RESUMO
Solasonine (SS) and solamargine (SM) are alkaloids known for their antioxidant and anticancer properties, which can be further enhanced by encapsulating them in nanoparticles. This led to a study on the potential therapeutic benefits of SS and SM against bladder cancer when encapsulated in lipid-polymer hybrid nanoparticles (LPHNP). The LPHNP loaded with SS/SM were prepared using the emulsion and sonication method and their physical-chemical properties characterized. The biological effects of these nanoparticles were then tested in both 2D and 3D bladder cancer cell culture models, as well as in a syngeneic orthotopic mouse model based on the MB49 cell line and ethanol epithelial injury. The LPHNP-SS/SM had an average size of 130 nm, a polydispersity index of 0.22 and a positive zeta potential, indicating the presence of chitosan coating on the nanoparticle surface. The dispersion of LPHNP-SS/SM was found to be monodispersed with a span index of 0.539, as measured by nanoparticle tracking analysis (NTA). The recrystallization index, calculated from DSC data, was higher for the LPHNP-SS/SM compared to LPHNPs alone, confirming the presence of alkaloids within the lipid matrix. The encapsulation efficiency (EE%) was also high, with 91.08 % for SS and 88.35 % for SM. Morphological analysis by AFM and Cryo-TEM revealed that the nanoparticles had a spherical shape and core-shell structure. The study showed that the LPHNP-SS/SM exhibited mucoadhesive properties by physically interacting with mucin, suggesting a potential improvement in interaction with mucous membrane. Both the free and nanoencapsulated SS/SM demonstrated dose-dependent cytotoxicity against bladder cancer cell lines after 24 and 72 h of treatment. In 3D bladder cell culture, the nanoencapsulated SS/SM showed an IC50 two-fold lower than free SS/SM. In vivo studies, the LPHNP-SS/SM displayed an antitumoral effect at high doses, leading to a significant reduction in bladder volume compared to the positive control. However, there were observed instances of systemic toxicity and liver damage, indicated by elevated levels of transaminases (TGO and TGP). Overall, these results indicate that the LPHNPs effectively encapsulated SS/SM, showing high encapsulation efficiency and stability, along with promising in vitro and in vivo antitumoral effects against bladder cancer. Further evaluation of its systemic toxicity effects is necessary to ensure its safety and efficacy for potential clinical application.
Assuntos
Lipídeos , Nanopartículas , Alcaloides de Solanáceas , Neoplasias da Bexiga Urinária , Animais , Nanopartículas/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Lipídeos/química , Alcaloides de Solanáceas/administração & dosagem , Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/farmacologia , Polímeros/química , Camundongos , Humanos , Feminino , Portadores de Fármacos/química , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Tamanho da Partícula , Sobrevivência Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Melanoma is the most aggressive type of skin cancer, and thus it is important to develop new drugs for its treatment. The present study aimed to examine the antitumor effects of solamargine a major alkaloid heteroside present in Solanum lycocarpum fruit. In addition solamargine was incorporated into nanoparticles (NP) of yttrium vanadate functionalized with 3-chloropropyltrimethoxysilane (YVO4:Eu3+:CPTES:SM) to determine antitumor activity. The anti-melanoma assessment was performed using a syngeneic mouse melanoma model B16F10 cell line. In addition, systemic toxicity, nephrotoxic, and genotoxic parameters were assessed. Solamargine, at doses of 5 or 10 mg/kg/day administered subcutaneously to male C57BL/6 mice for 5 days, decreased tumor size and frequency of mitoses in tumor tissue, indicative of a decrease in cell proliferation. Treatments with YVO4:Eu3+:CPTES:SM significantly reduced the number of mitoses in tumor tissue, associated with no change in tumor size. There were no apparent signs of systemic toxicity, nephrotoxicity, and genotoxicity initiated by treatments either with solamargine alone or plant alkaloid incorporated into NP. The animals treated with YVO4:Eu3+:CPTES:SM exhibited significant increase in spleen weight accompanied by no apparent histological changes in all tissues examined. In addition, animals treated with solamargine (10 mg/kg/day) and YVO4:Eu3+:CPTES:SM demonstrated significant reduction in hepatic DNA damage which was induced by tumor growth. Therefore, data suggest that solamargine may be considered a promising candidate in cancer therapy with no apparent toxic effects.
Assuntos
Antineoplásicos/farmacologia , Melanoma Experimental/tratamento farmacológico , Alcaloides de Solanáceas/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Dano ao DNA , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitose/efeitos dos fármacos , Nanopartículas/administração & dosagem , Silanos/química , Alcaloides de Solanáceas/toxicidade , Ítrio/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Fungal and bacterial infections remain a major problem worldwide, requiring the development of effective therapeutic strategies. Solanum mammosum L. (Solanaceae) ("teta de vaca") is used in traditional medicine in Peru to treat fungal infections and respiratory disorders via topical application. However, the mechanism of action remains unknown, particularly in light of its chemical composition. MATERIALS AND METHODS: The antifungal activity of TDV was determined against Trichophyton mentagrophytes and Candida albicans using bioautography-TLC-HRMS to rapidly identify the active compounds. Then, the minimum inhibitory concentration (MIC) of the fruit crude extract and the active compound was determined to precisely evaluate the antifungal activity. Additionally, the effects of the most active compound on the formation of Pseudomonas aeruginosa biofilms and pyocyanin production were evaluated. Finally, a LC-HRMS profile and a molecular network of TDV extract were created to characterize the metabolites in the fruits' ethanolic extract. RESULTS: Bioautography-TLC-HRMS followed by isolation and confirmation of the structure of the active compound by 1D and 2D NMR allowed the identification solamargine as the main compound responsible for the anti-Trichophyton mentagrophytes (MIC = 64 µg mL-1) and anti-Candida albicans (MIC = 64 µg mL-1) activities. In addition, solamargine led to a significant reduction of about 20% of the Pseudomonas aeruginosa biofilm formation. This effect was observed at a very low concentration (1.6 µg mL-1) and remained fairly consistent regardless of the concentration. In addition, solamargine reduced pyocyanin production by about 20% at concentrations of 12.5 and 50 µg mL-1. Furthermore, the LC-HRMS profiling of TDV allowed us to annotate seven known compounds that were analyzed through a molecular network. CONCLUSIONS: Solamargine has been shown to be the most active compound against T. mentoagrophytes and C. albicans in vitro. In addition, our data show that this compound affects significantly P. aeruginosa pyocyanin production and biofilm formation in our conditions. Altogether, these results might explain the traditional use of S. mammosum fruits to treat a variety of fungal infections and respiratory disorders.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Alcaloides de Solanáceas/farmacologia , Solanum/química , Antibacterianos/isolamento & purificação , Antifúngicos/isolamento & purificação , Arthrodermataceae/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Piocianina/metabolismo , Alcaloides de Solanáceas/isolamento & purificaçãoRESUMO
Objetivou-se identificar o perfil sociodemográfico de idosos vítimas de trauma, caracterizar doenças preexistentes e medicamentos utilizados no domicílio; calcular índices de trauma e desfecho clínico. Estudo retrospectivo e exploratório, com a análise de dados secundários de um banco de dados de um hospital geral terciário, entre 2008 e 2010. Foram estudados 131 idosos, média de idade 69,9 anos, 73,3% homens, 55,1% casados, 54,7% aposentados; 65,6% possuíam doenças preexistentes e 48,9% usavam medicamentos no domicílio. Houve representatividade de quedas (31,3%), seguidas por atropelamento (28,2%), com cabeça/pescoço sendo a região mais acometida (59,5%). Prevaleceu o trauma moderado (44,3%), com condições de sobrevida após o evento (80,2%). Houve associação entre mecanismo do trauma e doença preexistente (p=0,01) e entre mecanismo do trauma e sexo (p=0,03). O conhecimento das variáveis envolvidas com idosos vítimas de trauma possibilita aos profissionais de saúde o planejamento de medidas preventivas, visando aprimorar sua assistência.
The objective was to identify the sociodemographic profile of the elderly victims of trauma, to characterize preexisting conditions and medications taken at home, and to calculate indices of trauma and clinical outcomes. This is a retrospective and exploratory analysis from a database of a general hospital between 2008 and 2010. There were studied 131 elderly, mean age 69.9 years, 73.3% male, 55.1% married, 54.7% retired, 65.6% had preexisting conditions and 48.9% used drugs at home. There was a representative number of falls (31.3%), followed by running over (28.2%), with the head/neck region being the most affected (59.5%). Moderate trauma prevailed (44.3%), with conditions of survival after the event (80.2%). There was an association between mechanism of trauma and preexisting disease (p=0.01) and between mechanism of trauma and sex (p=0.03). The knowledge of the variables involved with the elderly victims of trauma enables healthcare professionals to plan preventive measures aimed at improving the assistance. Key words: Aged; Wounds and Injuries; Disease; Drug Utilization.
Se objetivó identificar el perfil sociodemográfico de ancianos víctimas de trauma, caracterizar condiciones preexistentes y medicamentos tomados en casa, y calcular índices de trauma y evolución clínica. Se realizó un análisis retrospectivo y exploratorio de una base de datos de un hospital general terciario entre 2008 y 2010. Se estudiaron 131 ancianos, media of 69,9 años, 73,3% hombres, 55,1% casados, 54,7% jubilados, 65,6% tienen condiciones preexistentes y 48,9% estaban tomando medicación en casa. Hubo representación de las caídas (31,3%), seguido de atropello (28,2%). La región cabeza/cuello fue el más afectado (59,5%). Prevaleció trauma moderado (44,3%), con condiciones de supervivencia después del evento (80,2%). Se observó una asociación entre mecanismo de lo trauma y enfermedad previa (p=0,01) y entre mecanismo de lo trauma y sexo (p=0,03). El conocimiento de las variables que intervienen con ancianos víctimas de trauma permite a los profesionales de la salud planificar medidas preventivas para mejorar su asistencia.
Assuntos
Animais , Masculino , Ratos , Dobutamina/farmacologia , Jejuno/irrigação sanguínea , Jejuno/efeitos dos fármacos , Alcaloides de Solanáceas/farmacologia , Dióxido de Carbono/metabolismo , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/efeitos dos fármacos , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologiaRESUMO
This report presents evidence that the following Solanum steroids: solasodine, diosgenin and solanine interact with human erythrocytes and molecular models of their membranes as follows: a) X-ray diffraction studies showed that the compounds at low molar ratios (0.1-10.0mol%) induced increasing structural perturbation to dimyristoylphosphatidylcholine bilayers and to a considerable lower extent to those of dimyristoylphosphatidylethanolamine; b) differential scanning calorimetry data showed that the compounds were able to alter the cooperativity of dimyristoylphosphatidylcholine, dimyristoylphosphatidylethanolamine and dimyristoylphosphatidylserine phase transitions in a concentration-dependent manner; c) in the presence of steroids, the fluorescence of Merocyanine 540 incorporated to the membranes decreased suggesting a fluidization of the lipid system; d) scanning electron microscopy observations showed that all steroids altered the normal shape of human erythrocytes inducing mainly echinocytosis, characterized by the formation of blebs in their surfaces, an indication that their molecules are located into the outer monolayer of the erythrocyte membrane.
Assuntos
Diosgenina/química , Membrana Eritrocítica/química , Bicamadas Lipídicas/química , Alcaloides de Solanáceas/química , Solanina/química , Varredura Diferencial de Calorimetria , Dimiristoilfosfatidilcolina/química , Diosgenina/farmacologia , Membrana Eritrocítica/efeitos dos fármacos , Corantes Fluorescentes/química , Humanos , Microscopia Eletrônica de Varredura , Transição de Fase/efeitos dos fármacos , Fosfatidiletanolaminas/química , Fosfatidilserinas/química , Pirimidinonas/química , Espalhamento a Baixo Ângulo , Alcaloides de Solanáceas/farmacologia , Solanina/farmacologia , Difração de Raios XRESUMO
Natural products are some of the important sources of new anticancer drugs. The Brazilian flora is considered one of the most diverse in the word, although not many large-scale pharmacological and phytochemical studies have been conducted to date. With this in mind, in the present study we evaluated the antiproliferative activity of Solanum lycocarpum fruit glycoalkaloid extract (SL) and its major compounds, solamargine (SM) and solasonine (SS), against different tumor cell lines: murine melanoma (B16F10), human colon carcinoma (HT29), human breast adenocarcinoma (MCF-7), human cervical adenocarcinoma (HeLa), human hepatocellular liver carcinoma (HepG2) and human glioblastoma (MO59J, U343 and U251). The antiproliferative activity was evaluated using XTT assay and results were expressed as IC50. The most pronounced antiproliferative activity was observed for SM, with IC50 values ranging from 4.58 to 18.23 µg/mL. The lowest IC50 values were observed against HepG2, being 9.60 µg/mL for SL, 4.58 µg/mL for SM and 6.01 µg/mL for SS. Thus, SL, SM and SS demonstrated antiproliferative activity against the tumor cell lines tested, and were most effective against the HepG2 cell line.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/farmacologia , Solanum , Alcaloides/isolamento & purificação , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Frutas , Humanos , Concentração Inibidora 50 , Melanoma Experimental , Camundongos , Estrutura Molecular , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Alcaloides de Solanáceas/farmacologia , Solanum/químicaRESUMO
The present investigation was to evaluate the potential trypanocidal activity of crude ethanolic extract of the fruits of Solanum palinacanthum, Solanum lycocarpum and the glycoalcaloid, solamargine. S. palinacanthum and S. lycocarpum fruit powders were submitted to exhaustively extraction with 96% ethanol and solamargine were isolated from the extract of S. palinacanthum. Both extracts and solamargine were analysed for trypanocidal activity by using MTT colorimetric assay. Extracts of S. palinacanthum showed to be more active (IC50 = 175.9 µg.ml-1) than S. lycocarpum (IC50 = 194.7 µg.ml-1). Solamargine presented a strong activity (IC50 = 15.3 µg.ml-1), which can explain the better activity of the both extracts. Benznidazol (IC50 = 9.0 µg.ml-1) is the only drug used to treat Chagas' disease. These findings demonstrate for the first time that ethanol extracts obtained from both fruits of S. palinacanthum and S. lycocarpum and also solamargine have a potential anti-trypanosomal activity.
Assuntos
Extratos Vegetais/farmacologia , Alcaloides de Solanáceas/farmacologia , Solanum/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Solanum/classificação , Tripanossomicidas/isolamento & purificaçãoRESUMO
Schistosomiasis is a chronic disease caused by trematode flatworms of the genus Schistosoma; it accounts for more than 280,000 deaths annually. In this work we investigated the effect of the alkaloidic extract obtained by acid-base extraction of the dried fruits of Solanum lycocarpum on schistosomiasis. We used this extract at concentrations of 10, 20, and 40 mg/kg to treat mice infected with Schistosoma mansoni in different phases of the parasite cycle, and we compared its effect with that of the positive control praziquantel (60 mg/kg). We evaluated the results on the basis of the number of macrophages, eggs, and granulomas; we also assessed nitric oxide (NO) and interferon-gamma (IFN-γ) production. Animals treated with a daily dose of 10 or 20 mg/kg alkaloidic extract between the 37th and 41st day of infection showed increased number of macrophages, elevated NO and IFN-γ concentrations, and reduced number of eggs and granulomas in the liver. The alkaloidic extract of S. lycocarpum fruits displayed an immunomodulatory effect on mice infected with S. mansoni, so its potential to treat schistosomiasis deserves further studies.
Assuntos
Frutas/química , Fatores Imunológicos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Alcaloides de Solanáceas/farmacologia , Solanum/química , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Contagem de Células , Feminino , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/uso terapêutico , Interferon gama/sangue , Interferon gama/metabolismo , Fígado/parasitologia , Fígado/patologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Contagem de Ovos de Parasitas , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Alcaloides de Solanáceas/isolamento & purificação , Alcaloides de Solanáceas/uso terapêuticoRESUMO
Solanum lycocarpum (Solanaceae), a Brazilian medicinal plant known as "wolf fruit," contains about 1.5% of glycoalkaloids in its dried fruits, consisting mainly of solamargine and solasonine. The present work reports the obtainment of the alkaloidic extract of the S. lycocarpum fruit by acid-base extraction and the isolation of the major alkaloid heterosides by chromatographic means, as well as the evaluation of their in vitro schistosomicidal activities. The in vitro schistosomicidal activities of the alkaloidic extract of S. lycocarpum fruits and its isolated steroidal alkaloids were undertaken against adult worms of Schistosoma mansoni. The alkaloidic extract (20, 32, and 50 µg mL(-1)), solasonine (50 µM), solamargine (32 and 50 µM), and equimolar mixture of glycoalkaloids (20, 32, and 50 µM) lead to the separation of all couple worms and extensive disruption on their teguments, such as sloughing, as well as their deaths within 24 h of incubation. In addition, the alkaloidic extract (10 and 15 µg mL(-1)), solasonine (50 µM), solamargine (10, 15, and 20 µM), and equimolar mixtures of glycoalkaloids (10 and 15 µM) reduced the development of eggs produced by the adult worms. Solamargine, containing the sugar chain moiety chacotriose, was more active than the solasonine, which contains solatriose sugar chain moiety. A synergistic effect was also observed for a mixture of solamargine and solasonine. Therefore, the alkaloidic extract of S. lycocarpum, and its major components, solamargine and solasonine, showed promising schistosomicidal activity.
Assuntos
Anti-Helmínticos/farmacologia , Frutas/química , Schistosoma mansoni/efeitos dos fármacos , Alcaloides de Solanáceas/farmacologia , Solanum/química , Animais , Anti-Helmínticos/isolamento & purificação , Brasil , Cromatografia , Testes de Sensibilidade Parasitária , Schistosoma mansoni/crescimento & desenvolvimento , Alcaloides de Solanáceas/isolamento & purificação , Análise de SobrevidaRESUMO
Solanum lycocarpum A. St. Hil. (Solanaceae) is a hairy shrub or small much-branched tree of the Brazilian Cerrado. S. lycocarpum fruits are commonly used in traditional medicine in powder form or as folk preparations for the treatment of diabetes and obesity, as well as for controlling cholesterol levels. The aim of the present study was to chemically characterize the hydroalcoholic extract (SL) of S. lycocarpum by determination of total flavonoids and total poyphenols and quantification of steroidal alkaloids, as well as to evaluate its mutagenic and/or antimutagenic potential on V79 cells and Swiss mice using chromosomal aberrations and bone marrow micronucleus assays, respectively. Three concentrations of SL (16, 32, and 24 µg/mL) were used for the evaluation of its mutagenic potential in V79 cells and four doses (0.25, 0.50, 1.0, and 2.0 g/kg body weight) were used for Swiss mice. In the antimutagenicity assays, the different concentrations of SL were combined with the chemotherapeutic agent doxorubicin (DXR). HPLC analysis of SL gave contents of 6.57â% ± 0.41 of solasonine and 4.60â% ± 0.40 of solamargine. Total flavonoids and polyphenols contents in SL were 0.04 and 3.60â%, respectively. The results showed that not only SL exerted no mutagenic effect, but it also significantly reduced the frequency of chromosomal aberrations induced by DXR in both V79 cells and micronuclei in Swiss mice at the doses tested.