to compare the shape and the charge modeling of combinations between PZQ and EPI or PPT. Supported by this data, in vitro association of PZQ-PPT, PZQ-EPI, and EPI-PPT was carried out, and the activity of these combinations against Schistosoma mansoni was assessed. The results showed synergistic activity with a combination index (CI) of 0.42 for the treatment with PZQ-PPT. Both PZQ-EPI and EPI-PPT combinations also showed synergistic effects, with CI values of 0.86 and 0.61, respectively. Surface alterations in the tegument of adult schistosomes after the treatments were observed using laser confocal microscopy and scanning electron microscopy. Additionally, the association of EPI-PPT decreased the cytotoxicity when compared with both isolated compounds in three different lines of mammalian cells. Thus, synergistic combinations of PZQ-PPT, PZQ-EPI, and EPI-PPT create the possibility of reduced doses to be used against Schistosoma mansoni.

17.
PLoS One ; 10(12): e0145071, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26661890

RESUMO

Proline-rich oligopeptides (PROs) are a large family which comprises the bradykinin-potentiating peptides (BPPs). They inhibit the activity of the angiotensin I-converting enzyme (ACE) and have a typical pyroglutamyl (Pyr)/proline-rich structure at the N- and C-terminus, respectively. Furthermore, PROs decrease blood pressure in animals. In the present study, the isolation and biological characterization of a novel vasoactive BPP isolated from the skin secretion of the frog Brachycephalus ephippium is described. This new PRO, termed BPP-Brachy, has the primary structure WPPPKVSP and the amidated form termed BPP-BrachyNH2 inhibits efficiently ACE in rat serum. In silico molecular modeling and docking studies suggest that BPP-BrachyNH2 is capable of forming a hydrogen bond network as well as multiple van der Waals interactions with the rat ACE, which blocks the access of the substrate to the C-domain active site. Moreover, in rat thoracic aorta BPP-BrachyNH2 induces potent endothelium-dependent vasodilatation with similar magnitude as captopril. In DAF-FM DA-loaded aortic cross sections examined by confocal microscopy, BPP-BrachyNH2 was found to increase the release of nitric oxide (NO). Moreover, BPP-BrachyNH2 was devoid of toxicity in endothelial and smooth muscle cell cultures. In conclusion, the peptide BPP-BrachyNH2 has a novel sequence being the first BPP isolated from the skin secretion of the Brachycephalidae family. This opens for exploring amphibians as a source of new biomolecules. The BPP-BrachyNH2 is devoid of cytotoxicity and elicits endothelium-dependent vasodilatation mediated by NO. These findings open for the possibility of potential application of these peptides in the treatment of endothelial dysfunction and cardiovascular diseases.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Anuros/metabolismo , Oligopeptídeos/metabolismo , Pele/metabolismo , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta Torácica/citologia , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Óxido Nítrico/metabolismo , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Prolina/química , Ligação Proteica , Estrutura Secundária de Proteína , Ratos , Ratos Wistar
18.
Pharmacogn Mag ; 10(Suppl 3): S456-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25298660

RESUMO

BACKGROUND: Mimosa caesalpiniifolia Benth. (Leguminosae) is widely found in the Brazilian Northeast region and markedly contributes to production of pollen and honey, being considered an important honey plant in this region. OBJECTIVE: To investigate the chemical composition of the ethanol extract of leaves from M. caesalpiniifolia by GC-MS after derivatization (silylation), as well as to evaluate the in vitro and in vivo toxicological effects and androgenic activity in rats. MATERIALS AND METHODS: The ethanol extract of leaves from Mimosa caesalpiniifolia was submitted to derivatization by silylation and analyzed by gas chromatography-mass spectrometry (GC-MS) to identification of chemical constituents. In vitro toxicological evaluation was performed by MTT assay in murine macrophages and by Artemia salina lethality assay, and the in vivo acute oral toxicity and androgenic evaluation in rats. RESULTS: Totally, 32 components were detected: Phytol-TMS (11.66%), lactic acid-2TMS (9.16%), α-tocopherol-TMS (7.34%) and ß-sitosterol-TMS (6.80%) were the major constituents. At the concentrations analyzed, the ethanol extract showed low cytotoxicity against brine shrimp (Artemia salina) and murine macrophages. In addition, the extract did not exhibit any toxicological effect or androgenic activity in rats. CONCLUSIONS: The derivatization by silylation allowed a rapid identification of chemical compounds from the M. caesalpiniifolia leaves extract. Besides, this species presents a good safety profile as observed in toxicological studies, and possess a great potential in the production of herbal medicines or as for food consumption.

19.
J Med Food ; 17(10): 1079-85, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25055183

RESUMO

Platonia insignis Mart. (Clusiaceae) is a medicinal plant from the Brazilian Amazon region. The present study evaluated the biological potential of the ethanol extract (Pi-EtOH) and ethyl acetate fraction (Pi-EtOAc) of the P. insignis fruit shells on the cardiovascular system of rats. Pi-EtOH or Pi-EtOAc (12.5, 25, and 50 mg/kg) was administered intravenously in normotensive rats (260-300 g), and the mean arterial pressure and the heart rate were monitored. The Pi-EtOH induced hypotension (-11.56±0.89, -7.43±0.85, and -17.56±1.97 mmHg) followed by bradycardia in two highest doses (-8.89±3.62 and -15.79±1.83 beats/min) and Pi-EtOAc, at the same doses, induced hypotension (-11.2±1.03, -14.48±1.13, -29.89±2.67 mmHg) more intensively, followed by tachycardia at the dose 12.5 and 25 mg/kg (15.64±2.06, 19.31±1.92 beats/min) and bradycardia at a dose of 50 mg/kg (-9.98±7.33 beats/min). The hypotensive response from Pi-EtOAc was not attenuated when used in the pretreatment with L-NAME, verapamil, propranolol, and hexamethonium. However, when using yohimbine, the hypotensive effect was inhibited (-4.42±1.28 (P<.05), -3.29±0.99 (P<.05), 2.06±1.18 mmHg (P<.05); Student's t-test). Hence, the Pi-EtOAc seems to act similarly to the α2-adrenergic agonist in this hypotensive effect.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Clusiaceae/química , Hipertensão/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Receptores Adrenérgicos alfa 2/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/genética
20.
Biomed Res Int ; 2014: 305610, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24683545

RESUMO

The Lippia origanoides H.B.K. ethanol extract (LOEE) and hexane (LOHEX), dichloromethane (LODCM), and ethyl acetate (LOEA) fractions were tested for their antimicrobial activity alone or in combination with antibiotics against a methicillin resistant Staphylococcus aureus (MRSA) strain. The natural products did not show antimicrobial activity against multidrug resistant strain at the clinically significant concentrations tested. However, a modulatory effect in the antibacterial activity of the neomycin and amikacin was verified when LOEE, LOHEX and LODCM were added to the growth medium at subinhibitory concentrations. A similar modulation was found when the natural products were changed for chlorpromazine, an inhibitor of bacterial efflux pumps, suggesting the involvement of resistance mediated by efflux system in the MRSA tested. The fractions LOHEX and LODCM showed a modulatory activity bigger than their majority compounds (carvacrol, thymol, and naringenin), indicating that this activity is not due to their majority compounds only, but it is probably due to a synergism between their chemical components. These results indicate that L. origanoides H.B.K. can be a source of phytochemicals able to modify the phenotype of resistance to aminoglycosides in MRSA.


Assuntos
Antibacterianos/farmacologia , Lippia/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Acetatos/química , Clorpromazina/farmacologia , Cimenos , Etanol/química , Flavanonas/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Hexanos/química , Cloreto de Metileno/química , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia , Extratos Vegetais/farmacologia , Timol/farmacologia
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