RESUMEN
Corni fructus is the fruit of Cornus officinalis Sieb. et Zucc. and has attracted much interest due to its traditional applications and active fraction that reportedly possesses antidiabetic effects. In this study, we isolated 12 compounds from Corni fructus including three flavonoids, two iridoid glycosides, three phenolic compounds, and two triterpenoids, together with cornuside (11) and 2-butoxybutanedioic acid (12). Chemical structures were identified by (1)H, (13)C NMR, DEPT, COSY, HSQC, and HMBC spectral analyses. Furthermore, the glucose uptake efficiency, messenger (m)RNA expression of phosphoenolpyruvate carboxykinase (PEPCK), and prevention of cytokine-mediated cytotoxicity in the presence of test agents were evaluated. While CH and CB significantly increased glucose uptake from muscle, compounds 3 and 8, each at 50 µM, significantly suppressed PEPCK mRNA expression. Finally, compound 5, at 50 and 100 µM, effectively attenuated ß-cell death. In conclusion, those compounds could contribute to the antihyperglycemic and ß-cell-protective actions of Corni fructus against diabetes mellitus.
Asunto(s)
Cornus/química , Diabetes Mellitus Tipo 1/prevención & control , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Línea Celular , Células Cultivadas , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animales de Enfermedad , Glucosa/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Células Secretoras de Insulina/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , RatasRESUMEN
The antihyperglycemic effect of catalpol (1) purified from the roots of Rehmannia glutinosa was investigated in streptozotocin-induced diabetic rats (STZ-diabetic rats) representing insulin-dependent diabetes mellitus. Bolus intravenous injection of 1 showed antihyperglycemic activity in a dose-dependent manner in STZ-diabetic rats. An effective dose of 0.1 mg/kg 1 significantly attenuated the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. Catalpol enhanced the uptake of radioactive glucose in the isolated soleus muscle of STZ-diabetic rats in a concentration-related manner. Moreover, an effect by 1 was established on glycogen incorporation in hepatocytes isolated from STZ-diabetic rats. Catalpol was found to increase glycogen synthesis in STZ-diabetic rats. These results suggest that 1 can increase glucose utilization to lower plasma glucose in diabetic rats lacking insulin.
Asunto(s)
Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Glucósidos/farmacología , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Insulina/metabolismo , Iridoides/farmacología , Plantas Medicinales/química , Rehmannia/química , Animales , Glucemia/análisis , Glucemia/metabolismo , Glucógeno/análisis , Hepatocitos/metabolismo , Hipoglucemiantes/química , Glucósidos Iridoides , Masculino , Estructura Molecular , Músculo Esquelético/metabolismo , Raíces de Plantas/química , Ratas , Ratas Wistar , TaiwánRESUMEN
Histone deacetylase (HDAC) inhibitors are regarded as promising therapeutics for the treatment of cancer. All reported HDAC inhibitors contain three pharmacophoric features: a zinc-chelating group, a hydrophobic linker, and a hydrophobic cap for surface recognition. In this study we investigated the effectiveness of osthole, a hydrophobic Chinese herbal compound, as the surface recognition cap in hydroxamate-based compounds as inhibitors of HDAC. Nine novel osthole-based N-hydroxycinnamides were synthesized and screened for enzyme inhibition activity. Compounds 9 d, 9 e, 9 g exhibited inhibitory activities (IC(50)=24.5, 20.0, 19.6 nM) against nuclear HDACs in HeLa cells comparable to that of suberoylanilide hydroxamic acid (SAHA; IC(50)=24.5 nM), a potent inhibitor clinically used for the treatment of cutaneous T-cell lymphoma (CTCL). While compounds 9 d and 9 e showed SAHA-like activity towards HDAC1 and HDAC6, compound 9 g was more selective for HDAC1. Compound 9 d exhibited the best cellular effect, which was comparable to that of SAHA, of enhancing acetylation of either alpha-tubulin or histone H3. Molecular docking analysis showed that the osthole moiety of compound 9 d may interact with the same hydrophobic surface pocket exploited by SAHA and it may be modified to provide class-specific selectivity. These results suggest that osthole is an effective hydrophobic cap when incorporated into N-hydroxycinnamide-derived HDAC inhibitors.