RESUMEN
Baccharin is one of the major compounds found in Brazilian green propolis and its botanical source, Baccharis dracunculifolia. Considering the biological effects of propolis and B. dracunculifolia, this study aims to evaluate the analgesic and anti-inflammatory potential of baccharin. The neurodepressor potential was performed by the open field test, analgesia by mechanical stimulation with Dynamic Plantar Aesthesiometer, and by thermal stimulation with Hargreaves apparatus. In addition, the anti-inflammatory potential was achieved by the paw edema assay, histopathological evaluation, and NF-kB expression. Doses of 2.5, 5, and 10 mg/kg of baccharin were evaluated. After euthanasia, plantar tissue was collected and prepared for histology. As a result, analgesic activity was observed at a dose of 10 mg/kg of baccharin in thermal stimulation under an inflammatory process and anti-inflammatory potential at a dose of 5 mg/kg of baccharin from the second hour in the paw edema test. A decrease in cellular infiltrate and down-modulation of NF-kB, besides the reduction of edema in the histopathology was observed. There was no evidence of kidney and liver toxicity and neurodepressive potential at the doses tested. Thus, baccharin has a promising anti-inflammatory effect possibly associated with antiedematogenic activity by inhibiting mediators such as prostaglandins, inhibiting the migration of polymorphonuclear cells, and modulating NF-kB expression.
Asunto(s)
Analgésicos , Antiinflamatorios , Baccharis , Edema , FN-kappa B , Própolis , Animales , Masculino , Ratas , Analgésicos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Baccharis/química , Brasil , Edema/tratamiento farmacológico , Edema/inducido químicamente , FN-kappa B/metabolismo , Própolis/farmacología , Ratas Wistar , TricotecenosRESUMEN
The use of various herbs and their compounds has been a strategy widely used in the fight against various human diseases. For example, rosmarinic acid, a bioactive phenolic compound commonly found in Rosemary plants (Rosmarinus officinalis Labiatae), has multiple therapeutic benefits in different diseases, such as cancer. Therefore, the study aimed to evaluate in silico and in vitro the inhibition potential of the enzyme Elastase from the porcine pancreas by rosmarinic acid isolated from the plant species R. officinalis Linn. Through Molecular Docking, the mechanism of action was investigated. In addition, rosmarinic acid presented a range of 5-60 µg/mL and significantly inhibited Elastase. At 60 µg/mL, there was an inhibition of 55% on the enzymatic activity. The results demonstrate the inhibition of Elastase by rosmarinic acid, which can lead to the development of new enzyme inhibitors that can be an inspiration for developing various drugs, including anticancer drugs.
Asunto(s)
Ácido Rosmarínico , Rosmarinus , Humanos , Elastasa Pancreática , Simulación del Acoplamiento Molecular , Extractos Vegetales/farmacología , Cinamatos/farmacología , Depsidos/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Copaifera species folkloric names are "copaíbas, copaibeiras, copaívas or oil stick", which are widely used in Brazilian folk medicine. Among all ethnopharmacological applications described for Copaifera spp oleoresins, their anti-inflammatory effect stands out. However, the knowledge of anti-inflammatory and antinociceptive properties of Copaifera pubiflora Benth is scarce. AIM OF THE STUDY: To investigate the cytotoxic, anti-inflammatory, and antinociceptive activities of C. pubiflora oleoresin (CPO), and its major compound ent-hardwickiic acid (HA). MATERIAL AND METHODS: The phosphatase assay was used to evaluate the cytotoxicity of CPO and HA in three different cell lines. CPO and HA doses of 1, 3, and 10 mg/kg were employed in the biological assays. The assessment of motor activity was performed using open-field and rotarod tests. Anti-inflammatory activity of CPO and HA was assessed through luciferase assay, measurement of INF-γ, IL-1ß, IL-6, IL-10, and TNF-α in a multi-spot system with the immortalized cell line THP-1, zymosan-induced arthritis, and carrageenan-induced paw edema. Acetic acid-induced abdominal writhing and formalin tests were undertaken to evaluate the antinociceptive potential of CPO and HA. In addition, the evaluation using carrageenan was performed to investigate the effect of CPO in pain intensity to a mechanical stimulus (mechanical hyperalgesia), using the von Frey filaments. A tail-flick test was used to evaluate possible central CPO and HA actions. RESULTS: In the cytotoxicity evaluation, CPO and HA were not cytotoxic to the cell lines tested. CPO and HA (10 mg/kg) did not affect animals' locomotor capacity in both open-field and rotarod tests. In the luciferase assay, CPO and HA significantly reduced luciferase activity (p < 0.05). This reduction indicates a decrease in NF-κB activity. HA and CPO decreased INF-γ, IL-1ß, IL-6, IL-10, and TNF-α at 24 and 72 h in the multi-spot system. In zymosan-induced arthritis, CPO and HA decreased the number of neutrophils in the joint of arthritic mice and the number of total leukocytes (p < 0.05). In experimental arthritis HA significantly decreased joint swelling (p < 0.05). CPO and HA also increased the mechanical threshold during experimental arthritis. HA and CPO significantly inhibited the carrageenan-induced paw edema, being the doses of 10 mg/kg the most effective, registering maximum inhibitions of 58 ± 8% and 76 ± 6% respectively, p < 0.05. CPO and HA reduced the nociceptive behavior in both phases of formalin at all tested doses. The highest doses tested displayed inhibitions of 87 ± 1% and 72 ± 4%, respectively, p < 0.001, in the first phase, and 87 ± 1% and 81 ± 2%, respectively, p < 0.001, in the second phase. Oral treatment of CPO and HA (1, 3, 10 mg/kg) significantly reduced the nociceptive response in acetic acid-induced abdominal writhings, and the 10 mg/kg dose was the most effective with maximum inhibitions of 86 ± 2% and 82 ± 1%, respectively, p < 0.001. Both HA and CPO significantly decreased the intensity of mechanical inflammatory hyper-nociception on carrageenan-induced hyperalgesia at all tested doses, and 10 mg/kg was the most effective dose with maximum inhibitions of 73 ± 5% and 74 ± 7%, respectively, p < 0.05.CPO increased the tail-flick latencies in mice, and concomitant administration of naloxone partially reduced its effect. CONCLUSIONS: CPO and HA may inhibit the production of inflammatory cytokines by suppressing the NF-κB signaling pathway, resulting in anti-inflammatory and antinociceptive activities.
Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Diterpenos/uso terapéutico , Edema/tratamiento farmacológico , Fabaceae/química , Extractos Vegetales/uso terapéutico , Ácido Acético/toxicidad , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Artritis Experimental/inducido químicamente , Conducta Animal/efectos de los fármacos , Brasil , Carragenina/toxicidad , Línea Celular , Citocinas/metabolismo , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Edema/inducido químicamente , Formaldehído/toxicidad , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Locomoción/efectos de los fármacos , Medicina Tradicional , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Zimosan/toxicidadRESUMEN
This study describes the in vitro anthelmintic activity of a hydroalcoholic extract from the fruit of Piper cubeba and its major isolated components against the eggs and larvae of gastrointestinal nematodes obtained from naturally-infected ovines. In vitro anthelmintic activity was evaluated using the egg hatch test (EHT), larval development test (LDT) and L3 migration inhibition test (LMT). The extract showed ovicidal and larvicidal activity, with an EC50 of 200⯵g/mL and 83.00⯵g/mL in the EHT and LDT, respectively. The extract inhibited 100% of larval migration at the lowest tested concentration (95⯵g/mL). The crude extract was purified using successive silica gel chromatographic columns, which revealed the lignans hinokinin, cubebin and dihydrocubebin as the major compounds that were present, which were then used in in vitro tests. Cubebin, dihydrocubebin and hinokinin showed higher activity than the crude extract, with an EC50 for ovicidal activity of 150.00⯵g/mL, 186.70⯵g/mL and 68.38⯵g/mL, respectively. In the LDT, cubebin presented an EC50 of 14.89⯵g/mL and dihydrocubebin of 30.75⯵g/mL. Hinokinin inhibited 100% the larval development at all concentrations evaluated. In the LMT, dihydrocubebin inhibited 100% the larval migration in all concentrations evaluated while cubebin and hinokinin showed EC50 values of 0.89⯵g/mL and 0.34⯵g/mL, respectively. P. cubeba extract is rich in several classes of active compounds, but here we demonstrate that the described anthelmintic activity may be related to the presence of these lignans, which are present in larger concentrations than other components of the extract. Our results demonstrate for first time the anthelmintic activity against gastrointestinal nematodes in sheep for this class of special metabolites that are present in P. cubeba fruit. However, future detailed studies are needed to evaluate the effectiveness of P. cubeba fruits extract and active lignans in in vivo tests.
Asunto(s)
Parasitosis Intestinales/veterinaria , Lignanos/farmacología , Nematodos/efectos de los fármacos , Infecciones por Nematodos/veterinaria , Piper/química , Extractos Vegetales/farmacología , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Animales , Benzodioxoles/química , Benzodioxoles/aislamiento & purificación , Benzodioxoles/farmacología , Cromatografía en Gel/veterinaria , Dioxolanos/química , Dioxolanos/aislamiento & purificación , Dioxolanos/farmacología , Heces/parasitología , Frutas/química , Parasitosis Intestinales/tratamiento farmacológico , Parasitosis Intestinales/parasitología , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Larva/fisiología , Lignanos/química , Lignanos/aislamiento & purificación , Microscopía Electrónica de Rastreo/veterinaria , Nematodos/crecimiento & desarrollo , Nematodos/fisiología , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/parasitología , Óvulo/efectos de los fármacos , Óvulo/fisiología , Extractos Vegetales/química , Ovinos , Enfermedades de las Ovejas/parasitologíaRESUMEN
Parasitic diseases continue to be a major worldwide health problem, and there is an urgent need for development of therapeutic drugs. This paper describes synthesis of dehydrodiferulic acid dilactone 1 and dehydrodisinapic acid dilactone 2 furofuran lignans by oxidative coupling of ferulic and sinapic acids, respectively. Their schistosomicidal, trypanocidal, and leishmanicidal activities were evaluated in vitro against Schistosoma mansoni adult worms, trypomastigote and amastigotes forms of Trypanosoma cruzi, and promastigote forms of Leishmania amazonensis. Compound 1 did not display significant schistosomicidal activity, but it presented potent trypanocidal activity, since it induced death of trypomastigotes and amastigotes with IC50/24h of 9.3µM and 7.3µM, respectively. Compound 2 had slight trypanocidal and schistosomicidal activities. None of the compounds were active against L. amazonensis. These results demonstrated that furofuran lignans are potentially useful for anti-parasitic drugs development and should be further investigated.
Asunto(s)
Furanos/síntesis química , Furanos/farmacología , Lignanos/síntesis química , Lignanos/farmacología , Esquistosomicidas/síntesis química , Esquistosomicidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Furanos/química , Humanos , Concentración 50 Inhibidora , Lactonas/síntesis química , Lactonas/química , Leishmania/efectos de los fármacos , Leishmania mexicana/efectos de los fármacos , Lignanos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Pruebas de Sensibilidad Parasitaria , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/química , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacosRESUMEN
The protozoan Trypanosoma cruzi causes Chagas' disease, a neglected illness that remains a relevant public health concern in Latin America. In Brazil, Benznidazole is available for its treatment. This compound is effective against circulating forms of the parasite in the acute phase of the disease, but its efficacy during the chronic stage is debatable. The search for new medications that can treat Chagas' disease is therefore mandatory. Natural sources display a wide range of secondary metabolites and may play an important role in the discovery of new potential drugs. Miconia is one of the largest genus of the family Melastomataceae and includes approximately 1,000 plant species; Brazil alone is home to approximately 250 of these species, which exist in forests and savannas. Studies on the various biological activities of the Miconia species have reported promising results. Several researchers have screened these plants as well as their extracts in vitro against trypomastigote forms of T. cruzi, which displayed significant trypanocidal activity. It has been demonstrated that the presence of ursolic and oleanolic determines this biological activity.
El protozoario Trypanosoma cruzi causa mal de Chagas, enfermedad que aún es problema de salud pública relevante en América Latina. El fármaco disponible en Brasil para el tratamiento es benznidazol. Este compuesto es eficaz contra la forma de circulación del parásito en la fase aguda de la enfermedad, pero su eficacia durante la fase crónica es discutible. Por lo tanto, la búsqueda de nuevos medicamentos que pueden tratar el mal de Chagas es necesaria. Las fuentes naturales presentan amplia gama de metabolitos secundarios y pueden desempeñar papel importante en el descubrimiento de nuevas drogas potenciales. Miconia es un género de los más grandes perteneciente a la familia Melatomateceae, incluyendo cerca de 1.000 especies de plantas; sólo en Brasil hay aproximadamente 250 de estas especies en florestas y sabanas. Los estudios sobre las diversas actividades biológicas de las especies Miconia han presentando resultados promisorios. Varios autores han evaluado extractos de estas plantas contra T. cruzi, comprobando que estos exiben actividad tripanocida significativa. La presencia de ácidos ursólico y oleanólico determinan la actividad biológica.
A doença de Chagas é uma doença negligenciada causada pelo protozoário Trypanosoma cruzi e ainda permanece como um relevante problema de saúde pública na América Latina. O medicamento disponível para o tratamento clínico no Brasil é o benzonidazol, que é efetivo contra as formas circulantes do parasita na fase aguda da doença, entretanto, sua eficácia na fase crónica permanece discutível. A pesquisa por novas drogas que possam ser utilizadas no tratamento dessa doença é urgentemente necessária e as fontes naturais com os seus metabólitos secundários diversificados, podem desempenhar um papel extremamente importante. Miconia é um dos maiores géneros pertencente à família Melastomataceae incluindo cerca de 1.000 espécies e, no Brasil existem cerca de 250 espécies em florestas e savanas. Estudos realizados com o objetivo de descrever as diferentes atividades biológicas de espécies de Miconia têm apresentado resultados promissores. Vários autores têm avaliado os extratos dessas plantas contra as formas tripomastigotas sanguíneas de T. cruzi (in vitro) e verificado que essas amostras exibem atvidade tripanocida significativa. A presença dos triterpenos ácidos ursólico oleanólico está relacionada com esta atividade biológica.
RESUMEN
Protozoans of the trypanosomatid family cause the neglected tropical diseases leishmaniasis and trypanosomiasis, for which few drugs are available. In this context our group has recently reported that the essential oil obtained by steam distillation of the fruits of Piper cubeba is active against Schistosoma mansoni. Therefore, we have investigated the in vitro effects of the essential oil against the trypomastigote and amastigote forms of Trypanosoma cruzi isolated from an LLCMK2 cell line culture and the promastigote forms of Leishmania amazonensis. The in vitro activity of the essential oil against trypomastigotes of T. cruzi increased upon rising concentrations, giving IC50 values of 45.5 and 87.9 µgâ·âmL⻹ against trypomastigotes and amastigotes, respectively. The essential oil was not active against L. amazonensis, since it displayed lyses of only 24â% at 400 µgâ·âmL⻹, and an IC50 of 326.5 µgâ·âmL⻹. Therefore, the essential oil should be further investigated to determine the compounds responsible for the observed activities, as well as its mechanism of action.
Asunto(s)
Antiparasitarios/farmacología , Leishmania/efectos de los fármacos , Aceites Volátiles/farmacología , Piper/química , Extractos Vegetales/farmacología , Trypanosoma cruzi/efectos de los fármacos , Línea Celular , Frutas/química , Concentración 50 Inhibidora , Leishmaniasis/microbiología , Estadios del Ciclo de Vida , Macrófagos , Pruebas de Sensibilidad ParasitariaRESUMEN
(-)-Cubebin (CUB) is a lignan isolated from dry seeds of Piper cubeba. We aimed to assess its genotoxic potential and influence on chromosomal damage (frequency of micronuclei - MN) induced by doxorubicin (DXR) in V79 cells and by urethane (URE) in somatic Drosophila melanogaster cells. Our findings indicate an absence of a CUB-mediated genotoxic effect at the concentrations tested. The results also revealed that CUB significantly reduced the frequency of MN induced by DXR, with a mean reduction of 63.88%. In a previous study, our research group demonstrated an absence of CUB-mediated mutagenic effects through the wing Somatic Mutation and Recombination Test (SMART) in Drosophila. In the present study, we used the standard and high bioactivation versions of the SMART to estimate the antigenotoxic effects of CUB associated with URE. At lower concentrations, the recombination level decreased, but at the highest concentration, the recombination level increased. Our data and previous studies suggest that CUB may act as a free radical scavenger at low concentrations, a pro-oxidant at higher concentrations when it interacts with the enzymatic system that catalyzes the metabolic detoxification of DXR or URE, and/or an inducer of recombinational DNA repair.
Asunto(s)
Antimutagênicos/farmacología , Lignanos/farmacología , Mutágenos/toxicidad , Recombinación Genética/efectos de los fármacos , Animales , Línea Celular , Cricetinae , Drosophila melanogasterRESUMEN
Cubebin, the most abundant lignan in Piper cubeba, has been described as having several effects as trypanocidal, antimycobacterial, antispasmodic, antimicrobial, anti-inflammatory, and analgesic. This study investigated the vasorelaxant effect produced by (-)-cubebin in isolated rat aortic rings pre-contracted with phenylephrine (Phe), and the possible mechanism involved in this event was evaluated. Endothelium-dependent relaxation was evoked by acetylcholine and (-)-cubebin in intact aortic rings, while endothelium-independent vasorelaxation was elicited by sodium nitroprusside and (-)-cubebin in denuded rings. Cumulative concentration-response curves for Phe (10(-10) -10(-5) M) were determined for endothelium-intact and endothelium-denuded aortic rings in either the presence or absence of (-)-cubebin. Dose-response curves were also constructed for pre-incubation of vascular rings with Nω-nitro-L-arginine methyl ester (L-NAME) (a non-specific nitric oxide synthase inhibitor), indomethacin (an unspecific cyclooxygenase inhibitor), and 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) (a guanylyl cyclase inhibitor). (-)-Cubebin was found to exert a vasorelaxant effect irrespective of the presence of endothelium, which was abolished by pretreatment with L-NAME and ODQ, but not with indomethacin. In addition, (-)-cubebin was able to reduce Phe contraction in the case of intact rings. These results suggest that (-)-cubebin promotes vasorelaxation via NO/cGMP pathway in rat aorta, without prostacyclin involvement.
Asunto(s)
Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Lignanos/farmacología , Óxido Nítrico/fisiología , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Animales , Aorta/fisiología , GMP Cíclico/fisiología , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Técnicas In Vitro , Indometacina/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Nitroprusiato/farmacología , Fenilefrina/farmacología , Piper/química , Quinoxalinas/farmacología , Ratas , Ratas WistarRESUMEN
Nifurtimox and benznidazole, medications currently used for the treatment of the Chagas disease, are not always successful. We determine whether (-)-cubebin and (-)-hinokinin could be used as alternative drugs for the treatment of parasitic infections by Trypanosoma cruzi. To this end, male BALB/c mice were treated with both drugs, and the nuclear parameters (largest diameter, smallest diameter, and perimeter) were determined from slides prepared from the spleen, liver, and heart. The cytotoxicity of the substances was determined after 24-h treatment. Results revealed increased cell nuclei in untreated infected animals as compared to uninfected mice. The values obtained for infected animals treated with (-)-cubebin and (-)-hinokinin were close to those observed for uninfected mice. For the spleen, perimeter values of 10.85 µm (p < 0.01) and 10.90 µm (p < 0.05) were obtained for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas untreated infected animals furnished a perimeter of 11.76 µm. As for the liver, perimeter values of 19.06 µm (p < 0.01) and 18.61 µm (p < 0.001) were achieved for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas a perimeter of 18.54 µm was obtained for untreated infected animals. The cytotoxicity assays demonstrated that (-)-cubebin and (-)-hinokinin does not display toxicity. Therefore, (-)-cubebin and (-)-hinokinin are promising therapeutic agents and could be used in future clinical studies concerning treatment of the Chagas disease. Even if the karyometry is not used frequently, it can complement other methods, such as PCR, and furthermore, it is a simple method which is easily possible to analyze the activity of substances in the tissues of treated infected animals compared to uninfected animals.
Asunto(s)
4-Butirolactona/análogos & derivados , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/patología , Dioxoles/administración & dosificación , Lignanos/administración & dosificación , 4-Butirolactona/administración & dosificación , 4-Butirolactona/efectos adversos , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/efectos adversos , Benzodioxoles , Biometría , Línea Celular , Enfermedad de Chagas/parasitología , Dioxoles/efectos adversos , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Cariotipificación , Lignanos/efectos adversos , Hígado/patología , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos BALB C , Bazo/patología , Trypanosoma cruzi/patogenicidadRESUMEN
Miconia langsdorffii Cogn. (Melastomataceae), Roupala montana Aubl. (Proteaceae), Struthanthus syringifolius (Mart.) (Loranthaceae), and Schefflera vinosa (Cham. & Schltdl.) Frodin (Araliaceae) are plant species from the Brazilian Cerrado whose schistosomicidal potential has not yet been described. The crude extracts, fractions, the triterpenes betulin, oleanolic acid, ursolic acid and the flavonoids quercetin 3-O-ß-D-rhamnoside, quercetin 3-O-ß-D-glucoside, quercetin 3-O-ß-D-glucopyranosyl-(1-2)-α-L-rhamnopyranoside and isorhamnetin 3-O-ß-D-glucopyranosyl-(1-2)-α-L-rhamnopyranoside were evaluated in vitro against Schistosoma mansoni adult worms and the bioactive n-hexane fractions of the mentioned species were also analyzed by GC-MS. Betulin was able to cause worm death percentage values of 25% after 120 h (at 100 µM), and 25% and 50% after 24 and 120 h (at 200 µM), respectively; besides the flavonoid quercetin 3-O-ß-D-rhamnoside promoted 25% of death of the parasites at 100 µM. Farther the flavonoids quercetin 3-O-ß-D-glucoside and quercetin 3-O-ß-D-rhamnoside at 100 µM exhibited significantly reduction in motor activity, 75% and 87.5%, respectively. Biological results indicated that crude extracts of R. montana, S. vinosa, and M. langsdorffii and some n-hexane and EtOAc fractions of this species were able to induce worm death to some extent. The results suggest that lupane-type triterpenes and flavonoid monoglycosides should be considered for further antiparasites studies.
RESUMEN
As shown in numerous studies, natural compounds may exert adverse effects, mainly when associated with some drugs. The hydroalcoholic extract of Mikania glomerata is the pharmaceutical form present in commercially available syrup used for the treatment of respiratory diseases in popular Brazilian medicine. The objective of the present investigation was (1) to evaluate the preventive effects of standardized hydroalcoholic extract of M. glomerata (MEx) against antitumoral drug doxorubicin (DXR)-induced micronucleated polychromatic erythrocytes (MNPCE) in a subchronic assay in mice, and (2) to determine the liver content of malondialdehyde (MDA) and the antioxidants glutathione (GSH) and vitamin E (VE). Male Swiss mice were treated for 30 d with MEx added to drinking water, combined or not with DXR (90 mg/kg body weight) injected intraperitoneally (ip) 24 h before analysis. The results demonstrated that MEx produced no genotoxic damage, but significantly increased the frequency of MNPCE induced by DXR, indicating a drug-drug interaction. This rise was not accompanied by lipid peroxidation or antioxidants level reduction, as measured by MDA, GSH, and VE. Despite the presence of coumarin (a known antioxidant), MEx may exert adverse effects probably in association with mutagenic compounds, although this effect on DNA damage did not involve oxidative stress.
Asunto(s)
Antioxidantes/metabolismo , Doxorrubicina/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Mikania/química , Extractos Vegetales/toxicidad , Animales , Daño del ADN/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Hígado/metabolismo , Masculino , Ratones , Pruebas de Micronúcleos , Mutágenos , Extractos Vegetales/químicaRESUMEN
The in vitro activity of the crude hydroalcoholic extract of the aerial parts of Miconia langsdorffii Cogn. was evaluated against the promastigote forms of L. amazonensis, the causative agent of cutaneous leishmaniasis in humans. The bioassay-guided fractionation of this extract led to identification of the triterpenes ursolic acid and oleanolic acid as the major compounds in the fraction that displayed the highest activity. Several ursolic acid semi-synthetic derivatives were prepared, to find out whether more active compounds could be obtained. Among these ursolic acid-derived substances, the C-28 methyl ester derivative exhibited the best antileishmanial activity.
Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Melastomataceae/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Bioensayo/métodos , Estructura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Triterpenos/química , Triterpenos/farmacología , Ácido UrsólicoRESUMEN
No fully effective treatment has been developed since the discovery of Chagas' disease. Since drug-resistant Trypanosoma cruzi strains are occurring and the current therapy is effective in the acute phase but with various adverse side effects, more studies are needed to characterize the susceptibility of T. cruzi to new drugs. Pre-mRNA maturation in trypanosomatids occurs through a process called trans-splicing, which is unusual RNA processing reaction, and it implies the processing of polycistronic transcription units into individual mRNAs; a short transcript spliced leader (SL RNA) is trans-spliced to the acceptor pre-mRNA, giving origin to the mature mRNA. Cubebin derivatives seem to provide treatments with less collateral effects than benznidazole and showed similar or better trypanocidal activities than benznidazole. Therefore, the cubebin derivatives ((-)-6,6'-dinitrohinokinin (DNH) and (-)-hinokinin (HQ)) interference in the mRNA processing was evaluated using T. cruzi permeable cells (Y and BOL (Bolivia) strains) following by RNase protection reaction. These substances seem to intervene in any step of the RNA transcription, promoting alterations in the RNA synthesis, even though the RNA processing mechanism still occurs. Furthermore, HQ presented better activity against the parasites than DNH, meaning that BOL strain seems to be more resistant than Y.
Asunto(s)
Antiprotozoarios/farmacología , Lignanos/farmacología , ARN Mensajero/metabolismo , Trans-Empalme/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/síntesis química , Lignanos/síntesis químicaRESUMEN
The dibenzylbutyrolactone lignan (-)-hinokinin (HK) was obtained by partial synthesis from (-)-cubebin, isolated from the dry seeds of the pepper, Piper cubeba. In view of the trypanocidal activity of HK and its potential as a lead compound for drug development, evaluation of its possible genotoxic activity is required. We have tested HK for possible genotoxicity and evaluated the compound's effect on the activity of the clastogens doxorubicin (DXR) and methyl methanesulfonate (MMS) in the micronucleus (MN) assay with Chinese hamster lung fibroblast V79 cells. HK alone did not induce MN, at concentrations up to 128microM. In combined treatments, HK reduced the frequency of MN induced by MMS. With respect to DXR, HK exerted a protective effect at lower concentrations, but at higher concentrations it potentiated DXR clastogenicity.
Asunto(s)
4-Butirolactona/análogos & derivados , Dioxoles/toxicidad , Doxorrubicina/toxicidad , Lignanos/toxicidad , Metilmetanosulfonato/toxicidad , Mutágenos/toxicidad , 4-Butirolactona/farmacología , 4-Butirolactona/toxicidad , Animales , Benzodioxoles , Línea Celular , Cricetinae , Cricetulus , Dioxoles/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fibroblastos/efectos de los fármacos , Lignanos/farmacología , Pulmón/efectos de los fármacos , Pruebas de MicronúcleosRESUMEN
The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC(50) values ranging from 12.16 to 83.96 microM. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (K(I) values ranging from 0.62 to 16.1 microM). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.
Asunto(s)
Complejo I de Transporte de Electrón/antagonistas & inhibidores , Lignanos/química , Animales , Respiración de la Célula/efectos de los fármacos , Cricetinae , Relación Dosis-Respuesta a Droga , Complejo I de Transporte de Electrón/química , Complejo I de Transporte de Electrón/metabolismo , Concentración 50 Inhibidora , Cinética , Lignanos/farmacología , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Modelos Moleculares , Complejos Multienzimáticos/antagonistas & inhibidores , Complejos Multienzimáticos/metabolismo , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/metabolismo , Conformación Proteica , Subunidades de Proteína/química , Subunidades de Proteína/metabolismoRESUMEN
(-)-Hinokinin, a dibenzylbutyrolactone lignan, exhibits significant trypanocidal activity both in vitro and in vivo, and was obtained by partial synthesis from (-)-cubebin isolated from the dry seeds of Piper cubeba. Considering the good trypanocidal activity of (-)-hinokinin, as well as its potential for the development of new drugs, it is extremely important to evaluate its possible mutagenic activity to allow its safe use in humans. In the present study, we evaluated the antimutagenic effect of (-)-hinokinin on the chromosome damage induced by the chemotherapeutic agent doxorubicin (DXR). The test system employed was the analysis of micronucleated polychromatic erythrocytes in peripheral blood of Wistar rats. Additionally, the antioxidant activity of (-)-hinokinin was evaluated in in vitro experiments by measuring the production of hydrogen peroxide and other peroxides. Our results showed that animals treated with different doses of (-)-hinokinin (10, 20, and 40mg/kgb.w.) exhibited micronucleated cell frequencies similar to that of the negative control. In addition, treatment with combinations of (-)-hinokinin and DXR resulted in lower micronucleated cell frequencies than those observed for animals treated with DXR alone. The present study shows that (-)-hinokinin not only has no genotoxic effect, but is also effective in reducing the chromosome damage induced by DXR. (-)-Hinokinin exerted a significant antioxidant effect on parasite mitochondria in the protocol used, which might be one possible mechanism by which this compound may exert a protective effect on the chromosome damage induced by the free radicals generated by DXR.
Asunto(s)
4-Butirolactona/análogos & derivados , Antimutagênicos/farmacología , Dioxoles/farmacología , Lignanos/farmacología , 4-Butirolactona/farmacología , Animales , Benzodioxoles , Aberraciones Cromosómicas , Doxorrubicina/toxicidad , Femenino , Masculino , Pruebas de Micronúcleos , Ratas , Ratas WistarRESUMEN
The structures of three benzylidenebenzyl butyrolactone lignans (gossypifan, carthamogenin, and savinin) have been established on basis of 1H NMR and 13C NMR spectroscopic data. The 1H NMR and 13C NMR spectra of these lignans have been fully assigned by the use of techniques such as gCOSY, non-edited gHSQC, and gHMBC. Complete assignment and most homonuclear hydrogen coupling constant measurements were performed, also providing enough data for the determination of the relative stereochemistry.
Asunto(s)
Lignanos/química , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/normas , Isótopos de Carbono , Estructura Molecular , Protones , Estándares de ReferenciaRESUMEN
We describe the complete 1H and 13C NMR analysis of three aryltetralin lignan lactones (polygamain, morelensin and 4,5-dimethoxymorelensin) using modern NMR techniques such as COSY, HMQC, HMBC, 2D-J-resolved and NOE experiments. The relative stereochemistry of these compounds, which is very important with regard to their biological activity, was completely determined.