Ouratea spectabilis and its Biflavanone Ouratein D Exert Potent Anti-inflammatory Activity in MSU Crystal-induced Gout in Mice.

Gouty arthritis (GA) is an inflammatory arthritis triggered by the deposition of monosodium urate monohydrate (MSU) crystals, causing pain, inflammation, and joint damage. Several drugs are currently employed to manage acute flares of GA, but they either have limited effectiveness or induce severe adverse reactions. Ouratea spectabilis is traditionally used in Brazil to treat gastric ulcers and rheumatism. The ethanolic extract of O. spectabilis stems (OSpC) and four biflavanones (ouratein A - D) isolated thereof were evaluated in a murine model of GA induced by the injection of MSU crystals. The underlying mechanism of action of ouratein D was investigated in vitro in cell cultures by measurement of IL-1ß levels by ELISA and Western blot analysis. The administration of OSpC (10, 30 or 100 mg/Kg, p. o.) reduced the migration of total inflammatory cells, monocytes, and neutrophils and diminished the levels of IL-1ß and CXCL1 in the synovial tissue. Among the tested compounds, only ouratein D (1 mg/Kg) reduced the migration of the inflammatory cells and it was shown to be active up to 0.01 mg/Kg (equivalent to 0.34 nM/Kg, p. o.). Treatment of pre-stimulated THP-1 cells (differentiated into macrophages) or BMDMs with ouratein D reduced the release of IL-1ß in both macrophage lines. This biflavanone reduced the activation of caspase-1 (showed by the increase in the cleaved form) in supernatants of cultured BMDMs, evidencing its action in modulating the inflammasome pathway. The obtained results demonstrate the anti-gout properties of O. spectabilis and point out ouratein D as the bioactive component of the assayed extract.

Oral sub-chronic treatment with Terminalia phaeocarpa Eichler (Combretaceae) reduces liver PTP1B activity in a murine model of diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: The endemic Brazilian medicinal plants of the genus Terminalia (Combretaceae), popularly known as capitão, comprising the similar species Terminalia phaeocarpa Eichler and Terminalia argentea, are traditionally and indistinguishably used in the country to treat diabetes. AIM OF THE STUDY: The present work investigated the effect of 28 days of treatment with the crude ethanolic extract (CEE) and its derived ethyl acetate fraction (EAF) from T. phaeocarpa leaves in a mice model of diabetes. MATERIALS AND METHODS: Streptozotocin-nicotinamide-fructose diabetic model was used to evaluate the antidiabetic activity of 28 days of treatment with the CEE and EAF from the leaves of T. phaeocarpa and metformin as a positive control. Serum levels of total cholesterol, triglycerides, uric acid, ALP, AST, and ALT were measured with specific commercial kits and glucose with a strip glucometer. The thiobarbituric acid method measured the liver MDA level, while a colorimetric assay measured the GSH level and PTP1B activity. A UPLC-DAD profile was obtained to identify the main polyphenolic compound in the EAF. RESULTS: Treatment with CEE and EAF reduced plasma glucose in diabetic mice. At the end of the treatment, the plasma glucose level was significantly lower in EAF-treated (100 mg/kg) diabetic mice (106.1 ± 13.7 mg/dL) than those treated with 100 mg/kg CEE (175.2 ± 20.9 mg/dL), both significantly lower than untreated diabetic mice (350.4 ± 28.1 mg/dL). The serum levels of total cholesterol, triglycerides, uric acid, ALP, AST, and ALT were significantly reduced in diabetic mice treated with CEE and EAF. In the livers of diabetic mice, the treatment with CEE and EAF reduced MDA levels and the activity of the enzyme PTP1B (96.9 ± 3.7%, 113.8 ± 2.8%, and 134.8 ± 4.6% for CEE-, EAF-treated, and untreated diabetic mice, respectively). Galloylpunicalagin was the main polyphenol observed in the EAF of T. phaeocarpa. CONCLUSION: The present results demonstrate the significant antidiabetic effect of CEE and EAF of T. phaeocarpa and their reduction on the markers of liver dysfunction in diabetic mice. Moreover, the antidiabetic activity of T. phaeocarpa might be associated with lowering the augmented activity of the PTP1B enzyme in the liver of diabetic mice.

Bioguided chemical characterization of pequi (Caryocar brasiliense) fruit peels towards an anti-diabetic activity.

Pequi fruit peels are an underexploited source of polyphenols. The anti-diabetic potential of an extract and fractions from the peels were evaluated in a panel of assays. The extract and fractions thereof inhibited the release of cytokines involved in insulin resistance - TNF, IL-1ß, and CCL2 - by lipopolysaccharide-stimulated THP-1 cells. The ethyl acetate fraction inhibited in vitro α-glucosidase (pIC50 = 4.8 ± 0.1), an enzyme involved in the metabolization of starch and disaccharides to glucose, whereas a fraction enriched in tannins (16C) induced a more potent α-glucosidase inhibition (pIC50 = 5.3 ± 0.1). In the starch tolerance test in mice, fraction 16C reduced blood glucose level (181 ± 10 mg/dL) in comparison to the vehicle-treated group (238 ± 11 mg/dL). UPLC-DAD-ESI-MS/MS analyses disclosed phenolic acids and tannins as constituents, including corilagin and geraniin. These results highlight the potential of pequi fruit peels for developing functional foods to manage type-2 diabetes.

Determination of l-(+)-bornesitol, the hypotensive constituent of Hancornia speciosa, in rat plasma by LC-MS/MS and its application on a pharmacokinetic study.

Hancornia speciosa is a medicinal plant with proven antihypertensive activity. The cyclitol l-(+)-bornesitol is the main constituent of its leaves and is a potent inhibitor of the angiotensin-converting enzyme. We herein investigated the pharmacokinetic properties of bornesitol administered orally to Wistar rats, as well as bornesitol permeation in Caco-2 cells. Bornesitol was isolated and purified from an ethanol extract of H. speciosa leaves. An ultra-high performance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated to quantify bornesitol in rat plasma based on Multiple Reaction Monitoring, using pentaerythritol as an internal standard. Pharmacokinetics was evaluated by the administration of single doses via intravenous in bolus (3 mg/kg) and gavage (3, 15 and 25 mg/kg). Bornesitol permeation was assayed in a transwell Caco-2 cells model, tested alone, or combined with rutin, or as a constituent of H. speciosa extract, using a developed and validated UPLC-ESI-MS/MS method. All assayed validation parameters (selectivity, residual effect, matrix effect, linearity, precision, accuracy and stability of analyte in plasma and solution) for the bioanalytical method met the acceptance criteria established by regulatory guidelines. Bornestiol reached peak plasma concentration within approximately 60 min after oral administration with a half-life ranging from 72.15 min to 123.69 min. The peak concentration and area under the concentration-time curve of bornesitol did not rise proportionally with the increasing doses, suggesting a non-linear pharmacokinetics in rats and the oral bioavailability ranged from 28.5%-59.3%. Bornesitol showed low permeability in Caco-2 cells, but the permeability apparently increased when it was administered either combined with rutin or as a constituent of H. speciosa extract. In conclusion, bornesitol was rapidly absorbed after a single oral administration to rats and followed a non-linear pharmacokinetics. The obtained data will be useful to guide further pre-clinical development of bornesitol-containing herbal preparations of H. speciosa as an antihypertensive agent.

(3,3″)-Linked Biflavanones from Ouratea spectabilis and Their Effects on the Release of Proinflammatory Cytokines in THP-1 Cells.

Ouratea spectabilis is an arborous species traditionally used in Brazil as an anti-inflammatory agent. Four new (3,3″)-linked biflavanone O-methyl ethers, named ouratein A (1), B (2), C (3), and D (4), were isolated from the bark extract of the species. Ouratein A (1) is an enantiomer of neochamagesmine A, which has never been described before. The structures were elucidated by extensive spectroscopic data analyses, whereas their absolute configurations were defined by electronic circular dichroism data. Ouratein D (4) inhibited in vitro the release of the pro-inflammatory cytokine CCL2 by lipopolysaccharide-stimulated THP-1 cells (IC50 of 3.1 ± 1.1 µM), whereas TNF and IL-1ß release were not reduced by any of the biflavanones. These findings show ouratein D (4) as a selective CCL2 inhibitor, which may have potential for the development of new anti-inflammatory agents to prevent or treat cardiovascular diseases.

The Cyclitol L-(+)-Bornesitol as an Active Marker for the Cardiovascular Activity of the Brazilian Medicinal Plant Hancornia speciosa.

The cyclitol bornesitol is the main constituent of the leaves from the antihypertensive medicinal plant Hancornia speciosa. This study aimed to investigate the ability of bornesitol to reduce blood pressure and its mechanism of action. Normotensive Wistar rats were divided into control group and bornesitol groups treated intravenously with bornesitol (0.1, 1.0 and 3.0 mg/kg). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded in non-anesthetized awake animals. Nitric oxide (NO) and angiotensin-converting enzyme (ACE) were measured in plasma by using colorimetric methods. Vascular reactivity study was performed in rat aorta rings and the involvement of nitric oxide synthase (NOS), calcium-calmodulin complex and phosphatidylinositol-3-kinase (PI3K)/Akt pathway in the vasodilator effect was investigated. Administration of bornesitol significantly reduced the SBP, increased the plasmatic level of nitrite, and decreased ACE activity in normotensive rats. In the rat aorta, bornesitol induced endothelium-dependent vasodilatation, which was abolished by NOS blockade. While calcium-calmodulin complex inhibition decreased the vasodilator effect of bornesitol, the inhibition of PI3K/Akt pathway did not alter it. Bornesitol reduced the blood pressure by a mechanism involving an increased production or bioavailability of NO, inhibition of ACE, and by an endothelium- and NO-dependent vasodilator effect. The present results support the use of bornesitol as an active marker for the cardiovascular activity of Hancornia speciosa.

Production of the Cytotoxic Cardenolide Glucoevatromonoside by Semisynthesis and Biotransformation of Evatromonoside by a Digitalis lanata Cell Culture.

Recent studies demonstrate that cardiac glycosides, known to inhibit Na+/K+-ATPase in humans, have increased susceptibility to cancer cells that can be used in tumor therapy. One of the most promising candidates identified so far is glucoevatromonoside, which can be isolated from the endangered species Digitalis mariana ssp. heywoodii. Due to its complex structure, glucoevatromonoside cannot be obtained economically by total chemical synthesis. Here we describe two methods for glucoevatromonoside production, both using evatromonoside obtained by chemical degradation of digitoxin as the precursor. 1) Catalyst-controlled, regioselective glycosylation of evatromonoside to glucoevatromonoside using 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as the sugar donor and 2-aminoethyldiphenylborinate as the catalyst resulted in an overall 30 % yield. 2) Biotransformation of evatromonoside using Digitalis lanata plant cell suspension cultures was less efficient and resulted only in overall 18 % pure product. Structural proof of products has been provided by extensive NMR data. Glucoevatromonoside and its non-natural 1-3 linked isomer neo-glucoevatromonoside obtained by semisynthesis were evaluated against renal cell carcinoma and prostate cancer cell lines.

In Vitro TNF-α Inhibitory Activity of Brazilian Plants and Anti-Inflammatory Effect of Stryphnodendron adstringens in an Acute Arthritis Model.

Stryphnodendron species, popularly named "barbatimão," are traditionally used in Brazil as anti-inflammatory agents. This study aimed to investigate the effect of barbatimão and 11 other species on the production of tumor necrosis factor-alpha (TNF-α) in lipopolysaccharide- (LPS-) stimulated THP-1 cells, as well as their anti-arthritis activity. The extracts of Stryphnodendron adstringens, Stryphnodendron obovatum, Campomanesia lineatifolia, and Terminalia glabrescens promoted a concentration-dependent inhibition of TNF-α. Mice injected with LPS in the knee joint were treated per os with fractions from the selected extracts. Both the organic (SAO) and the aqueous (SAA) fractions of S. adstringens promoted a dose-dependent reduction of leukocyte migration and neutrophil accumulation into the joint, but none of them reduced CXCL1 concentration in the periarticular tissue. In contrast, treatment with C. lineatifolia and T. glabrescens fractions did not ameliorate the inflammatory parameters. Analyses of SAO by Ultra Performance Liquid Chromatography (UPLC) coupled to electrospray ionization mass spectrometry (ESI-MS) led to the identification of gallic acid along with 11 prodelphinidins, characterized as monomers and dimers of the B-type. Our findings contribute to some extent to corroborating the traditional use of S. adstringens as an anti-inflammatory agent. This activity is probably related to a decrease of leukocyte migration into the inflammatory site. Polyphenols like gallic acid and prodelphinidins, identified in the active fraction, may contribute to the observed activity.

Potent antihypertensive effect of Hancornia speciosa leaves extract.

BACKGROUND: Hancornia speciosa Gomes is an herb traditionally used in Brazil for blood pressure control. PURPOSE: The present work investigated the antihypertensive effect of an extract from Hancornia speciosa leaves (SFH) and analyzed its underlying mechanisms of action. METHODS: Hypertension was induced in mice by surgical removal of a kidney and by subcutaneous administration of a pellet with deoxycorticosterone. Vasodilatation was measured in mesenteric arteries with a wire myograph. Nitrites were measured by fluorescence with 2,3-diaminonaphthalene and H2O2 was measured with carbon microsensors. RESULTS: SFH (0.03, 0.1 or 1 mg/kg; po) induced a dose-dependent, long-lasting reduction in the systolic blood pressure in conscious DOCA-salt hypertensive mice (DOCA). Administration of SFH produced a significant increase in the plasmatic level of nitrites. The systemic inhibition of nitric oxide synthase by L-NAME (20 mg/kg) reduced its antihypertensive effect. SFH also induced a concentration-dependent vasodilatation of mesenteric resistance arteries contracted with phenylephrine, which was more potent in arteries from DOCA mice. Removal of the endothelium or pretreatment with L-NAME or catalase reduced the vasodilator response for SFH. The nitrite production induced by SFH was significantly bigger in mesenteric arteries from DOCA than in SHAM mice. However, the production of H2O2 induced by SFH was twice higher in DOCA mice. CONCLUSION: Altogether, our results point to an antihypertensive effect of SFH due to a reduction in peripheral resistance through the production of NO and by a mechanism involving an increased production of H2O2 in the mesenteric arteries from hypertensive mice. These findings are further evidence to support the use of Hancornia speciosa by traditional medicine as an antihypertensive drug.

Anti-TNF-α Activity of Brazilian Medicinal Plants and Compounds from Ouratea semiserrata.

Several plant species are used in Brazil to treat inflammatory diseases and associated conditions. TNF-α plays a pivotal role on inflammation, and several plant extracts have been assayed against this target, both in vitro and in vivo. The effect of 11 Brazilian medicinal plants on TNF-α release by LPS-activated THP-1 cells was evaluated. The plant materials were percolated with different solvents to afford 15 crude extracts, whose effect on TNF-α release was determined by ELISA. Among the evaluated extracts, only Jacaranda caroba (Bignoniaceae) presented strong toxicity to THP-1 cells. Considering the 14 non-toxic extracts, TNF-α release was significantly reduced by seven of them (inhibition > 80%), originating from six plants, namely Cuphea carthagenensis (Lythraceae), Echinodorus grandiflorus (Alismataceae), Mansoa hirsuta (Bignoniaceae), Ouratea semiserrata (Ochnaceae), Ouratea spectabilis and Remijia ferruginea (Rubiaceae). The ethanol extract from O. semiserrata leaves was fractionated over Sephadex LH-20 and RP-HPLC to give three compounds previously reported for the species, along with agathisflavone and epicatechin, here described for the first time in the plant. Epicatechin and lanceoloside A elicited significant inhibition of TNF-α release, indicating that they may account for the effect produced by O. semiserrata crude extract.

Evaluation of the Effects of Some Brazilian Medicinal Plants on the Production of TNF- α and CCL2 by THP-1 Cells.

Several plant species are traditionally used in Brazil to treat various inflammatory diseases. Tumor necrosis factor- (TNF-) α and chemokine (C-C motif) ligand 2 (CCL2) are key inflammatory mediators in diseases like rheumatoid arthritis and atherosclerosis, respectively; nevertheless, only a few extracts have been assayed against these targets. We herein report the effect of 19 plant extracts on TNF-α and CCL2 release by lipopolysaccharide- (LPS-) stimulated THP-1 cells, a human monocytic leukemia cell line, along with their radical scavenging activity on DPPH. The extracts of Caryocar brasiliense, Casearia sylvestris, Coccoloba cereifera, and Terminalia glabrescens inhibited TNF-α production in a concentration-dependent manner. Fractionation of these extracts potentiated the anti-TNF-α effect, which was shown to concentrate in polar fractions, mainly composed by polyphenols. Significant CCL2 inhibition was elicited by Lippia sidoides and Terminalia glabrescens extracts, whose fractionation resulted in highly active low polar fractions. All assayed extracts showed strong radical scavenging activity, but antioxidant activity did not correlate with inhibition of TNF-α or CCL2 production. Our results allowed identifying extracts with selective capacity to block cytokine production; therefore, further purification of these extracts may yield molecules that could be useful in the treatment of chronic inflammatory diseases.

Lithothamnion muelleri treatment ameliorates inflammatory and hypernociceptive responses in antigen-induced arthritis in mice.

Rheumatoid Arthritis (RA) is a chronic disease characterized by persistent inflammation and pain. Alternative therapies to reduce these symptoms are needed. Marine algae are valuable sources of diverse bioactive compounds. Lithothamnion muelleri (Hapalidiaceae) is a marine algae with anti-inflammatory, antitumor, and immunomodulatory properties. Here, we investigated the potential anti-inflammatory and analgesic activities of L. muelleri in a murine model of antigen-induced arthritis (AIA) in mice. Our results demonstrate that treatment with L. muelleri prevented inflammation and hypernociception in arthritic mice. Mechanistically, the crude extract and the polysaccharide-rich fractions of L. muelleri may act impairing the production of the chemokines CXCL1 and CXCL2, and consequently inhibit neutrophil influx to the knee joint by dampening the adhesion step of leukocyte recruitment in the knee microvessels. Altogether our results suggest that treatment with L.muelleri has a potential therapeutic application in arthritis treatment.

Hancornia speciosa Gomes (Apocynaceae) as a potential anti-diabetic drug.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Hancornia speciosa Gomes are traditionally used to treat diabetes in Brazil. The aim of the study is to evaluate the potential anti-diabetic effect of Hancornia speciosa extract and derived fractions. MATERIALS AND METHODS: The ethanolic extract from Hancornia speciosa leaves and chromatographic fractions thereof were evaluated on α-glucosidase assay, on hyperglycemic effect and glucose uptake. The chemical composition of the extract and its most active fraction was investigated by ESI-LC-MS. RESULTS: The ethanolic extract and derived fractions inhibited α-glucosidase in vitro. However, only the crude extract and the dichloromethane fraction inhibited the hyperglycemic effect induced by starch or glucose. Both the extract and dichloromethane fraction were also able to increase glucose uptake in adipocytes. Bornesitol, quinic acid, and chorogenic acid were identified in the extract, along with flavonoid glycosides, whereas the dichloromethane fraction is majorly composed by esters of lupeol and/or α/ß-amirin. CONCLUSIONS: Hancornia speciosa has a potential anti-diabetic effect through a mechanism dependent on inhibition of α-glucosidase and increase on glucose uptake. These results give support to the use on traditional medicine of this medicinal plant.

Cancer chemoprevention activity of labdane diterpenes from rhizomes of Hedychium coronarium

Hedychium coronarium J. Koenig, Zingiberaceae, is a medicinal plant popularly used to treat inflammatory conditions in different countries. Three labdane diterpenes [isocoronarin D (1), methoxycoronarin D (2), ethoxycoronarin D (3)] and benzoyl eugenol (4) were isolated from rhizomes and their chemopreventive potential was evaluated using in vitro assays, namely the inhibition of NF-κB, COX-1 and -2, the induction of antioxidant response element (ARE), and the inhibition of cell proliferation. Diterpene 1 activated ARE (EC50 57.6 ± 2.4 µM), while 2, 3 and 4 significantly inhibited NF-κB (IC50 of 7.3 ± 0.3, 3.2 ± 0.3 and 32.5 ± 4.9 µM, respectively). In addition, 2 and 3 selectively inhibited COX-1 (IC50 values of 0.9 ± 0.0 and 3.8 ± 0.0 µM, respectively). These data support the potential chemopreventive activity of constituents from H. coronarium rhizomes.

Anti-biofilm activity of Marula - a study with the standardized bark extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Marula (Sclerocarya birrea; family - Anacardiaceae) is an African plant, which enjoys wide socio-economic importance particularly in southern part of Africa. The fruits are consumed as food and also as alcoholic beverage (cream liquor). In different parts of Africa, the decoction of the bark is traditionally used for the treatment of dysentery, diarrhoea, and various other infectious conditions. The aim of the study was to investigate the anti-biofilm properties of the methanol extract of Marula bark (stem bark of Sclerocarya birrea), with a view towards combating the emergence of antimicrobial resistance often associated with bacterial biofilms. MATERIALS AND METHODS: The standardized methanol extract was initially tested for its antimicrobial property. The crystal violet assay was used for evaluating anti-biofilm (biofilm formation by Pseudomonas aeuginosa) activity. Further in order to study the mechanism of anti-biofilm activity, the same was evaluated for understanding its role on various quorums sensing mediated phenomenon (swarming motility assay, protease and pyoverdin assay) that are known to be associated with the formation of biofilms and pathogenicity. RESULTS: The methanol extract showed no inhibition of bacterial growth up to a concentration of 200 µg/ml. Interestingly, the sample produced anti-biofilm activity (around 75% decrease; 100 µg/ml) at sub-lethal concentration. Further it also significantly reduced the QS mediated swarming motility. The release of various virulent factors (protease and pyoverdin) was found to be lowered when pre-treated with the extract. CONCLUSION: The present study illustrates the anti-biofilm property Sclerocarya birrea. The standardized extract significantly disrupted the quorum sensing mediated production of biofilm formation and also inhibited swarming ability of the cells. The extract displayed a regulatory role on the secretion of protease and pyoverdin, two QS dependent pathogenic factors found in Pseudomonas aeruginosa. This study also validates the ethnobotanical use of Marula.

TNF-α inhibition elicited by mansoins A and B, heterotrimeric flavonoids isolated from Mansoa hirsuta.

Mansoins A (1) and B (2) isolated from the fruits of Mansoa hirsuta represent new glucosylated heterotrimeric flavonoids with a flavanone core linked to two 1,3-diarylpropane C6-C3-C6 units. Their structures and absolute configurations were established by analysis of their NMR and electronic circular dichroism spectroscopic data. Compounds 1 and 2 inhibited TNF-α release by LPS-stimulated THP-1 cells with different potencies, with mansoin B (2) being active at lower concentrations than mansoin A (1) (IC50 values 20.0±1.4 and 48.1±1.8 µM, respectively). These results indicate potential anti-inflammatory properties for this structural type of oligoflavonoids, especially for mansoin B (2).

Isolation and HPLC quantitation of kaurane-type diterpenes and cinnamic acid derivatives of long-term stored leaves of Mikania laevigata and Mikania glomerata.

The leaves of Mikania laevigata and Mikania glomerata are used in Brazil to treat respiratory affections, being kaurane-type diterpenes and coumarin considered as the bioactive compounds. The present study reports an investigation on the HPLC-DAD profiles and contents of coumarin (1), trans-o-coumaric (2), kaurenoic (3), benzoylgrandifloric (4) and cinnamoylgrandifloric (5) acids in dried leaves of Mikania species stored in dark room under controlled conditions. Excepting 2, the constituents were isolated and purified to be employed as reference compounds. The samples were analyzed at three monthly intervals up to 18 months for M. laevigata and 12 months for M. glomerata. trans-o-Coumaric was not detected in both, whereas 1 occurred only in M. laevigata. The concentrations of the assayed constituents did not vary significantly within the evaluated period (p < 0.05), for both species. In contrast, changes in the chromatographic profiles and spectral purity of peaks from 3, 4 and 5 were detected in samples of both Mikania stored for three months, while the coumarin profile in M. laevigata modified after six months of storage. The evaluation of chromatographic profiles based on spectral purity analyses of selected peaks was shown to be a more robust tool to access chemical stability of Mikania samples than the quantitation of chemical markers' contents.

Seasonal variation on the contents of coumarin and kaurane-type diterpenes in Mikania laevigata and M. glomerata leaves under different shade levels.

Coumarin (1) and kaurane-type diterpenes are considered the bioactive constituents of Mikania glomerata and M. laevigata, used in Brazil to treat respiratory affective disorders. The seasonal variation of 1, ortho-coumaric acid (2), benzoylgrandifloric acid (3), cinnamoylgrandifloric acid (4), and kaurenoic acid (5) in leaves of both species, cultivated in full sunlight and under shade levels of 40 and 80%, was quantified by HPLC. Compound 2 was detected solely in M. laevigata in concentrations below the limit of quantification. Coumarin was not found in M. glomerata, whereas its concentration reached 0.94±0.24% (w/w) in M. laevigata farmed in summer under 80% shading. Both Mikania species produced higher amounts of kaurane diterpenes when cultivated in plenty of sunlight. Hence, maximum contents of 1 are reached in M. laevigata cultivated under high shading, but with reduced concentrations of 3-5. Conversely, M. glomerata should be cultivated under full sunlight and harvested in winter for highest concentrations of kaurane-type diterpenes.

Evaluation of Brazilian plants on cancer chemoprevention targets in vitro.

Cancer is a leading cause of death worldwide. Cancer chemoprevention is one of the promising strategies to decrease its incidence and both plant extracts and natural products may constitute sources of new chemoprevention agents. Some Brazilian species popularly used to treat inflammatory conditions were selected for evaluation for cancer chemoprevention. A total of 32 extracts/fractions from Hancornia speciosa, Davilla elliptica, Jacaranda caroba, Mansoa hirsuta, Remija ferrugina, Solanum paniculatum and Xyris pterygoblephara, along with a mixture of ursolic and oleanolic acids obtained from J. caroba and a dihydroisocoumarin isolated from aerial parts of X. pterygoblephara were tested for their cancer chemoprevention activity [inhibition of 12-O-tetradecanoyl-13-acetate (TPA)-mediated NF-kappaB activation, ornithine decarboxylase (ODC) and cyclooxygenase-1 (COX-1); induction of antioxidant response element (ARE)]. Several extracts/fractions were active in more than one assay and those from H. speciosa, M. hirsuta and J. caroba mediated strong responses with NF-kappaB, COX-1 and ARE, respectively.

Plant-derived antimalarial agents: new leads and efficient phythomedicines: part 1: Alkaloids

Malaria remains one of the most serious world health problem and the major cause of mortality and morbidity in the endemic regions. Brazil is among the 30 high-burden countries and most of the cases occur in the Legal Amazonian Region. New chemotherapeutical agents are needed for the treatment of malaria. Many plant species are used in traditional medicines of malarious countries and a relatively few number of these have been investigated for evaluation of their antimalarial effect. Still lower is the number of those that have had the active natural compounds isolated and the toxicity determined. This area is, then, of great research interest. discovery project of antimalarial natural products from plants traditionally used to treat malaria must include in vitro and in vivo assays as well as bioguided isolation of active compounds. The final products would be antimalarial chemical entities, potential new drugs or templates for new drugs development, and/or standardized antimalarial extracts which are required for pre-clinical and clinical studies when the aim is the development of effective and safe phythomedicines. This review discusses these two approaches, presents briefly the screening methodologies for evaluation of antimalarial activity and focuses the activity of alkaloids belonging to different structural classes as well as its importance as new antimalarial drugs or leads and chemical markers for phytomedicines.

A malária ainda é um dos mais sérios problemas de saúde pública e a principal causa de mortalidade e morbidade nas regiões endêmicas. O Brasil está entre os 30 países com maior incidência de malária e a maior parte dos casos ocorre na Amazônia Legal. Novos agentes terapêuticos são necessários para o tratamento da malária. Muitas espécies vegetais são utilizadas na medicina tradicional de vários países endêmicos mas é relativamente reduzido o número daquelas que já foram investigadas quanto à sua atividade antimalárica. Menor ainda é o número de espécies das quais foram isoladas substâncias ativas e tiveram sua toxidade determinada. Esta área de pesquisa é, portanto, de alta relevância. Um projeto de descoberta de produtos naturais antimaláricos a partir de plantas de uso tradicional deve incluir ensaios in vitro e in vivo bem como o isolamento biomonitorado de substâncias ativas. Os produtos finais serão substâncias naturais antimaláricas, potenciais fármacos ou protótipos para o desenvolvimento de novos fármacos, e/ou extratos padronizados, com atividade antimalárica, os quais são necessários para estudos pré-clínicos e clínicos quando o objetivo é o desenvolvimento de fitoterápicos (fitomedicamentos) eficazes e seguros. A presente revisão discute estas duas abordagens, apresenta resumidamente as metodologias de bioensaios para avaliação de atividade antimalárica e focaliza a atividade de alcalóides pertencentes a diferentes classes estruturais bem como sua importância como fármacos ou protótipos e como marcadores químicos de fitoterápicos.