RESUMO
Oxidized low-density lipoprotein (oxLDL) and reactive oxygen species (ROS) play key roles in the early stage of atherosclerosis. Nitric oxide (NO) and ROS are responsible for regulation of the transcriptional pathways of nuclear Factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK), key regulators of cellular inflammatory and immune responses. Previously, we examined LDL-antioxidant activities of the nine flavonoids isolated from Sophora flavescens. Among these, two lavandulyl flavonoids, kurarinone (1) and kuraridin (2) inhibited inducible nitric oxide synthase (iNOS)-dependent NO production and ROS generation, and suppressed remarkably the expression of inflammatory cytokines, CCL2, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and iNOS in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Moreover, compounds 1 and 2 attenuated NF-kappaB activation by inhibition of IkappaBalpha proteolysis and p65 nuclear translocation, as well as phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), and p38 MAP kinases.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Chalconas/farmacologia , Flavonoides/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monoterpenos/farmacologia , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Sophora/química , Animais , Linhagem Celular , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Oxidation of low density lipoprotein (LDL) is strongly implicated as a key process in the onset of atherosclerosis. In this study, nine alkylated (C10-C5) flavonoids from Sophora flavescens were examined for their inhibitory effects on copper-induced LDL oxidation. Of the flavonoids tested, sophoraflavanone G (1), kurarinone (2), kurarinol (3), norkurarinol (4), and kuraridin (9) inhibited the generation of thiobarbituric acid reactive substances (TBARS) with IC50s of 7.9, 14.5, 22.0, 26.9, and 17.5 microM, respectively. The most potent inhibitor, compound 1, also demonstrated significant activities in complementary in vitro investigations, such as lag time (130 min at 5 microM), relative electrophoretic mobility (REM) of ox-LDL (80% inhibition at 20 microM), and fragmentation of apoB-100 (inhibition of 71% at 20 microM). Analysis of the structures of these compounds reveals that a resorcinol moiety in the B-ring is strongly correlated with protection of LDL-oxidation.
Assuntos
Antioxidantes/farmacologia , Flavonoides/farmacologia , Lipoproteínas LDL/química , Sophora/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Apolipoproteína B-100/química , Cromatografia Líquida de Alta Pressão , Sulfato de Cobre/farmacologia , Ensaio de Desvio de Mobilidade Eletroforética , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Lipoproteínas LDL/sangue , Estrutura Molecular , Oxirredução , Raízes de Plantas/química , Relação Estrutura-Atividade , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
In order to access beta-secretase (BACE1), and enzyme strongly implicated in the cause of Alzheimer's disease, inhibitors must possess sufficient lipophilicity to traverse two lipid bilayers. Current drug candidates, which are almost totally peptide-derived, are thus inefficient because cell permeability presents a serious limiting factor. In this study, lipophilic alkylated (C(10)-C(5)) flavanones from Sophora flavescens were examined for their inhibitory effects against beta-secretase. Lavandulyl flavanones (1, 2, 5, 6, and 8) showed potent beta-secretase inhibitory activities with IC(50)s of 5.2, 3.3, 8.4, 2.6, and 6.7microM, respectively, while no significant activity was observed in the corresponding hydrated lavandulyl flavanones (4 and 7) and prenylated flavanone (3). As we expected, lavandulyl flavanones reduced Abeta secretion dose-dependently in transfected human embryonic kidney (HEK-293) cells. In kinetic studies, all compounds screened were shown to be noncompetitive inhibitor.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Flavanonas/farmacologia , Sophora/química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Linhagem Celular , Humanos , Concentração Inibidora 50 , Cinética , TransfecçãoRESUMO
We have proven that xanthones 1-8 isolated from the root of C. tricuspidata possess highly potent alphaalpha-glucosidase inhibition properties. Compound 1 was identified as a new isoprenylated tetrahydroxy xanthone, 1,3,6,7-tetrahydroxy-2-(3-methylbut-2-enyl)-8-(2-methylbut-3-en-2-yl)-9H-xanthen-9-one (1). These are the first natural xanthones documented to exhibit such inhibition. The IC(50) values of compounds 1-8 inhibiting alpha-glucosidase activity were determined to be up to 16.2microM. Mechanistic analysis showed the xanthones 1-8 exhibited full mixed inhibition.
