RESUMO
Background: Endometriosis is defined by implantation and invasive growth of endometrial tissue in extra-uterine locations causing heterogeneous symptoms, and a unique clinical picture for each patient. Understanding the complex biological mechanisms underlying these symptoms and the protein networks involved may be useful for early diagnosis and identification of pharmacological targets. Methods: In the present study, we combined three approaches (i) a text-mining analysis to perform a systematic search of proteins over existing literature, (ii) a functional enrichment analysis to identify the biological pathways in which proteins are most involved, and (iii) a protein-protein interaction (PPI) network to identify which proteins modulate the most strongly the symptomatology of endometriosis. Results: Two hundred seventy-eight proteins associated with endometriosis symptomatology in the scientific literature were extracted. Thirty-five proteins were selected according to degree and betweenness scores criteria. The most enriched biological pathways associated with these symptoms were (i) Interleukin-4 and Interleukin-13 signaling (p = 1.11 x 10-16), (ii) Signaling by Interleukins (p = 1.11 x 10-16), (iii) Cytokine signaling in Immune system (p = 1.11 x 10-16), and (iv) Interleukin-10 signaling (p = 5.66 x 10-15). Conclusion: Our study identified some key proteins with the ability to modulate endometriosis symptomatology. Our findings indicate that both pro- and anti-inflammatory biological pathways may play important roles in the symptomatology of endometriosis. This approach represents a genuine systemic method that may complement traditional experimental studies. The current data can be used to identify promising biomarkers for early diagnosis and potential therapeutic targets.
Assuntos
Endometriose , Endometriose/metabolismo , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Mapas de Interação de ProteínasRESUMO
Cerebrospinal fluid (CSF) analysis is routinely used in the diagnostic work-up of multiple sclerosis (MS), by detecting CSF-specific oligoclonal bands (OCB). More recently, several studies have reported CSF free light chains (FLC) as an alternative. We show that absolute CSF κFLC concentrations were highly sensitive - more than OCB testing - and specific for clinically isolated syndrome, relapsing remitting and primary progressive MS. Measurement of κFLC alone was sufficient. Our results suggest that CSF κFLC levels measured by nephelometry, if validated in a larger series, are a preferred test to OCB analysis in the diagnostic work-up of patients suspected of having MS.
Assuntos
Cadeias kappa de Imunoglobulina/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Bandas Oligoclonais/líquido cefalorraquidiano , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. METHODS: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. RESULTS: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. CONCLUSIONS: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Cadeias Leves de Imunoglobulina/sangue , Neoplasias Hepáticas/diagnóstico , Albumina Sérica/análise , alfa-Fetoproteínas/análise , Humanos , Espectrometria de MassasRESUMO
INTRODUCTION: Serum concentrations of polyclonal free light chains (FLC) represent the activity of the adaptive immune system. This study assessed the relationship between polyclonal FLC and the established marker of innate immunity, C-reactive protein (CRP), in chronic and acute disease. METHODS: We utilized four cross-sectional chronic disease patient cohorts: chronic kidney disease (CKD), diabetes, vasculitis and kidney transplantation; and a longitudinal intensive care case series to assess the kinetics of production in acute disease. RESULTS: There was a weak association between polyclonal FLC and high-sensitivity CRP (hs-CRP) in the study cohorts. A longitudinal assessment in acute disease showed a gradual increase in FLC concentrations over time, often when CRP levels were falling, demonstrating clear differences in the response kinetics of CRP and FLC in this setting. CONCLUSION: Polyclonal FLC and hs-CRP provide independent information as to inflammatory status. Prospective studies are now required to assess the utility of hs-CRP and polyclonal FLC in combination for risk stratification in disease populations.
Assuntos
Proteína C-Reativa/metabolismo , Diabetes Mellitus/sangue , Cadeias Leves de Imunoglobulina/sangue , Transplante de Rim , Insuficiência Renal Crônica/sangue , Vasculite Sistêmica/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença Crônica , Estudos Transversais , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Vasculite Sistêmica/diagnóstico , Vasculite Sistêmica/fisiopatologiaRESUMO
O gênero Saccharomyces tem sido usado como indutor de resistência ou para controle biológico em muitos patossistemas. Neste trabalho objetivou-se a indução de fitoalexinas em mesocótilos de sorgo e cotilédones de soja pela levedura Saccharomyces boulardii na forma do produto comercial Floratil (Merck) (com 2 x 106 células/mg produto comercial - pc) e massa de células obtidas de meio líquido YEPG (primeiramente com 14 dias de cultivo e, posteriormente, com 7, 14, 21, 28 e 35 dias) ambos em concentrações de 0,005; 0,05; 0,5; 5; 15 e 25 mg/mL, além de filtrado desse meio nas concentrações de 0,01; 0,1; 1; 5; 10 e 20%. Como tratamentos controle utilizou-se água e S. cerevisiae (25 mg/mL de pc) para soja e água e acibenzolar-S-metil (ASM) (125 mg i.a./L) para sorgo. Em soja os três produtos apresentaram efeito dose-dependente, com ajustes de equações de 1° grau e R2 de 0,64; 0,94 e 0,98 não tendo efeito do tempo de cultivo da levedura na indução de fitoalexinas. Em sorgo apenas o filtrado e Floratil tiveram efeito dose-dependente com equação de 1° grau e R2 de 0,63 e 0,94 respectivamente e obteve-se nos diferentes dias de cultivo R2 de 0,62 com a massa de células somente. Portanto, pode-se evidenciar o potencial indutor de fitoalexinas dos produtos a base de S. boulardii para ensaios com indução de resistência em patossistemas envolvendo sorgo e soja.
Saccharomyces yeast compounds have been used as a resistance elicitor or for biological control in many pathosystems. Thus, the aim of this research was to verify the induction of phytoalexins in sorghum mesocotyls and soybean cotyledons by using Saccharomyces boulardii in the form of the commercial product Floratil (Merck) (with 2 x 106 cells/mg) and yeast-cell mass obtained from liquid culture in YEPG medium (with 7, 14, 21, 28 and 35 days old), both at concentrations of 0.005, 0.05, 0.5, 5, 15 and 25 mg/mL, as well as the filtrate of this medium in concentrations of 0.01, 0.1, 1, 5, 10 and 20%. The control treatments consisted of distilled water and S. cerevisiae (25 mg of commercial product per mL) for the soybean tests and distilled water and acibenzolar-S-methyl (125 mg of active ingredient per L) for the sorghum tests. In soybeans the three tested S. boulardii products presented a dose-dependent effect with R2 of 0.64, 0.94 and 0.98 for the culture filtrate, cell suspension and commercial product of S. boulardii, respectively, with no effect of culture time of yeasts on phytoalexin induction. In sorghum, only the culture filtrate and Floratil presented a dose-dependent effect, with R2 of 0.63 and 0.94, respectively, and the cell suspension of S. boulardii showed dependence of culture time with R2 of 0.62. Thus, S. boulardii and its derivates induce phytoalexins and have potential to be used as an elicitor for assays with induction resistance in pathosystems involving sorghum and soybean plants.
Assuntos
Glycine max/fisiologia , Cotilédone/microbiologia , Sorghum/fisiologia , Saccharomyces boulardiiRESUMO
Neutrophils die by apoptosis spontaneously within 12-24 h of their release from the bone marrow. The mechanism regulating entry of neutrophils into apoptosis at the end of their life-span is currently under debate. Our data suggest that neutrophil apoptosis involves a novel mechanism of caspase 8 activation that is indirectly regulated by accumulation of reactive oxygen species. We detected early activation of caspase 8 upstream of caspase 3 activation, suggesting death receptor signalling. The CD95 DISC (death-inducing signalling complex) was detected in neutrophils, but blocking antibodies to death receptors did not inhibit apoptosis, suggesting a novel mechanism for caspase 8 activation. Death receptor clustering in ceramide-rich lipid rafts is thought to be an early event in their signalling, so we investigated the role of ceramide generated by ASM (acid sphingomyelinase) in neutrophil apoptosis. Ceramide was generated early in neutrophil apoptosis, and ASM activity was required for neutrophil apoptosis. Moreover, neutrophil apoptosis was significantly delayed in ASM(-/-) mice compared with their wild-type littermates. CD95 DISC components were present in lipid rafts in neutrophils, and were progressively clustered in cultured neutrophils. Generation of ceramide was blocked by desferrioxamine, suggesting that hydroxyl radicals are important for the activation of ASM. This observation was in line with our earlier observation of a precipitous drop in reduced glutathione in the aging neutrophil.
Assuntos
Apoptose , Microdomínios da Membrana/química , Neutrófilos/patologia , Receptores do Fator de Necrose Tumoral/química , Animais , Caspase 3 , Caspase 8 , Caspases/metabolismo , Ceramidas/metabolismo , Desferroxamina/química , Ativação Enzimática , Glutationa/metabolismo , Radical Hidroxila , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Neutrófilos/citologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio , Esfingomielina Fosfodiesterase/metabolismo , Fatores de Tempo , Receptor fas/biossínteseRESUMO
Neutrophils are very abundant, short-lived leucocytes and their death by apoptosis is central to homoeostasis and the resolution of inflammation, yet the trigger for apoptosis is still a topic of debate. Depolarization of the mitochondrial membrane has been supposed to initiate neutrophil spontaneous apoptosis, as neutrophils gradually lose the anti-apoptotic protein Mcl-1 and Bax translocates and inserts into the mitochondrial membrane. However, other reports show that caspase 8 is required for neutrophil apoptosis, suggesting the involvement of DR (death receptor) signalling. As DR ligation is not required for neutrophil apoptosis, this raises the intriguing possibility that activation of caspase 8 during neutrophil apoptosis occurs via a novel mechanism. In the present paper, we discuss the current evidence for mechanisms occurring in neutrophil apoptosis, which could trigger DR signalling in the absence of DR ligation.
Assuntos
Apoptose , Neutrófilos/patologia , Animais , Caspase 8 , Caspases/metabolismo , Cicloeximida/farmacologia , Relação Dose-Resposta a Droga , Humanos , Leucócitos/metabolismo , Microdomínios da Membrana/química , Mitocôndrias/patologia , Modelos Biológicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/metabolismo , Neutrófilos/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2RESUMO
The isolation and structural elucidation of a new naphthylisoquinoline alkaloid, 8-O-methyldioncophyllinol B, from Triphyophyllum peltatum (Hutch. et Dalz.) Airy Shaw (Dioncophyllaceae) is described, together with the revised structures of other 'B-type' compounds previously misidentified as dioncophylline D, dioncophyllinol D, and 8-O-methyldioncophylline D. All of the presently described structures are 7,6'-coupled and thus have to be addressed as 'B-type' naphthylisoquinoline alkaloids. This is in contrast to the initially defined 'D-type' structures, which are 7,8'-coupled as confirmed by a total synthesis of dioncophylline D. Some of these natural and synthetic naphthylisoquinolines were found to display good in vitro antiplasmodial activities.
Assuntos
Alcaloides/química , Isoquinolinas/química , Naftóis/química , Plantas Medicinais/química , Alcaloides/isolamento & purificação , Cromatografia Gasosa-Espectrometria de Massas , Isoquinolinas/isolamento & purificação , Modelos Moleculares , Conformação Molecular , Naftóis/isolamento & purificação , Folhas de Planta/químicaRESUMO
The growth and droserone content of callus cultures of Triphyophyllum peltatum grown in liquid 1/5 Linsmaier and Skoog medium was studied. During a lag phase in growth, droserone concentrations in the medium reached a value of 2.1 mg g-1 fr. wt. After this maximum value the concentration decreased slightly to 1.8 mg g-1 fr. wt., while the growth of the calli was enhanced (25% increase in fr. wt. within 7 days). Plumbagin and isoshinanolone were likewise present in the medium. By feeding 13C2-labelled acetate to the cultures the biosynthesis of droserone was elucidated. The incorporation of whole C2-units unambiguously shows its acetogenic origin and fits well in the biosynthetic scheme suggested for the structurally--and biogenetically--related naphthylisoquinoline alkaloids.
Assuntos
Naftoquinonas/isolamento & purificação , Plantas/metabolismo , Células Cultivadas , Naftoquinonas/química , Naftoquinonas/metabolismo , Células VegetaisRESUMO
Four-week-old OF1 mice, infected with synchronized Plasmodium chabaudi chabaudi blood forms, were intraperitoneally injected with the naphthylisoquinoline alkaloid dioncophylline B (10 mg kg(-1) day(-1)) at three consecutive days. The respective groups were treated when rings, trophozoites, and schizonts were predominant. Microscopical observations of thin blood smears were made every two hours after the start of the experiment. A clear dependency of the effectiveness of dioncophylline B treatments on the timing of drug administration was demonstrated. Based upon the evolution of total parasitaemia and the survival rates, it was concluded that ring stages are insensitive to dioncophylline B, while the drug is highly effective when given at the trophozoite stage and partially effective when given at the schizont stage. Dioncophylline B seems to act by inhibiting the haemozoin degradation, as indicated by pigment clumping, and by impairing the segmentation of schizonts.
Assuntos
Antimaláricos/uso terapêutico , Isoquinolinas/uso terapêutico , Malária/tratamento farmacológico , Malária/parasitologia , Plasmodium chabaudi/efeitos dos fármacos , Plasmodium chabaudi/crescimento & desenvolvimento , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Eritrócitos/parasitologia , Feminino , Isoquinolinas/química , Isoquinolinas/farmacologia , Camundongos , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Plasmodium chabaudi/fisiologia , Fatores de TempoRESUMO
Natural and synthetic anthranoid compounds were subjected to an evaluation against asexual erythrocytic stages of the human malaria parasite Plasmodium falciparum in vitro. Stimulated by the good activities of Vismia guineënsis extracts, a more detailed investigation of the active principles revealed the pre-nylated preanthraquinone vismione H (1) to be a potent antimalarial [50% growth-inhibitory concentration (IC50) 0.088 microg/ml]. On the basis of this finding a series of chemically related phlegmacins (2-5), flavomannins (6-8), and rufoolivacins (9-11) isolated from several species of Cortinarius, a genus of higher fungi, and 5 synthetic vismione-like anthranoids (12-16) were evaluated as well. Although these compounds displayed weaker antiplasmodial effects than did vismione H (1) itself, considerable levels of activity were obtained with phlegmacin B1 (2), flavomannin-6,6'-di-O-methyl ether A1 (6), trans-4-hydroxy-flavomannin-6,6'-di-O-methyl ether A (8), and rufoolivacin B (10). Initial preconditions for activity within the vismiones and related anthranoids were established.
Assuntos
Antracenos/farmacologia , Antimaláricos/farmacologia , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Agaricales/metabolismo , Animais , Antracenos/síntese química , Antracenos/química , Antimaláricos/síntese química , Antimaláricos/química , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Humanos , Extratos Vegetais/química , Relação Estrutura-AtividadeRESUMO
Hannoa chlorantha and Hannoa klaineana (Simaroubaceae) are used in traditional medicine of Central African countries against fevers and malaria. Four stem bark extracts from H. klaineana and four quassinoids from H. chlorantha were examined in vitro against Plasmodium falciparum NF 54. The extracts displayed good activities, while the quassinoids were highly active, with IC50 values well below 1 microgram ml-1, those of chaparrinone and 15-desacetylundulatone being much lower than 0.1 microgram ml-1 (0.037 and 0.047 microgram ml-1, respectively). Chaparrinone is five times more active than 14-hydroxychaparrinone against P. falciparum, indicating that the hydroxyl function at C-14 is unfavourable for antiplasmodial activity. As 14-hydroxychaparrinone has a seven-times higher cytotoxic activity against P-388 cells than chaparrinone, the latter compound has the better antiplasmodial therapeutic index. All four quassinoids were evaluated in vivo in a standard 4-day test as well. 15-Desacetylundulatone was proven to be the most active compound, almost totally suppressing the parasitaemias of OF1 mice for at least 7 days, while both chaparrinone and 14-hydroxychaparrinone were active for at least 4 days. Quassinoids have ED50 values much lower than 50 mg kg-1 body weight day-1 and none of them caused obvious side effects. The keto function at C-2 in 15-desacetylundulatone is apparently of crucial importance for its high activity. 6-alpha-Tigloyloxyglaucarubol was not active at all. Chaparrinone is considered the most interesting of the investigated quassinoids and its in-vivo antimalarial potential will be examined further.
Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Extratos Vegetais/farmacologia , Plantas Medicinais , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quassinas , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Feminino , Glaucarubina/análogos & derivados , Glaucarubina/química , Glaucarubina/farmacologia , Glaucarubina/toxicidade , Leucemia P388 , Camundongos , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Raízes de Plantas/química , Plantas Medicinais/química , Sementes/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Peroxidase active preparations from three Ancistrocladus species and from Triphyophyllum peltatum have been partially purified. They catalyze the oxidative dimerization of korupensamines A and B to michellamines A and C, respectively, as well as the mixed coupling to michellamines A, B, and C. All of these enzymes consist of single polypeptides of approximately 65 kDa with peroxidase activity as monomers. They were characterized as soluble proteins predominantly localized in the leaf phloem of all species examined. Comparative studies with various naphthol precursors revealed an unexpected substrate specificity. Only korupensamines were dimerized by the enzymes, while other monomers, even if closely related, were not accepted as substrates. The coupling reactions described here represent the first direct synthesis of michellamines from korupensamines without previous protection of these precursors.
Assuntos
Alcaloides/metabolismo , Fármacos Anti-HIV/metabolismo , Isoquinolinas/metabolismo , Magnoliopsida/enzimologia , Naftalenos/metabolismo , Peroxidases/metabolismo , Oxirredução , Especificidade da Espécie , Distribuição TecidualRESUMO
Naphthylisoquinoline alkaloid-containing extracts from species of the families Dioncophyllaceae and Ancistrocladaceae and purified alkaloids derived therefrom were shown to exhibit antiparasitic activity in Plasmodium berghei-infected mice. Several extracts and alkaloids, especially dioncophylline C and dioncopeltine A, isolated from Triphyophyllum peltatum (Dioncophyllaceae), displayed high levels of activity. Dioncopeltine A was able to suppress parasitemia almost totally, while dioncophylline C cured infected mice completely after oral treatment with 50 mg kg of body weight(-1) day(-1) for 4 days without noticeable toxic effects. Analysis of the dose-response relationship of dioncophylline C revealed a 50% effective dosage (ED50) of 10.71 mg kg(-1) day(-1) under these conditions. Although four daily treatments with 50 mg kg(-1) day(-1) are needed to achieve radical cure, one oral dose is sufficient to kill 99.6% of the parasites. Intravenous application of dioncophylline C is even more effective, with an ED50 of 1.90 mg kg(-1) day(-1) and no noticeable toxic effects. The compound also suppressed more established P. berghei infections when orally applied at day 3 after infection. Both dioncopeltine A and dioncophylline C are active against the chloroquine-resistant P. berghei Anka CRS parasites. Sustained release of these compounds at 20 mg kg(-1) day(-1) by implanted miniosmotic pumps exhibited curative effects. The naphthylisoquinoline alkaloids are therefore promising new antimalarial agents.
Assuntos
Antimaláricos/uso terapêutico , Isoquinolinas/uso terapêutico , Malária/tratamento farmacológico , Naftóis/uso terapêutico , Plasmodium berghei , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos , Plasmodium berghei/efeitos dos fármacosRESUMO
The known lupane-type triterpene betulinic acid (3) was isolated for the first time from Triphyophyllum peltatum and Ancistrocladus heyneanus. It was found to exhibit moderate to good in vitro antimalarial activity against asexual erythrocytic stages of the human malaria parasite Plasmodium falciparum. A first X-ray structure analysis succeeded after conversion into its benzyl ester 4.
Assuntos
Antimaláricos/isolamento & purificação , Plantas Medicinais , Plasmodium falciparum/efeitos dos fármacos , Triterpenos/isolamento & purificação , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Cristalografia por Raios X , Eritrócitos/parasitologia , Humanos , Modelos Moleculares , Estrutura Molecular , Triterpenos Pentacíclicos , Triterpenos/química , Triterpenos/toxicidade , Ácido BetulínicoRESUMO
Retarded development of exoerythrocytic stages of the rodent malaria parasite Plasmodium berghei in human hepatoma cells by extracts from Dioncophyllaceae and Ancistrocladaceae species. International Journal for Parasitology 27: 29-32. Naphthylisoquinoline alkaloid-containing extracts (10 micrograms ml-1) of species belonging to the Dioncophyllaceae and the Ancistrocladaceae, 2 small tropical plant families, display pronounced in vitro activities against exoerythrocytic stages of Plasmodium berghei (Anka), developing in human hepatoma cells (Hep G2). The highest activities were obtained with CH2Cl2 root and bark extracts, and a CH2Cl2/NH3 leaf extract from Triphyophyllum peltatum, a CH2Cl2/NH3 root extract from Ancistrocladus abbreviatus, and a CH2Cl2 leaf extract from A. tectorius. The degrees of growth inhibition ranged within 27.7-70.0%. The commercially available drug primaquine diphosphate (25 micrograms ml-1) caused a comparable effect (62.1%) in the same test system.
Assuntos
Antimaláricos/farmacologia , Malária/fisiopatologia , Extratos Vegetais/farmacologia , Plantas Medicinais , Plasmodium berghei/fisiologia , Animais , Carcinoma Hepatocelular , Linhagem Celular , Humanos , Neoplasias Hepáticas , Medicina Tradicional , Raízes de Plantas , Caules de Planta , Plasmodium berghei/efeitos dos fármacos , Roedores , Células Tumorais CultivadasRESUMO
Naphthylisoquinoline alkaloids are derived from Dioncophyllaceae and Ancistrocladaceae species and comprise a new class of promising antimalarials with a demonstrated potential against asexual erythrocytic Plasmodium falciparum and P. berghei stages in vitro. We report herein the pronounced activity of pure naphthylisoquinoline alkaloids against exoerythrocytic malaria parasites. P. berghei-infected human hepatoma cells (Hep G2) were incubated with culture medium containing selected alkaloids at 10 micrograms/ml. The most active compounds, showing inhibitory activity of more than 40%, were dioncophylline A (compound 1), dioncophyllacine A (compound 6), and ancistrobarterine A (compound 12). For structure-activity investigations of dioncophyllines A (compound 1) and C (compound 3) and ancistrocladine (compound 7) a selection of their analogs from natural or synthetic sources was examined. Dioncophylline A (compound 16), 5'-O-demethyl-8-O-methyl-7-epi-dioncophylline A (compound 17), N-formyl-8-O-methyl-dioncophylline C (compound 21), and N-formyl-8-O-benzoyldioncophylline C (compound 24) were found to display high levels of activity as well, although the former two compounds caused damage to the host-cell monolayers. As naphthylisoquinoline alkaloids are also highly active against blood forms of Plasmodium spp., they should be regarded as lead compounds for further development as drugs against erythrocytic and exoerythrocytic stages of Plasmodium spp.
Assuntos
Antimaláricos/farmacologia , Isoquinolinas/farmacologia , Naftóis/farmacologia , Plasmodium berghei/efeitos dos fármacos , Tetra-Hidroisoquinolinas , Alcaloides/farmacologia , Animais , Células Cultivadas , Humanos , Plasmodium berghei/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
The naphthylisoquinoline alkaloids dioncophylline A (1) and 5'-O-demethyl-8-O-methyl-7-epi-dioncophylline A (2) represent a new structural type of molluscicidal compounds and the active principle of extracts of the tropical lianas Ancistrocladus abbreviates and Triphyophyllum peltatum. The activity of 1 was further improved by derivatization.
RESUMO
The antiplasmodial activities of organic and aqueous extracts from the West African plant Picralima nitida (Apocynaceae) were examined in an in vitro model, against asexual erythrocytic forms of Plasmodium falciparum. Root and leaf extracts of this species had never been examined before. Several extracts displayed considerable inhibitory activities. The highest activities were found in root, stem bark and fruit rind extracts, with IC50 values of 0.188, 0.545 and 1.581 micrograms/ml, respectively. The leaf and seed extracts generally yielded much lower activity or were completely inactive.