Natural-product-inspired design and synthesis of two series of compounds active against Trypanosoma cruzi: Insights into structure-activity relationship, toxicity, and mechanism of action.

Chemical scaffolds of natural products have historically been sources of inspiration for the development of novel molecules of biological relevance, including hit and lead compounds. To identify new compounds active against Trypanosoma cruzi, we designed and synthesized 46 synthetic derivatives based on the structure of two classes of natural products: tetrahydrofuran lignans (Series 1) and oxazole alkaloids (Series 2). Compounds were screened in vitro using a cellular model of T. cruzi infection. In the first series of compounds, 11 derivatives of hit compound 5 (EC50 = 1.1 µM) were found to be active; the most potent (7, 8, and 13) had EC50 values of 5.1-34.2 µM. In the second series, 17 analogs were found active at 50 µM; the most potent compounds (47, 49, 59, and 63) showed EC50 values of 24.2-49.1 µM. Active compounds were assessed for selectivity, hemocompatibility, synergistic potential, effects on mitochondrial membrane potential, and inhibitory effect on trypanothione reductase. All active compounds showed low toxicity against uninfected THP-1 cells and human erythrocytes. The potency of compounds 5 and 8 increased steadily in combination with benznidazole, indicating a synergistic effect. Furthermore, compounds 8, 47, 49, 59, and 63 inhibited parasitic mitochondria in a dose-dependent manner. Although increased reactive oxygen species levels might lead to mitochondrial effects, the results indicate that the mechanism of action of the compounds is not dependent on trypanothione reductase inhibition. In silico calculation of chemical descriptors and principal component analysis showed that the active compounds share common chemical features with other trypanocidal molecules and are predicted to have a good ADMET profile. Overall, the results suggest that the compounds are important candidates to be further studied for their potential against T. cruzi.

Clerodane Diterpenes from the Marine Sponge Raspailia bouryesnaultae Collected in South Brazil.

The marine sponge Raspailia bouryesnaultae, collected in South Brazil, was selected for detailed investigation considering the results of a screening that pointed to an in vitro antiproliferative effect against non-small cells of human lung cancer (A549) and anti-herpes activity against Herpes Simplex virus type 1 (KOS and 29R strains) of ethanolic extracts. The fractionation and chemical investigation of the sponge's hexanic fraction led to the isolation and structural elucidation of six clerodane diterpenes. The main component was identified as the already-reported raspailol (1), isolated from a sponge of the same genus collected in New Zealand. The structure of a new diterpene (2) with a rearranged skeleton was established by high-resolution mass spectrometry (HRMS) and 1D and 2D Nuclear magnetic resonance spectroscopy (NMR) experiments, and named here as raspadiene. Furthermore, four diterpenes were elucidated as isomers of clerodane diterpenes previously obtained from plants, namely kerlinic acid (3), kerlinic acid methyl ester (4), annonene (5), and 6-hydroxyannonene (6). They differ in their stereochemistry, since these diterpenes are characterized by a trans ring fusion at the decalin moiety and the relative configuration of the two methyl groups at C-8 and C-9 in a cis relationship (type trans/cis). The Raspailia diterpenes have a cis ring fusion at the decalin moiety, and the two methyl groups at C-8 and C-9 are in a trans relationship (type cis/trans). The isolated compounds were evaluated for their potential antiproliferative effects on human cancer cell line A549, and it was observed that the diterpenes bearing a hydroxyl group at C-6 exhibited moderate cytotoxic activity, with 50% inhibitory concentration (IC50) values lower than 25 µM. The evaluation of the potential anti-herpes activity against Herpes Simplex Virus type 1 (HSV-1, KOS and 29R strains) showed that the more promising results were observed for the new compound 2, since it inhibited HSV-1 (KOS and 29R strains) replication by 83% and 74%, respectively.

Synthesis and biological evaluation of isoxazolyl-sulfonamides: A non-cytotoxic scaffold active against Trypanosoma cruzi, Leishmania amazonensis and Herpes Simplex Virus.

In this study we report the synthesis, characterization, biological evaluation, and druglikeness assessment of a series of 20 novel isoxazolyl-sulfonamides, obtained by a four-step synthetic route. The compounds had their activity against Trypanosoma cruzi, Leishmania amazonensis, Herpes Simplex Virus type 1 and cytotoxicity evaluated in phenotypic assays. All compounds have drug-like properties, showed low cytotoxicity and were promising regarding all other biological activities reported herein, especially the inhibitory activity against T. cruzi. The compounds 8 and 16 showed significant potency and selectivity against T. cruzi (GI50 = 14.3 µM, SI > 34.8 and GI50 = 11.6 µM, SI = 29.1, respectively). These values, close to the values of the reference drug benznidazole (GI50 = 10.2 µM), suggest that compounds 8 and 16 represent promising candidates for further pre-clinical development targeting Chagas disease.

Antitumor effectiveness of a combined therapy with a new cucurbitacin B derivative and paclitaxel on a human lung cancer xenograft model.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.

Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549.

Cucurbitacins and their derivatives are triterpenoids that are found in various plant families, and are known for their pharmacological and biological activities, including anti-cancer effects. Lung cancer represents a major public health problem, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer. The objective of this work was to evaluate four cucurbitacins (CUCs) for their cytotoxic activity, effects on apoptosis induction, cell cycle progression, anti-migratory, and anti-invasive effects on the human NSCLC cell line (A549 cells). Our findings showed that these CUCs could suppress human NSCLC cell growth in vitro through their effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion. Additionally, these effects culminate in apoptosis induction and G2/M cell cycle arrest by modulating cyclin B1 expression, and in the mitigation of strategic steps of lung cancer metastasis, including migration and invasion of A549 cells. These results suggest that two natural (DDCB and CB) and two novel semisynthetic derivatives of cucurbitacin B (ACB and DBCB) could be considered as promising compounds with antitumor potential.

Ilex paraguariensis Pellets from a Spray-Dried Extract: Development, Characterization, and Stability.

Several studies have shown the potential use of Ilex paraguariensis in developing products with the aim to protect biological systems against oxidative stress-mediated damages. In the same way, technological studies have demonstrated the feasibility of obtaining dry products, by spray-drying process, from aqueous extracts of I. paraguariensis in laboratory. The present work was designed to develop pellets by extrusion/spheronization process, from an I. paraguariensis spray-dried powder. The pellets were characterized with respect to their chemical, physical, and technological properties, and the thermal and the photostability of the main polyphenol constituents were investigated. The pellets exhibited adequate size, shape, and high process yield (78.7%), as well as a good recovery of the total polyphenols (>95%) and a good dissolution in water (89.44 to 100.05%). The polyphenols were stable against light when conditioned in amber glass bottles; unstable against heat when the samples were conditioned either in open glass bottles or in hermetically sealed glass bottles and demonstrated to be hygroscopic and sensible to the temperature, especially when stored in permeable flasks. These findings pointed to the relevance of reducing the residual moisture content of pellets as well as of conditioning them in opaque humidity tight packages under low temperatures. The feasibility of obtaining pellets from an I. paraguariensis spray-dried powder using extrusion/spheronization technique was, for the first time, demonstrated. This finding represents a novelty for the herbal products in both pharmaceutical and food fields.

Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549.

Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer.

Anti HSV-1 activity of halistanol sulfate and halistanol sulfate C isolated from Brazilian marine sponge Petromica citrina (Demospongiae).

The n-butanol fraction (BF) obtained from the crude extract of the marine sponge Petromica citrina, the halistanol-enriched fraction (TSH fraction), and the isolated compounds halistanol sulfate (1) and halistanol sulfate C (2), were evaluated for their inhibitory effects on the replication of the Herpes Simplex Virus type 1 (HSV-1, KOS strain) by the viral plaque number reduction assay. The TSH fraction was the most effective against HSV-1 replication (SI = 15.33), whereas compounds 1 (SI = 2.46) and 2 (SI = 1.95) were less active. The most active fraction and these compounds were also assayed to determine the viral multiplication step(s) upon which they act as well as their potential synergistic effects. The anti-HSV-1 activity detected was mediated by the inhibition of virus attachment and by the penetration into Vero cells, the virucidal effect on virus particles, and by the impairment in levels of ICP27 and gD proteins of HSV-1. In summary, these results suggest that the anti-HSV-1 activity of TSH fraction detected is possibly related to the synergic effects of compounds 1 and 2.

Anti-infective potential of marine invertebrates and seaweeds from the Brazilian coast.

This manuscript describes the evaluation of anti-infective potential in vitro of organic extracts from nine sponges, one ascidian, two octocorals, one bryozoan, and 27 seaweed species collected along the Brazilian coast. Antimicrobial activity was tested against Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212), Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231) by the disk diffusion method. Antiprotozoal activity was evaluated against Leishmania braziliensis (MHOM/BR/96/LSC96-H3) promastigotes and Trypanosoma cruzi (MHOM/BR/00/Y) epimastigotes by MTT assay. Activity against intracellular amastigotes of T. cruzi and L. brasiliensis in murine macrophages was also evaluated. Antiviral activity was tested against Herpes Simplex Virus type 1 (HSV-1, KOS strain) by the plaque number reduction assay (IC50). Cytotoxicity on VERO cells was evaluated by the MTT assay (CC50). The results were expressed as SI = CC50/IC50. The most promising antimicrobial results were obtained against S. aureus and C. albicans with Dragmacidon reticulatum. Among the seaweeds, only Osmundaria obtusiloba showed moderate activity against P. aeruginosa. Concerning antiprotozoal activity, Bugula neritina, Carijoa riseii, Dragmaxia anomala and Haliclona (Halichoclona) sp. showed the most interesting results, mainly against extracellular promastigote forms of L. braziliensis (66, 35.9, 97.2, and 43.6% inhibition, respectively). Moreover, six species of seaweeds Anadyomene saldanhae, Caulerpa cupressoides, Canistrocarpus cervicornis, Dictyota sp., Ochtodes secundiramea, and Padina sp. showed promising results against L. braziliensis (87.9, 51.7, 85.9, 93.3, 99.7, and 80.9% inhibition, respectively), and only Dictyota sp. was effective against T. cruzi (60.4% inhibition). Finally, the antiherpes activity was also evaluated, with Haliclona (Halichoclona) sp. and Petromica citrina showing the best results (SI = 11.9 and SI > 5, respectively). All the active extracts deserve special attention in further studies to chemically characterize the bioactive compounds, and to perform more refined biological assays.

Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives.

Two cucurbitacins, dihydrocucurbitacin B (1) and cucurbitacin B (2), which can be obtained in large amounts from the roots of Wilbrandia ebracteata and from the fruits of Luffa operculata, respectively, were used as starting materials for the preparation of a library of 29 semi-synthetic derivatives. The structural changes that were performed include the removal, modification or permutation of functional groups in rings A and B as well as in the side chain. All new semisynthetic compounds, as well as 1 and 2, were tested in vitro for their cytotoxic effects on non-small-cell lung cancer cells (A549 cells). Some of these compound displayed potent to moderate activity against A549 tumor cells, especially those cucurbitacin B derivatives which were modified at ring A.

Analysis of C-glycosyl flavonoids from South American Passiflora species by HPLC-DAD and HPLC-MS.

INTRODUCTION: Leaves and fruits of Passiflora species are widely used around the world in popular medicine, mainly as sedatives and tranquilisers. C-glycosyl flavonoids are the main components of these species. OBJECTIVE: To investigate the constituent patterns and to develop a chromatographic method for the characterisation of the C-glycosyl flavonoids profile of the extracts of the leaves and the pericarp of South American Passiflora species. METHODOLOGY: The chemical composition of extracts from the leaves and the fruits' pericarp of Passiflora edulis var. flavicarpa, P. edulis var. edulis, Passiflora alata, Passiflora tripartita var. mollissima, Passiflora quadrangularis, Passiflora manicata and Passiflora ligularis was evaluated for the presence of C-glycosyl flavonoids. Two separate HPLC methods were developed suitable for a diode array detector (DAD) and a MS detector. Separation by HPLC-DAD was achieved on a Luna C-18 column, using solvent A (tetrahydrofuran-isopropanol-acetonitrile) and solvent B (H3PO4 0.5%) in an isocratic elution mode. In the HPLC-MS, the components were separated on a Luna RP-18A column by a gradient elution (water-acetonitrile-formic acid). RESULTS: The presence of C-glycosyl flavonoids was identified in leaves and pericarp of P. edulis var. flavicarpa, P. alata, P. edulis var. edulis and P. tripartita var. molissima, but only in leaf extracts of P. quadrangularis and P. manicata and not at all in P. ligularis. The different species and varieties showed different major constituents. The C-glycosyl flavonoids identified more frequently were orientin, isoorientin, vitexin and isovitexin. CONCLUSION: The methods established are simple and can be used as a tool for the characterisation and quality control of pharmaceutical preparations containing these Passiflora extracts.

Antifouling activities against colonizer marine bacteria of extracts from marine invertebrates collected in the Colombian Caribbean Sea and on the Brazilian coast (Santa Catarina).

The growth inhibition of 12 native marine bacteria isolated from Aplysina sponge surfaces, the shell of a bivalve, and Phytagel immersed for 48 h in sea water were used as indicator of the antifouling activity of the extracts of 39 marine organisms (octocorals, sponges, algae, and zoanthid) collected in the Colombian Caribbean Sea and on the Brazilian coast (Santa Catarina). Gram-negative bacteria represented 75% of the isolates; identified strains belonged to Oceanobacillus iheyensis, Ochrobactrum pseudogrignonense, Vibrio campbellii, Vibrio harveyi, and Bacillus megaterium species and seven strains were classified at genus level by the 16S rRNA sequencing method. The extracts of the octocorals Pseudopterogorgia elisabethae, four Eunicea octocorals, and the sponges Topsentia ophiraphidites, Agelas citrina, Neopetrosia carbonaria, Monanchora arbuscula, Cliona tenuis, Iotrochota imminuta, and Ptilocaulis walpersii were the most active, thus suggesting those species as antifoulant producers. This is the first study of natural antifoulants from marine organisms collected on the Colombian and Brazilian coasts.

Cytotoxic halogenated metabolites from the Brazilian red alga Laurencia catarinensis.

Seven new (1-7) and seven previously reported (8-14) halogenated metabolites were isolated from the organic extract of the Brazilian red alga Laurencia catarinensis. The structure elucidation and the assignment of the relative configurations of the new natural products were based on detailed NMR and MS spectroscopic analyses, whereas the structure of metabolite 6 was confirmed by single-crystal X-ray diffraction analysis. The absolute configuration of metabolite 1 was determined using the modified Mosher's method. The in vitro cytotoxicity of compounds 1-14 was evaluated against HT29, MCF7, and A431 cell lines.

Neuropharmacological activity of the pericarp of Passiflora edulis flavicarpa degener: putative involvement of C-glycosylflavonoids.

Passiflora edulis has been used in traditional medicine as a sedative and to treat or prevent central disorders such as anxiety and insomnia. In this study, the central effects of the aqueous extract (AE), the butanolic fraction (BF), and the aqueous residual fraction (ARF) obtained from the pericarp of P. edulis flavicarpa were investigated in mice and the possible compounds involved in these putative neuropharmacologic effects were determined. AE, BF, and ARF increased the total time spent in the light compartment of the light:dark box, an anxiolytic-like effect, and AE also potentiated the hypnotic effects of ethyl ether, a sedative effect. The thin layer chromatography and high-performance liquid chromatography analysis indicated the predominance of C-glycosylflavonoids in these extracts and fractions, which were identified as isoorientin, vicenin-2, spinosin, and 6,8-di-C-glycosylchrysin.

Bioassay-guided isolation of anti-inflammatory C-glucosylflavones from Passiflora edulis.

Passiflora edulis, commonly known as "maracujá", is widely cultivated in Brazil for the industrial production of juice. The species of Passiflora are popularly used as a sedative or tranquillizer, and also against intermittent fever and skin inflammation. In this study we evaluated the anti-inflammatory activity of four sub-fractions and three isolated compounds from the butanolic fraction of P. edulis var. flavicarpa leaves, using the mouse model of pleurisy induced by carrageenan. The butanolic fraction obtained from an aqueous extract of P. edulis (50 and 100 mg/kg, I. P.) showed anti-inflammatory activity by inhibiting leukocytes and neutrophils (p < 0.01). Sub-fraction C showed itself to be more effective than the other sub-fractions (p < 0.01). Isoorientin ( 1), vicenin-2 ( 2) and spinosin ( 3) were isolated from the active sub-fraction C derived from the butanolic fraction. The sub-fraction C (50 mg/kg, I. P.), as well as its major isolated compounds (25 mg/kg, I. P.), inhibited leukocytes and neutrophils (p < 0.05). Additionally, the butanolic fraction and isoorientin also inhibited myeloperoxidase activity (p < 0.05). The present study showed that the C-glucosylflavones isolated from P. edulis leaves can be responsible for the anti-inflammatory effect of P. edulis on the mouse model of pleurisy.

The anti-inflammatory modulatory role of Solidago chilensis Meyen in the murine model of the air pouch.

The aim of this study was to investigate the anti-inflammatory efficacy of an aqueous extract (AE), and its butanolic (BuOH) and aqueous residual (AR) fractions, derived from the rhizome of Solidago chilensis in inflammation caused by carrageenan in mice. Solidago chilensis Meyen rhizome was extracted using hot water at 90 degrees C under infusion. The extract was filtered and lyophilized. Part of the aqueous extract was fractionated with n-BuOH, resulting in butanolic (BuOH) and aqueous residual (AR) fractions. Adult Swiss mice were used in the in-vivo experiments. We evaluated the effect of rhizome aqueous extract of Solidago chilensis and these two derived fractions on the inflammation induced by carrageenan in the mouse model of the air pouch. The aqueous extract and its derived fractions significantly inhibited leucocytes, neutrophils, exudation, myeloperoxidase and adenosine deaminase activity, as well as nitric oxide, interleukin-1 beta (IL-1beta), neutrophil chemokine (KC) and tumour necrosis factor-alpha (TNF-alpha) levels (P < 0.05). Indometacin and dexamethasone inhibited all the studied inflammatory parameters (P < 0.01) with the exceptions that indometacin did not inhibit TNF-alpha levels and dexamethasone did not inhibit KC levels (P > 0.05). These results indicate that Solidago chilensis has a significant anti-inflammatory action on acute inflammatory responses and that its inhibitory activity may be due not only to the inhibition of proinflammatory mediators, but also to the inhibition of leucocyte infiltration.

The sedative activity of flavonoids from Passiflora quadrangularis is mediated through the GABAergic pathway.

The aim of this study was to investigate the sedative activity of the aqueous leaf extract of Passiflora quadrangularis, a species that is widely cultivated and consumed in South America, and to identify its main constituents and elucidate the involvement of the GABAergic pathway in its mechanism of action. The bioguided fractionation of the crude extract showed a positive relationship between the sedative activity of the extract and its flavonoids. The methods employed to identify and isolate its main flavonoids resulted in the identification of vitexin-2''-O-xyloside, vitexin-2''-O-glucoside, orientin-2''-O-xyloside and orientin-2''-O-glucoside. Vitexin-2"-O-xyloside, the major flavonoid of the extract, showed sedative activity after oral administration in mice.

TSH fraction from Petromica citrina: A potential marine natural product for the treatment of sepsis by Methicillin-resistant Staphylococcus aureus (MRSA).

BACKGROUND AND PURPOSE: Antibiotic resistance is now a worldwide public health problem. A potential alternative source in the search for new antibiotics is the bioactive molecules obtained from marine products, as the halistanol trisulfate, obtained from Petromica citrina, and herein investigated from its antimicrobial and anti-inflammatory properties. EXPERIMENTAL APPROACH: The antimicrobial activity of the fractionation products (TSH fraction, halistanol sulfate (HS) and halistanol sulfate C (HS-C)) of the marine sponge Petromica citrina was evaluated against twenty bacteria and two fungi strains by the disk diffusion and microdilution methods. After initial in vitro tests, an in vivo assay was proposed, to evaluate survival and inflammatory parameters in an animal model of peritonitis mediated by MRSA. The animals are treated with TSH fraction (1, 2.5 and 5 mg kg-1) or Vancomycin (30 mg kg-1) twice (6 and 18 h after induction) until organ removal for evaluation of the inflammatory profile, or for 3 days, 12 h each (6 h, 18 h, 30 h, 42 h, 54 h and 66 h after induction) in animals which were followed-up for by five days, for the evaluation of survival. KEY RESULTS: The BF fraction, TSH fraction, HS and HS-Cinhibited, in vitro, the Enterococcus faecalis, Staphylococcus aureus and Candida albicans growth. Moreover, these samples were effective against S. aureus (MSSA), MRSA and Vancomycin-Resistence Enterococcus (VRE). The in vivo results demonstrated that TSH fraction reduced mortality when compared to the saline group. To evaluate the role of inflammation in outcomes of peritonitis, cytokines (IL-1ß, IL-6, TNF-α) and MPO activity were measured. In general, anti-inflammatory activity was detected in animals treated with TSH in different doses. CONCLUSION AND IMPLICATIONS: These data suggest that TSH may be an interesting alternative for the treatment infections by Gram-positive resistant bacteria, due to its antimicrobial profile associated with its anti-inflammatory properties.

Evidence of anti-inflammatory effects of Passiflora edulis in an inflammation model.

UNLABELLED: The popular medicine Passiflora edulis has been used as a sedative, tranquilizer, against cutaneous inflammatory diseases and intermittent fever. Most of the pharmacological investigations of Passiflora edulis have been addressed to its Central Nervous System activities, such as anxiolytic, anticonvulsant and sedative actions. Otherwise, there are few reports about the anti-inflammatory activity of the Passiflora species. The aim of this study was to investigate the mechanism of the anti-inflammatory effect of aqueous lyophilized extract obtained from leaves of Passiflora edulis var. flavicarpa Degener (Passifloraceae) in the mouse model of pleurisy induced by carrageenan (Cg), bradykinin, histamine or substance P, observing the effects upon leucocytes migration, myeloperoxidase (MPO), nitric oxide (NO) concentrations and tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1beta) levels. RESULTS: Passiflora edulis (250mg/kg) administered by intraperitoneal route (i.p.) inhibited the leukocyte, neutrophils, myeloperoxidase, nitric oxide, TNFalpha and IL-1beta levels (P<0.01) in the pleurisy induced by carrageenan. Passiflora edulis (250-500mg/kg, i.p.) also inhibited total and differential leukocytes in the pleurisy induced by bradykinin, histamine or substance P (P<0.05). CONCLUSION: Several mechanisms, including the inhibition of pro-inflammatory cytokines (TNFalpha, IL-1beta), enzyme (myeloperoxidase) and mediators (bradykinin, histamine, substance P, nitric oxide) release and/or action, appear to account for Passiflora edulis's actions.

Anti-inflammatory evaluation of Solidago chilensis Meyen in a murine model of pleurisy.

UNLABELLED: The aim of this study was to investigate the anti-inflammatory effects and the mechanism of action of the aqueous extracts obtained from rhizomes, leaves and inflorescences of Solidago chilensis in the mouse model of pleurisy. The extracts were prepared by infusion and were lyophilized. RESULTS: The aqueous extracts of rhizomes, leaves or inflorescences inhibited leukocytes, neutrophils and exudation (P<0.05) in the inflammation induced by carrageenan. The rhizomes aqueous extract, butanolic and aqueous residual fractions inhibited leukocytes, neutrophils, myeloperoxidase, adenosine-deaminase, and tumor necrosis factor alpha levels in the inflammation induced by carrageenan (P<0.05). The rhizome aqueous extract and butanolic fraction also inhibited exudation, nitric oxide, and interleukin-1 beta levels (P<0.05). The rhizomes aqueous extract and its two derived fractions reduced leukocytes and mononuclears in the pleurisy induced by bradykinin, histamine, or substance P (P<0.05) and neutrophils in the pleurisy induced by histamine or substance P (P<0.05). Only aqueous residual fraction inhibited neutrophils induced by bradykinin (P<0.05). CONCLUSION: Solidago chilensis aqueous extracts from leaves, inflorescences and rhizomes demonstrated an important anti-inflammatory effect, inhibiting cells in the inflammation caused by carrageenan. In addition, the rhizomes aqueous extract and its derived fractions also decreased pro-inflammatory mediators release into the site of the inflammatory process. The rhizomes aqueous extract and the butanolic fraction showed more evident anti-inflammatory actions.