RESUMO
Natural triterpenes exhibit a wide range of biological activities. Since this group of secondary metabolites is structurally diverse, effects may vary due to distinct biochemical interactions within biological systems. In this work, we investigated the anticancer-related activities of the quinone-methide triterpene maytenin and its derivative compound 22-ß-hydroxymaytenin, obtained from Maytenus ilicifolia roots cultivated in vitro. Their antiproliferative and pro-apoptotic activities were evaluated in monolayer and three-dimensional cultures of immortalized cell lines. Additionally, we investigated the toxicity of maytenin in SCID mice harboring tumors derived from a squamous cell carcinoma cell line. Both isolated molecules presented pronounced pro-apoptotic activities in four cell lines derived from head and neck squamous cell carcinomas, including a metastasis-derived cell line. The molecules also induced reactive oxygen species (ROS) and down-regulated microRNA-27a and microRNA-20a/miR-17-5p, corroborating with the literature data for triterpenoids. Intraperitoneal administration of maytenin to tumor-bearing mice did not lead to pronounced histopathological changes in kidney tissue, suggesting low nephrotoxicity. The wide-ranging activity of maytenin and 22-ß-hydroxymaytenin in head and neck cancer cells indicates that these molecules should be further explored in plant biochemistry and biotechnology for therapeutic applications.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Maytenus/química , Triterpenos/química , Triterpenos/farmacologia , Injúria Renal Aguda/induzido quimicamente , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Queratinócitos/efeitos dos fármacos , Camundongos SCID , MicroRNAs/genética , Extratos Vegetais/química , Raízes de Plantas/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Triterpenos/efeitos adversos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rotavirus is one of the leading causes of severe acute gastroenteritis in children under 5 years of age, mainly affecting developing countries. Once the disease is acquired, no specific treatment is available; as such, the development of new drugs for effective antirotaviral treatment is critical. Ursolic acid is a pentacyclic triterpenoid with antiviral activity, which has been studied extensively in vitro and in vivo. To study the potential antirotaviral activity of ursolic acid, its toxic potential for viral particles (virucidal effect) and cultured cells (cytotoxicity) was analysed. No effect on virion infectivity was observed with treatments of up to 40 µM ursolic acid, while incipient cytotoxicity started to be evident with 20 µM ursolic acid. The antiviral potential of ursolic acid was evaluated in in-vitro rotavirus infections, demonstrating that 10 µM ursolic acid inhibits rotavirus replication (observed by a decrease in viral titre and the level of the main viral proteins) and affects viral particle maturation (a process associated with the endoplasmic reticulum) 15 h post infection. Interestingly, ursolic acid was also found to hamper the early stages of the viral replication cycle, as a significant reduction in the number and size of viroplasms, consistent with a decrease in VP6 and NSP2 viral proteins, was observed 4 h post infection. As such, these observations demonstrate that ursolic acid exhibits antiviral activity, suggesting that this chemical could be used as a new treatment for rotavirus.
Assuntos
Antivirais/uso terapêutico , Gastroenterite/tratamento farmacológico , Infecções por Rotavirus/tratamento farmacológico , Rotavirus/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antígenos Virais/metabolismo , Antivirais/efeitos adversos , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Pré-Escolar , Chlorocebus aethiops , Gastroenterite/virologia , Humanos , Testes de Sensibilidade Microbiana , Proteínas de Ligação a RNA/metabolismo , Triterpenos/efeitos adversos , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Ácido UrsólicoRESUMO
Plants belonging to the genus Maytenus are routinely used in folk medicine for the treatment of pain diseases. Our previous phytochemical study of the roots of Maytenus imbricata resulted in the isolation and characterization of tingenone, a pentacyclic triterpene. Natural triterpenoids are of growing interest because they have several biological activities, including analgesic properties. The present study assessed the involvement of the opiodergic pathway in the tingenone-induced antinociceptive effect against hyperalgesia induced by prostaglandin E2 (2 µg) in the peripheral pathway. We evaluated the effect of several antagonists to opioid receptors using the mouse paw pressure test. Tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a nonselective antagonist to opioid receptors. Clocinnamox, naltrindole, and nor-binaltorphimine are selective antagonists to µ, δ, and κ receptors, respectively, which reverted the peripheral antinociception induced by tingenone. Bestatine acts as an inhibitor of aminopeptidase, an enzyme that degrades endogenous opioid peptides, and was shown to intensify the antinociceptive effect of tingenone. The results suggest that the opioidergic system participates in the peripheral antinociception induced by tingenone.
Assuntos
Analgésicos Opioides/farmacologia , Analgésicos/farmacologia , Maytenus/química , Triterpenos/farmacologia , Analgésicos/efeitos adversos , Analgésicos/isolamento & purificação , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/isolamento & purificação , Animais , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Triterpenos/efeitos adversos , Triterpenos/isolamento & purificaçãoRESUMO
Ursolic acid (UA), a pentacyclic triterpene acid found in apple peels (Malus domestica, Borkh, Rosaceae), has a large spectrum of pharmacological effects. However, the vegetal matrix usually produces highly viscous and poorly soluble extracts that hamper the isolation of this compound. To overcome this problem, the crude EtOH-AcOEt extract of commercial apple peels was exhaustively treated with diazomethane, after which methyl ursolate (MU) was purified by column chromatography and characterized spectrometrically. The anti-inflammatory effects of UA and MU (50 mg/kg) were analyzed by zymosan-induced paw edema, pleurisy and in an experimental arthritis model. After 4 h of treatment with UA and MU, paw edema was reduced by 46 and 44 %, respectively. Both UA and MU inhibited protein extravasation into the thoracic cavity; tibio-femoral edema by 40 and 48 %, respectively; and leukocyte influx into the synovial cavity after 6 h by 52 and 73 %, respectively. Additionally, both UA and MU decreased the levels of mediators related to synovial inflammation, such as KC/CXCL-1 levels by 95 and 90 %, TNF-α levels by 76 and 71 %, and IL-1ß levels by 57 and 53 %, respectively. Both the compounds were equally effective when assayed in different inflammatory models, including experimental arthritis. Hence, MU may be considered to be a useful anti-inflammatory derivative to overcome the inherent poor solubility of UA for formulating pharmaceutical products.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Artrite Reumatoide/tratamento farmacológico , Malus/química , Extratos Vegetais/química , Triterpenos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/imunologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Modelos Animais de Doenças , Edema/tratamento farmacológico , Frutas/química , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Óxido Nítrico/metabolismo , Triterpenos/efeitos adversos , Triterpenos/farmacologia , Triterpenos/uso terapêuticoRESUMO
UNLABELLED: Galphimia glauca Cav. has demonstrated anxiolytic activity attributable to nor-seco-triterpenes denominated galphimines, the most active of which is galphimine-B. Galphimine-B inhibits ventral tegmental area dopaminergic neurons and interacts with the serotoninergic system of the dorsal hippocampus. A previous clinical study that administered a G. glauca herbal medicinal product for 4 weeks evidenced high percentages of therapeutic effectiveness and safety in patients with generalized anxiety disorder. Based on the previous findings, the goal of the present study was to evaluate the effectiveness, safety, and tolerability of G. glauca herbal medicinal product administered during 15 weeks in patients with generalized anxiety disorder. STUDY DESIGN: double-blind, randomized, lorazepam-controlled clinical trial. STUDY SUBJECTS: adult males and females, ambulatory, diagnosed with generalized anxiety disorder, with 20 or more points on the Hamilton anxiety scale, without data of depression, and without anxiolytic treatment in the previous month. Interventions were as follows. Experimental treatment: G. glauca herbal medicinal product in capsules containing the dry extract of G. glauca standardized in 0.175 mg of galphimine-B, one or two capsules twice a day, during 12 weeks plus 3 withdrawal weeks, and control treatment: lorazepam 0.5 mg with the same presentation and posology. PRIMARY OUTCOME: anxiolytic effectiveness (≥ 50â% reduction of initial Hamilton anxiety scale score). SECONDARY OUTCOMES: tolerability and safety. One hundred ninety-one patients initiated the study with 94 in the experimental group. One hundred four patients concluded the study, 51 of these in the experimental group. Anxiolytic effectiveness, measured as 0 in a negative case and as 1 in a positive case, was assessed 593 times in the experimental group and 631 in the control; the mean effectiveness observed was 0.686 ± 0.019 vs. 0.588 ± 0.019 (repeated-measures ANOVA; p = 0.0003). In the same way, G. glauca-herbal medicinal product diminished the score in the Hamilton anxiety scale to 11.51 ± 8.27 points and lorazepam to 12.40 ± 8.07 points (repeated-measures ANOVA; p = 0.05). The tolerability analysis, which comprised patients who concluded the treatment plus 11 patients who withdrew due to adverse reactions did not show differences between treatments (p = 0.35), nor did therapeutic safety demonstrate differences between groups (p = 0.21). There were no cases of tolerance, intoxication, dependence, or suppression syndrome. We concluded that G. glauca herbal medicinal product, standardized in 0.175 mg of galphimine-B and administered for 15 weeks to patients with generalized anxiety disorder, showed greater anxiolytic effectiveness than that obtained with lorazepam, with high percentages of therapeutic tolerability and safety.
Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Galphimia/química , Lorazepam/uso terapêutico , Extratos Vegetais/uso terapêutico , Triterpenos/uso terapêutico , Adulto , Ansiolíticos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lorazepam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Caules de Planta/química , Plantas Medicinais/química , Triterpenos/efeitos adversos , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Baccharis dracunculifolia (Asteraceae), the most important plant source of the Brazilian green propolis (GPE), displayed in vitro activity against Leishmania donovani, with an IC(50) value of 45 microg/mL, while GPE presented an IC(50) value of 49 microg/mL. Among the isolated compounds of B. dracunculifolia, ursolic acid, and hautriwaic acid lactone showed IC(50) values of 3.7 microg/mL and 7.0 microg/mL, respectively. Uvaol, acacetin, and ermanin displayed moderate antileishmanial activity. Regarding the antiplasmodial assay against Plasmodium falciparum, BdE and GPE gave similar IC(50) values (about 20 microg/mL), while Hautriwaic acid lactone led to an IC(50) value of 0.8 microg/mL (D6 clone).
Assuntos
Antimaláricos/farmacologia , Baccharis/química , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Tripanossomicidas/farmacologia , Animais , Antimaláricos/efeitos adversos , Antimaláricos/isolamento & purificação , Chlorocebus aethiops , Leishmania donovani/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Fenóis/efeitos adversos , Fenóis/isolamento & purificação , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Folhas de Planta , Plasmodium falciparum/efeitos dos fármacos , Própole , Triterpenos/efeitos adversos , Triterpenos/isolamento & purificação , Tripanossomicidas/efeitos adversos , Tripanossomicidas/isolamento & purificação , Células VeroRESUMO
AIM OF THE STUDY: Vochysia tucanorum is an important medicinal plant used in the Cerrado of Brazil against gastric disorders and this study reveals the pharmacological action of this traditional medicine use. MATERIALS AND METHODS: The methanolic extract (E-MeOH) and buthanolic fraction (Fr-Bu) obtained from V. tucanorum were challenged by different necrotizing agents in rodents. NO-synthase inhibitor (L-NAME) and SH blocker (NEM) were used to evaluate the participation of cytoprotective factors in E-MeOH and Fr-Bu gastroprotection. Antiulcerogenic action of V. tucanorum was evaluated in rats and mice at doses 250, 500 or 1000 mg/kg (E-MeOH) and 37.5, 75 or 150 mg/kg (Fr-Bu). RESULTS: Both E-MeOH and Fr-Bu present elevated gastroprotective action in all in vivo experimental models, without signs of acute toxicity. The mechanisms involved in the gastroprotective action of E-MeOH and Fr-Bu are related to the antioxidant activity and protection to gastric mucosa NO levels. Phytochemical investigations of Fr-Bu identified different pentacyclic triterpenoids such as betulinic acid, erythrodiol, epi-betulinic acid and mixtures of ursolic acid and oleanolic acid derivatives as the major constituents. The presence of such triterpenoids in Fr-Bu is probably related to the potent gastroprotective action of this medicinal plant species. CONCLUSION: Effectiveness in gastroprotection and the absence of acute toxicity indicate this species as a promising herbal drug that is in accordance with ethnopharmacological use against gastric disorders.