RESUMO
Septic shock sometimes starts with unspecific symptoms that hamper the clinical diagnosis and, therefore an appropriate treatment. When the septic shock follows a fulminating course with a fatal outcome, the etiological diagnosis has to be conducted post-mortem. Sudden unexpected deaths in children and young adults are frequently the object of medico-legal autopsies. Some sudden unexpected deaths have an infectious origin, which requires further analyses, including microbiology, to establish the cause of death. Here, the case of a fatal septic shock in a 19-month old male infant is presented. After a mild foot injury, an infection by Streptococcus pyogenes progressed to septic shock with a fatal outcome as post-mortem studies demonstrated.
Assuntos
Autopsia , Medicina Legal , Choque Séptico/diagnóstico , Evolução Fatal , Traumatismos do Pé/patologia , Humanos , Lactente , Masculino , Choque Séptico/microbiologia , Choque Séptico/patologia , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenesRESUMO
BACKGROUND: Malassezia pachydermatis is part of the skin microbiota of dogs and cats. M. pachydermatis has been associated with external otitis and seborrhoeic dermatitis, reported more often in dogs than in cats. When the physical, chemical or immunological mechanisms of the skin are altered, M. pachydermatis could act as a pathogen. Thus, several virulence factors, such as the ability to produce esterase, lipase, lipoxygenase, protease, chondroitin sulphatase, and hyaluronidase, have been studied. AIMS: In the present study, we aim to identify the phospholipase activity measured at pH 6.3, and the proteinase activity measured at pH 6.3 and pH 6.8 (pH from ears of dogs with external otitis) of M. pachydermatis strains isolated from dogs with and without external otitis. METHODS: The phospholipase activity was measured using a semi-quantitative method with egg yolk, and the proteinase activity with a semi-quantitative method using bovine serum albumin agar. The study was performed on 96 isolates of M. pachydermatis, 43 isolated from dogs without clinical symptoms of otitis, and 52 isolated from dogs with otitis. RESULTS: In our study, 75.8% of the isolates showed phospholipase activity at pH 6.3, and 81 and 97.9% of them showed proteinase activity measured at pH 6.3 and 6.8, respectively. A higher phospholipase activity was detected in strains isolated from dogs with otitis. The proteinase activity was increased at a pH of 6.8 (97.9%) in comparison to a pH of 6.3 (81%). CONCLUSIONS: Our results suggest that the phospholipase activity may play an important role in the invasion of host tissues in chronic canine otitis cases. The proteinase activity results obtained in this study suggest that a reduction in the pH of the treatment may improve its efficacy in the resolution of M. pachydermatis otitis.
Assuntos
Dermatomicoses/veterinária , Doenças do Cão/microbiologia , Proteínas Fúngicas/análise , Malassezia/enzimologia , Otite Externa/veterinária , Peptídeo Hidrolases/análise , Fosfolipases/análise , Animais , Dermatomicoses/enzimologia , Dermatomicoses/microbiologia , Doenças do Cão/enzimologia , Cães , Proteínas Fúngicas/fisiologia , Concentração de Íons de Hidrogênio , Malassezia/patogenicidade , Otite Externa/enzimologia , Otite Externa/microbiologia , Peptídeo Hidrolases/fisiologia , Fosfolipases/fisiologia , VirulênciaRESUMO
INTRODUCTION: The increasing prevalence of cognitive dysfunction and dementia associated, among others, to population aging in developed countries has grown a great interest in the study of the etiopathogenesis of cognitive deficit and the likely pharmacological targets which improve intellectual function or alter the neurodegeneration underlying these symptoms. DEVELOPMENT AND CONCLUSIONS: An essential tool for that purpose is the use of animal models of human-related pathologies which clinically develop with cognitive impairment and dementia. In this review we will analyse the animal models of these disorders and, specially, the main tests that, by means of the observational evolution of the experimental animal, allow assessing its cognitive functions and its modification by experimental treatments that are wanted to investigate for its eventual introduction into clinics.
Assuntos
Transtornos Cognitivos/diagnóstico , Modelos Animais de Doenças , Animais , Atenção , Cognição , Aprendizagem , Memória , Testes PsicológicosRESUMO
BACKGROUND AND PURPOSE: Avarol is a marine sesquiterpenoid hydroquinone with anti-inflammatory and antipsoriatic properties. The aim of this study was to evaluate the in vitro and in vivo pharmacological behaviour of the derivative avarol-3'-thiosalicylate (TA) on some inflammatory parameters related to the pathogenesis of psoriasis. EXPERIMENTAL APPROACH: Human neutrophils and monocytes as well as the human keratinocyte cell line HaCaT were used to study the effect of TA on oxidative stress, the arachidonic acid pathway, tumour necrosis factor-alpha (TNF-alpha) release and nuclear factor-kappaB (NF-kappaB) activation. All these parameters were also determined in vivo using the zymosan induced mouse air pouch model and the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse epidermal hyperplasia model. KEY RESULTS: TA showed antioxidant properties in human neutrophils and in the hypoxanthine/xanthine oxidase assay. This compound reduced, in a concentration-dependent manner, leukotriene B(4), prostaglandin E(2) and TNF-alpha production in activated leukocytes. Oral and intrapouch administration of TA in the mouse air pouch model produced a dose-dependent reduction of all these inflammatory mediators. TA also inhibited secretory phospholipase A(2) activity and NF-kappaB DNA-binding in HaCaT keratinocytes. In TPA-induced mouse epidermal hyperplasia, topical administration of TA reduced oedema, leukocyte infiltration, eicosanoid levels and TNF-alpha in skin. In addition, interleukin (IL)-1beta and IL-2 production were also inhibited. Finally, TA was also capable of suppressing NF-kappaB nuclear translocation in vivo. CONCLUSIONS AND IMPLICATIONS: TA inhibited several key biomarkers up-regulated in the inflammatory response of psoriatic skin and this compound could be a promising antipsoriatic agent.
Assuntos
Antioxidantes/farmacologia , NF-kappa B/efeitos dos fármacos , Psoríase/tratamento farmacológico , Salicilatos/farmacologia , Sesquiterpenos/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Ácido Araquidônico/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Hiperplasia/tratamento farmacológico , Hiperplasia/fisiopatologia , Mediadores da Inflamação/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Psoríase/fisiopatologia , Salicilatos/administração & dosagem , Sesquiterpenos/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Vasoactive intestinal peptide (VIP) has demonstrated therapeutic effects in arthritis by inhibiting both innate and acquired immune responses. We investigated the potential effects of VIP in the regulation of Toll-like receptor (TLR) expression and function in synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA and OA. The effects of VIP on basal or TNF-alpha or lipopolysaccharide (LPS)-induced TLR2, TLR4 and MyD88 expression and its effects on TLR4-mediated CCL2 and CXCL8 chemokine production were studied by reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: TLR2, TLR4 and MyD88 mRNA expression was increased in RA FLS compared with OA FLS. The largest increase was observed for TLR4 and there was also overexpression at the protein level in RA FLS. TLR4 and MyD88 mRNA and proteins were induced by LPS and TNF-alpha in RA FLS. VIP down-regulated the induced but not the constitutive expression of TLR4 and MyD88 in RA FLS. VIP treatment decreased CCL2 and CXCL8 chemokine production in response to TLR4 activation with LPS in RA FLS. CONCLUSIONS: We demonstrate that VIP down-regulates LPS and TNF-alpha activation of TLR4 expression and the TLR4 functional response in terms of proinflammatory chemokine production. These studies suggest that the pleiotropic anti-inflammatory actions of VIP involve inhibitory effects on TLR4 expression and signalling.
Assuntos
Artrite Reumatoide/imunologia , Quimiocinas/biossíntese , Regulação para Baixo/efeitos dos fármacos , Receptor 4 Toll-Like/biossíntese , Peptídeo Intestinal Vasoativo/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Western Blotting , Células Cultivadas , Fibroblastos/imunologia , Humanos , Fator 88 de Diferenciação Mieloide , Osteoartrite do Joelho/imunologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Membrana Sinovial/imunologia , Receptor 2 Toll-Like/biossíntese , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaAssuntos
Hipersensibilidade Alimentar/etiologia , Carne/efeitos adversos , Animais , Bovinos , Pré-Escolar , Feminino , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/diagnóstico , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Hipersensibilidade Respiratória/complicações , Testes CutâneosRESUMO
Rapanone (2,5-dihydroxy-3-tridecyl-1,4-benzoquinone), a natural compound isolated from Myrsine guianensis growing in the Andean highlands of Colombia, was studied in different in vitro and in vivo models as a potential antioxidant and anti-inflammatory drug. Rapanone showed a mild anti-lipoperoxidative profile in rat liver microsomes and inhibited potently degranulation (IC(50) of 9.8 microM) and superoxide chemiluminescence (IC(50) of 3.0 microM) in human neutrophils. In addition, rapanone is a selective and potent human synovial PLA(2) inhibitor (IC(50) of 2.6 microM). In vivo experiments using the carrageenan paw oedema and the zymosan air pouch model in mice as well as the adjuvant arthritis model in rats have proved that rapanone is very efficient in controlling the inflammatory process by different administration routes.
Assuntos
Benzoquinonas/farmacologia , Inflamação/tratamento farmacológico , Fitoterapia , Primulaceae , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Benzoquinonas/química , Benzoquinonas/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Feminino , Humanos , Isoenzimas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas de Membrana , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Prostaglandina-Endoperóxido Sintases/metabolismo , RatosRESUMO
Two new sesquiterpene cyclopentenones, dysidenones A and B (2, 3), and a new sesquiterpene aminoquinone, dysidine (4), all containing the same rearranged drimane skeleton, have been isolated from a Dysidea sp. sponge, along with bolinaquinone (1). The structures were established from 2D NMR data. Bolinaquinone (1), dysidine (4), and a 1:1 mixture of dysidenones A and B (2, 3) significantly inhibited human synovial phospholipase A2 (PLA2) at 10 microM. Compound 4, which shows an IC50 value of 2.0 microM, exerts a higher potency and selectivity toward this enzyme than the reference inhibitor manoalide. In addition, all of these compounds modulated at 10 microM other human leukocyte functions such as the degranulation process measured as elastase release and the superoxide production measured by chemiluminescence.
Assuntos
Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Leucócitos/efeitos dos fármacos , Fosfolipases A/antagonistas & inibidores , Poríferos/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Animais , Degranulação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Humanos , Elastase de Leucócito/antagonistas & inibidores , Medições Luminescentes , Espectroscopia de Ressonância Magnética , Fosfolipases A2 , Espectrofotometria UltravioletaRESUMO
In a previous study, we reported a new bioactive sesquiterpenoid, named dysidotronic acid, to be a potent, selective human synovial phospholipase A(2) inhibitor. Dysidotronic acid is a novel, non-complex manoalide analogue lacking the pyranofuranone ring. We now investigate the effect of this compound on cytokine, nitric oxide and prostanoid generation on the mouse macrophage cell line RAW 264.7, where it showed a dose-dependent inhibition with inhibitory concentration 50% values in the micromolar range. This effect was also confirmed in the mouse air pouch injected with zymosan. Dysidotronic acid inhibited the production of tumor necrosis factor alpha and interleukin-1 beta as well as the production of nitric oxide, prostaglandin E(2) and leukotriene B(4). Decreased nitric oxide generation was the consequence of inhibition of the expression of nitric oxide synthase, whereas PGE(2) and LTB(4) reduction was due to inhibition of arachidonic acid bioavailability through a direct inhibitory effect of dysodotronic acid on secretory phospholipase A(2).
Assuntos
Dinoprostona/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Macrófagos/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2 , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Dinoprostona/metabolismo , Diterpenos/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Nitritos/antagonistas & inibidores , Nitritos/metabolismo , Fosfolipases A/antagonistas & inibidores , Fosfolipases A/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Sesquiterpenos/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Zimosan/farmacologiaAssuntos
Aspergilose/veterinária , Aspergillus fumigatus/isolamento & purificação , Mastite/veterinária , Penicilinas/administração & dosagem , Doenças dos Ovinos/microbiologia , Animais , Aspergilose/patologia , Cloxacilina/administração & dosagem , Feminino , Mastite/etiologia , Mastite/patologia , Ovinos , Doenças dos Ovinos/patologiaRESUMO
Four new bioactive pyridinium alkaloids, named spongidines A-D (5-8), have been isolated from a Vanuatu sponge of the genus Spongia, together with known petrosaspongiolides D (1) and G (2). Compounds 3 and 4 are 21-hydroxy derivatives of petrosaspongiolides K and P. Structure elucidation was accomplished through extensive 2D NMR experiments (COSY, ROESY, HMBC, HMQC) and IR, UV, and FABMS data. All compounds significantly inhibited human synovial phospholipase A(2) (PLA(2)) at 10 microM, with an IC(50) value of 5.8 microM for compound 4, which is the most potent inhibitor, with a higher selectivity toward this enzyme than the reference inhibitor manoalide. Pyridinium alkaloids (5-8) mainly inhibited human synovial PLA(2). Compound 8, which contains a sulfonic acid group, is the most interesting inhibitor.
Assuntos
Alcaloides/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Fosfolipases A/antagonistas & inibidores , Poríferos/química , Alcaloides/química , Alcaloides/farmacologia , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Compostos de Piridínio/química , Análise EspectralRESUMO
We have synthesised some lipidic diamines and aminoalcohols and examined their behaviour as inhibitors of secretory and cytosolic PLA2. Some structure-activity relationships considerations have been deduced. Compound 14 was a potent and selective inhibitor of cPLA2 and compound 4 showed a dual inhibitory profile against both types of PLA2 while no cytotoxicity at 10 microM on human neutrophils or on murine macrophage line was observed for both.
Assuntos
Amino Álcoois/síntese química , Citosol/enzimologia , Diaminas/síntese química , Fosfolipases A/metabolismo , Amino Álcoois/farmacologia , Animais , Linhagem Celular , Diaminas/farmacologia , Humanos , Lipídeos/química , Camundongos , Fosfolipases A/antagonistas & inibidores , Fosfolipases A2 , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The oncogenic retrovirus bovine leukaemia virus (BLV) primarily infects B cells. Most infected animals remain asymptomatic for long periods of time before an increase in circulating B cells or localized tumours can be observed. This long clinical latency period may be explained by cells of the monocyte/macrophage lineage (M/M) becoming infected and acting as a reservoir for the virus, as shown for other retroviruses (human immunodeficiency virus-1, feline immunodeficiency virus). M/M cells in different stages of differentiation (HL-60, THP-1, U-937, J774, BGM, PM2, primary macrophages of sheep and cows) were cultured with BLV produced by permanently infected donor cells (FLKBLV and BLV-bat(2)). Donor cells were inhibited from multiplying by either irradiation or treatment with mitomycin C. In other experiments, supernatant from donor cells containing virus was used. In co-culture with the donor cells, the less differentiated monocytic cells showed severe cellular changes such as differentiation, vacuolization, cell lysis and membrane blebbing; apoptosis was a frequent phenomenon. Budding and extracellular viruses were also observed. The more differentiated macrophage cells, although they showed less signs of infection by microscopy, had a complete BLV protein profile, as seen by Western blotting; bands corresponding to p24CA (Gag) and its precursors were clearly seen. In addition, gp51SU was identified by syncytia formation assays. It is concluded that M/M cells may be infected by BLV, the consequences of the infection differing according to the type of cell.
Assuntos
Vírus da Leucemia Bovina/fisiologia , Macrófagos/virologia , Monócitos/virologia , Animais , Apoptose , Western Blotting , Bovinos , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Técnicas de Cocultura , Efeito Citopatogênico Viral , Produtos do Gene gag/biossíntese , Células Gigantes/fisiologia , Vírus da Leucemia Bovina/ultraestrutura , Macrófagos/ultraestrutura , Microscopia Eletrônica , Monócitos/ultraestrutura , Ovinos , Proteínas do Envelope Viral/biossíntese , Vírion/fisiologiaRESUMO
Many in vitro studies have used cell cultures to focus on the relationships between cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) isoforms. We have investigated the time-course of regulation and the role of COX-2 and iNOS in a model of experimental inflammation in mice, the air pouch injected with zymosan. This study demonstrates that there is an early acute phase (4 h) mediated mainly by eicosanoids, with high levels of prostaglandin E2 (PGE2) produced by cyclo-oxygenase-1. In addition, in the later phase (from 12 h) there is a participation of nitric oxide (NO) and PGE2 accompanied by co-induction of both iNOS and COX-2. These enzymes were detected in migrating leukocytes as well as in macrophages lining the air pouch. Administration of NS398 or indomethacin inhibited PGE2 levels and COX activity, but also nitrite levels and iNOS activity, which was accompanied by a reduction in iNOS expression. Aminoguanidine inhibited nitrite levels and iNOS activity in addition to exerting inhibitory effects on the COX pathway. Treatment of animals with dexamethasone reduced nitrite and PGE2 concentrations in air pouch exudates, as well as iNOS and COX-2 expression in migrating cells. Our results indicate that PGE2 and NO may play in vivo mutual modulatory roles in the inflammatory response caused by zymosan injection into the mouse air pouch, a suitable model to study drugs acting on those pathways.
Assuntos
Inflamação/enzimologia , Isoenzimas/biossíntese , Óxido Nítrico Sintase/biossíntese , Prostaglandina-Endoperóxido Sintases/biossíntese , Animais , Anti-Inflamatórios/farmacologia , Western Blotting , Colchicina/farmacologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Dexametasona/farmacologia , Dinoprostona/biossíntese , Eicosanoides/biossíntese , Indução Enzimática , Exsudatos e Transudatos/citologia , Exsudatos e Transudatos/efeitos dos fármacos , Feminino , Imunofluorescência , Inflamação/induzido quimicamente , Leucócitos/efeitos dos fármacos , Leucócitos/enzimologia , Camundongos , Óxido Nítrico Sintase Tipo II , Fatores de Tempo , ZimosanRESUMO
The inhibitory effect of cavernolide, a novel C2, terpene lactone isolated from the sponge Fasciospongia cavernosa, on PLA2 and other enzyme activities involved in the inflammatory process was studied. Cavernolide inhibited human synovial sPLA2 in a concentration-dependent manner with an IC50 value of 8.8 microM. Besides, this compound decreased in the nanomolar range the myeloperoxidase degranulation process using different stimuli. Cavernolide also inhibited TNFalpha, NO and PGE2 production in intact cell experiments. NO and PGE2 reduction was the consequence of the inhibition on iNOS and COX-2 expression because it did not affect inducible nitric oxide synthase and cyclooxygenase-2 activities in intact cells.
Assuntos
Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Terpenos/farmacologia , Animais , Western Blotting , Degranulação Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/biossíntese , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Proteínas de Membrana , Camundongos , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo II , Peroxidase/metabolismo , Fosfolipases A/metabolismo , Fosfolipases A2 , Prostaglandina-Endoperóxido Sintases/biossíntese , Membrana Sinovial/enzimologia , Fator de Necrose Tumoral alfa/metabolismo , Zimosan/farmacologiaRESUMO
BACKGROUND: To determine the nonfulfillment of antiinfectious therapy in clinical practice. MATERIAL AND METHODS: Fulfillment was quantified by tablet counting (TC) in the homes of 366 patients undergoing antibiotic treatment and the motives and predictive factors were identified. RESULTS: Nonfulfillment was of 61% (95% confidence interval [CI] 55.4-66.6%). Patient improvement was the main reason for discontinuation (54.5%). The predictive factors were greater length of treatment (p = 0.000004), dose (p = 0.0019) and number of tablets (p = 0.0000). CONCLUSIONS: Nonfulfillment of antiinfectious treatment in clinical practice is high, mainly due to clinical improvement and to the greater complexity and length of treatment.
Assuntos
Antibacterianos/uso terapêutico , Infecções/tratamento farmacológico , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Adulto , Assistência Ambulatorial/estatística & dados numéricos , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Amostragem , EspanhaRESUMO
Manoalide is a potent analgesic and antiinflammatory sesterterpene isolated in 1980 from a marine sponge. The antiinflammatory activity of manoalide is due to inhibition of PLA2, through irreversible binding to several lysine residues. The binding is realized by means of the two masked aldehyde functions present in the polar part of manoalide. Of the two aldehyde groups, only that present in the g-hydroxybutenolide ring seems to be essential, since cacospongionolides, naturally occurring analogues lacking the second masked aldehyde group, were also shown to be irreversible PLA2 inhibitors. It appears that the minimum structural requirement for exhibiting manoalide-like PLA2 inhibition would be the presence in the inhibitor of functional groups able to seize the amino groups of PLA2 lysine residues with formation of stable covalent bonds. Many manoalide analogues have been isolated from marine sponges, most of them sharing PLA2 inhibitory properties. Other interesting bioactivities have also been reported for some of these compounds.
Assuntos
Terpenos/química , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Fosfolipases A/antagonistas & inibidores , Fosfolipases A2 , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/farmacologiaRESUMO
The marine product petrosaspongiolide M is a novel inhibitor of phospholipase A2 (PLA2), showing selectivity for secretory PLA2 versus cytosolic PLA2, with a potency on the human synovial enzyme (group II) similar to that of manoalide. This compound was more potent than manoalide on bee venom PLA2 (group III) and had no effect on group I enzymes (Naja naja and porcine pancreatic PLA2). Inhibition of PLA2 was also observed in vivo in the zymosan-injected rat air pouch, on the secretory enzyme accumulated in the pouch exudate. Petrosaspongiolide M decreased carrageenan paw edema in mice after the oral administration of 5, 10, or 20 mg/kg. This marine metabolite (0.01-1.0 micromol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E2, leukotriene B4, and tumor necrosis factor-alpha in the mouse air pouch injected with zymosan 4 h after the stimulus. It also had a weaker effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by petrosaspongiolide M, which also inhibited leukotriene B4 levels in serum and PGE2 levels in paw homogenates. In contrast with indomethacin, this marine compound did not reduce PGE2 levels in stomach homogenates. Petrosaspongiolide M is a new inhibitor of secretory PLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Inflamação/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Fosfolipases A/antagonistas & inibidores , Animais , Artrite Experimental/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Exsudatos e Transudatos/enzimologia , Exsudatos e Transudatos/metabolismo , Humanos , Técnicas In Vitro , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Leucotrieno B4/metabolismo , Masculino , Camundongos , Ácido Oleanólico/farmacologia , Fosfolipases A2 , Poríferos/química , Ratos , Ratos Endogâmicos Lew , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Células U937RESUMO
1. Cacospongionolide B is a novel marine metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide. 2. This activity was confirmed in vivo in the 8 h zymosan-injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis. 3. This marine metabolite showed topical anti-inflammatory activity on the mouse ear oedema induced by 12-O-tetradecanoylphorbol acetate (TPA) and decreased carrageenin paw oedema in mice after oral administration of 5, 10 or 20 mg kg(-1). 4. In the mouse air pouch injected with zymosan, cacospongionolide B administered into the pouch, induced a dose-dependent reduction in the levels of eicosanoids and tumour necrosis factor alpha (TNFalpha) in the exudates 4 h after the stimulus. It also had a weak effect on cell migration. 5. The inflammatory response of adjuvant arthritis was reduced by cacospongionolide B, which did not significantly affect eicosanoid levels in serum, paw or stomach homogenates and did not induce toxic effects. 6 Cacospongionolide B is a new inhibitor of sPLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation. This marine metabolite was active after oral administration and able to modify TNFalpha levels, and may offer an interesting approach in the search for new anti-inflammatory agents.