Kaurenoic acid [ent-kaur-16-en-19-oic acid (1)] is a diterpene present in several plants including Sphagneticola trilobata. The only documented evidence for its antinociceptive effect is that it inhibits the writhing response induced by acetic acid in mice. Therefore, the analgesic effect of 1 in different models of pain and its mechanisms in mice were investigated further. Intraperitoneal and oral treatment with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid. Oral treatment with 1 also inhibited overt nociception-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), and both phases of the formalin test. Compound 1 also inhibited acute carrageenin- and PGE(2)-induced and chronic CFA-induced inflammatory mechanical hyperalgesia. Mechanistically, 1 inhibited the production of the hyperalgesic cytokines TNF-α and IL-1β. Furthermore, the analgesic effect of 1 was inhibited by l-NAME, ODQ, KT5823, and glybenclamide treatment, demonstrating that such activity also depends on activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that 1 exhibits an analgesic effect in a consistent manner and that its mechanisms involve the inhibition of cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.
Abstract. Pimenta pseudocaryophyllus is a Brazilian native plant that presents high concentrations of flavonoids and other polyphenolic compounds. Herein, we evaluated: (1) the chemical properties of P. pseudocaryophyllus ethanolic extract (PPE), (2) the in vitro antioxidant activity (AA) of PPE and of two different topical formulations (F1 and F2) containing PPE, (3) physico-chemical and functional stability, (4) in vitro release of PPE, and (5) in vivo capacity of formulations to prevent UV-B irradiation-induced skin damage. Results show that the polyphenol and flavonoid contents in PPE were 199.33 and 28.32 mg/g, respectively, and HPLC results show the presence of eugenol, tannic acid, and rutin. Evaluation of the in vitro AA of PPE demonstrated a dose-dependent effect and an IC 50 of 4.75 μg/mL in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 3.0 μg/mL in 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. The ferric-reducing antioxidant power (FRAP assay) was 0.046 μmol/L trolox equivalent/ μg/mL of extract. Among the AA, only the capacity to scavenge DPPH radical of PPE was maintained in F1 and F2. In addition, both formulations satisfactorily released the extract. The evaluation of the functional stability of F1 and F2 did not demonstrate loss of activity by storage at room temperature and at 4°C/6 months. In irradiated mice, treatment with F1 and F2 added with PPE significantly increased the capacity to scavenge ABTS radical and the FRAP of skin compared to vehicle-treated mice. In conclusion, the present results suggest that formulations containing PPE may be a topical source of antioxidant compounds to decrease oxidative damages of the skin.
Hypericum perforatum is a medicinal plant with anti-inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)-induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15-3.0 g/kg, p.o.) induced dose-dependent mortality. The sub-maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30-300 mg/kg, i.p.) dose-dependently reduced paracetamol-induced lethality. Paracetamol-induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL-1β, TNF-α, and IFN-γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate radical cation; ABTS˙(+) ) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol-induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol-induced cytokine production, neutrophil recruitment, and oxidative stress.
Five structurally related pimarane diterpenes isolated from the roots of Viguiera arenaria and a further compound obtained by chemical derivatization were evaluated in vitro against the trypomastigote forms of Trypanosoma cruzi. The natural compound ent-15-pimarene-8 beta,19-diol and the derivative ent-8(14),15-pimaradiene-3beta-acetoxy showed the highest trypanocidal activity, displaying IC(50) values of 116.5 +/- 1.21 and 149.3 +/- 1.07 microM, respectively, while the positive control, violet gentian, showed an IC(50) of 76 microM. Based on the results, it can be concluded that minor structural differences among the tested diterpenes influence significantly the trypanocidal activity, thus bringing new perspectives to the establishment of structure-activity relationships among this type of metabolites to the treatment of Chagas' disease.
A biotransformação da lignana tetraidrofurânica, (-)-grandisina, pelo fungo endofítico Phomopsis sp, obtido de Viguiera arenaria, conduziu à formação de um novo metabólito caracterizado como 3,4-dimetil-2-(4'-hidróxi-3',5'-dimetóxifenil)-5-metóxi-tetraidrofurano. O metabólito foi analisado contra o parasita Trypanosoma cruzi, o agente causador da doença de Chagas, e mostrou uma atividade tripanocida (IC 50 9,8 µmol L -1 ) similar ao precursor natural (IC 50 3,7 µmol L -1 ).The biotrasformation of the tetrahydrofuran lignan, (-)-grandisin, by the endophitic fungus Phomopsis sp, obtained from Viguiera arenaria, led to the formation of a new compound determined as 3,4-dimethyl-2-(4'-hydroxy-3',5'-dimethoxyphenyl)-5-methoxy-tetrahydrofuran. The metabolite was evaluated against the parasite Trypanosoma cruzi, the causative agent of Chagas's disease, and showed a trypanocidal activity (IC 50 9.8 µmol L -1 ) similar to the natural precursor (IC 50 3.7 µmol L -1 ).Keywords: biotransformation, 2,5-diaryltetrahydrofuran, endophytic fungus, (-)-grandisin, trypanocidal activity IntroductionThe lignan family is a large group of natural products with noteworthy therapeutic activity as illustrated by podophyllotoxin derivatives (e. g. etoposide) with antitumoral activity. 1 In particular, the optically active tetrahydrofuran lignans display a wide range of pharmacological activities, including anti-parasite, 2-4 antibacterial, 5 antifungal, 6 antitumoral, 7 anti-inflammatory 8,9 and platelet-activating factor (PAF) inhibition. [10][11][12] Several non-symmetrical 2,5-diaryltetrahydrofuran lignans, shown in Table 1, have been isolated from Piper species (Piperaceae) containing either piperonyl, veratryl or 3,4,5-trimethoxyphenyl substituent at 2 and 5 positions and methyl groups at 3 and 4 positions attached to the tetrahydrofuran ring, as illustrated by (+)-calopiptin P. futokadsura, P. hancei, P. puberculum, P.wallichii), (-)-galbelgin (5, P. attenuatum, P. futokadsura, P. thomsoni, P. wightii), (+)-grandisin (6, P. polysyphorum), (+)-machilin G (7, P. schmidtii, P. wightii), (+)-veraguensin (8, P. cuneifolium, P. futokadsura, P. puberculum) and (-)-zuonin A (9, P. schmidtii). 13 Other bis-tetrahydrofuran lignans have also been described from Achillea lingulata (Asteraceae). 14 In previous reports, Martins et al. 3 described the isolation of (-)-grandisin (6) from Piper solmsianum and Lopes and co-workers 4,15 from Virola surinamensis (Rol.) Warb, which belong to Piperaceae and Myristicaceae, respectively. The tetrahydrofuran lignan (-)-grandisin (6) showed a potent trypanocidal activity against the trypomastigote form of Trypanosoma cruzi, responsible for Chagas´s disease in Latin America, at 5 µg mL -1 leading to a total parasite lysis after 24 h, without hematiae damage. 4 Furthermore, veraguensin (8) also isolated from Virola surinamensis 4 preserved this anti-parasite pattern along with a potent platelet-activating factor (PAF) inhibitory activity that may be involved in the mechanisms of the parasite growing and diffe...
Através do emprego da técnica de microamostragem de tricomas glandulares e análises por CLAE em sistema isocrático, foi efetuada a investigação química dos tricomas glandulares de diferentes populações de duas espécies de Viguiera. Nas seis amostras de V. robusta analisadas, o furanoeliangolido budleína A e seus isômeros contendo tiglato e metacrilato foram detectados como constituintes majoritários. Também foram detectados vários outros constituintes, na maioria em quantidades bem menores ou apenas traços. O perfil químico de todas as amostras foi qualitativamente muito similar, caracterizando V. robusta como um táxon com elevada "quimioconsistência". Por outro lado, V. quinqueremis representou um exemplo de "quimiodiversidade". Embora a budleína A e seus derivados também estivessem presentes em cinco das seis populações analisadas, outros heliangolidos e germacranolidos também ocorreram e dominaram parcialmente em quantidade. Padrões distintos destas substâncias dividiram as amostras de V. quinqueremis em três subgrupos químicos.A chemical survey on the glandular trichome chemistry of different populations of two Brazilian Viguiera species has been performed by the glandular trichome microsampling technique and isocratic HPLC analyses. In all six analysed samples of V. robusta, the furanoheliangolide budlein A and its tiglate and methacrylate isomers were detected as the major compounds. They were accompanied by various constituents in mostly minor or trace amounts. The chemical pattern of all samples was qualitatively very similar, thus featuring V. robusta as a taxon of high "chemoconsistency". In contrast, V. quinqueremis represented an example of "chemodiversity". Although budlein A and its derivatives were present in five of the six analysed populations, other heliangolides and germacrolides co-occurred and partly dominated in quantity. Distinct compound patterns divided the samples of V. quinqueremis into three chemical subgroups.
This work is dedicated to the late Prof. Sílvio J. Sarti (FCFRP-USP)In addition to known heliangolides, a new eudesmanolide was isolated from the leaf rinse extract of Viguiera robusta (Asteraceae). Structural elucidation was based on spectral analysis. It is the first report on eudesmanolides in members of the subgenus Calanticaria of Viguiera. In this work, the main isolated compound, the furanoheliangolide budlein A, besides its previously reported in vitro and in vivo anti-inflammatory activities, inhibited human neutrophil elastase release. The inhibition was at the concentration of (16.83 ð 1.96) μm for formylated bacterial tripeptide (fMLP) stimulation and (11.84 ð 1.62) μm for platelet aggregation factor (PAF) stimulation, being slightly less active than the reference drug parthenolide. The results are important to demonstrate the potential anti-inflammatory activities of sesquiterpene lactones and corroborate the previous studies using other targets.
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