RESUMEN
BACKGROUND/OBJECTIVES: This study was designed to investigate the improvement effect of white ginseng extract (GS-KG9) on D-galactosamine (Ga1N)-induced oxidative stress and liver injury. SUBJECTS/METHODS: Sixty Sprague-Dawley rats were divided into 6 groups. Rats were orally administrated with GS-KG9 (300, 500, or 700 mg/kg) or silymarin (25 mg/kg) for 2 weeks. The rats of the GS-KG9- and silymarin-treated groups and a control group were then intraperitoneally injected Ga1N at a concentration of 650 mg/kg for 4 days. To investigate the protective effect of GS-KG9 against GalN-induced liver injury, blood liver function indicators, anti-oxidative stress indicators, and histopathological features were analyzed. RESULTS: Serum biochemical analysis indicated that GS-KG9 ameliorated the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in GalN-treated rats. The hepatoprotective effects of GS-KG9 involved enhancing components of the hepatic antioxidant defense system, including glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). In addition, GS-KG9 treatment inhibited reactive oxygen species (ROS) production induced by GalN treatment in hepatocytes and significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins, which are antioxidant proteins. In particular, by histological analyses bases on hematoxylin and eosin, Masson's trichrome, α-smooth muscle actin, and transforming growth factor-ß1 staining, we determined that the administration of 500 mg/kg GS-KG9 inhibited hepatic inflammation and fibrosis due to the excessive accumulation of collagen. CONCLUSIONS: These findings demonstrate that GS-KG9 improves GalN-induced liver inflammation, necrosis, and fibrosis by attenuating oxidative stress. Therefore, GS-KG9 may be considered a useful candidate in the development of a natural preventive agent against liver injury.
RESUMEN
Black ginseng (BG), which is produced by repeated steaming and drying of fresh ginseng, has various pharmacological and therapeutic properties. This study investigated the anti-hyperglycemic and hypolipidemic effects of BG ethanolic extract in type 2 diabetic db/db mice. The levels of fasting blood glucose, HbA1c, insulin levels and thiobarbituric acid reactive substances values were decreased in the groups fed BG extract (BG) (100 and 900 mg/kg BW/day), compared to the control group (CON). In the BG compared with the CON, hepatic steatosis in the liver and the size of adipocytes in muscle tissue were improved. The administration of BG regulated the glucose transporter type (GLUT) 4 and 2, and peroxisome proliferator-activated receptor (PPAR) α and γ in muscle and liver. Moreover, ginsenosides (Rh4, Rg5, and Rk1), which profiled by HPLC, regulated the markers for lipid metabolism and glucose metabolism; PPARs and GLUTs in muscle and C2C12 rather than liver cells and tissue. These findings suggested that ginsenosides (Rh4, Rg5, and Rk1) from BG extract can ameliorate type 2 diabetes through their anti-hyperglycemic and hypolipidemic effects.
RESUMEN
2-(3-Benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor, is newly developed for the control of type 2 diabetes mellitus (T2DM) and metabolic syndrome. A method for the determination of KR-66344 in rat plasma was developed by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS) to evaluate the pharmacokinetics of KR-66344. Plasma samples were processed by a liquid-liquid extraction method with ethyl acetate and introduced onto the LC-MS-MS system. The analyte and imipramine (internal standard) were analyzed by multiple reaction monitoring based on transitions at m/z 420.1 â 105.0 and 282.2 â 86.0, respectively. The calibration curve was linear (r = 0.9993) over the concentration range of 1.0-1,000 ng/mL. The mean recovery values for KR-66344 and imipramine were 83.8 and 86.2%, respectively. The mean inter-day and intra-day assay precision values were 3.9 and 2.4%, respectively. KR-66344 was stable under various handling and storage conditions. This developed method was applied to a pharmacokinetic study after the oral administration of KR-66344 in rats. The concentration of KR-66344 was readily measurable in rat plasma up to 24 h post-dose after an oral administration, suggesting that current assay is applicable to pharmacokinetic studies for KR-66344.
Asunto(s)
Óxidos S-Cíclicos/aislamiento & purificación , Hipoglucemiantes/aislamiento & purificación , Tiazinas/aislamiento & purificación , 11-beta-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Administración Oral , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión/normas , Óxidos S-Cíclicos/administración & dosificación , Óxidos S-Cíclicos/farmacocinética , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Imipramina/aislamiento & purificación , Masculino , Ratas Sprague-Dawley , Estándares de Referencia , Espectrometría de Masas en Tándem/normas , Tiazinas/administración & dosificación , Tiazinas/farmacocinéticaRESUMEN
Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity. We have investigated methods to predict various toxic effects of drug candidates to reduce the failure rate of drug discovery. An electrophysiological method was used to assess the cardiotoxicity of drug candidates. Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition. Nefazodone inhibited hERG channel activity in our system. However, nefazodone-induced hERG inhibition indicated only a theoretical risk of cardiotoxicity. Nefazodone inhibited the hERG channel in a concentration-dependent manner with an IC50 of 45.3nM in HEK-293 cells. Nefazodone accelerated both the recovery from inactivation and its onset. Nefazodone also accelerated steady-state inactivation, although it did not modify the voltage-dependent character. Alanine mutants of hERG S6 and pore region residues were used to identify the nefazodone-binding site on hERG. The hERG S6 point mutants Y652A and F656A largely abolished the inhibition by nefazodone. The pore region mutant S624A mildly reduced the inhibition by nefazodone but T623A had little effect. A docking study showed that the aromatic rings of nefazodone interact with Y652 and F656 via π-π interactions, while an amine interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding.
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Cardiotoxinas/química , Fenómenos Electrofisiológicos , Canales de Potasio Éter-A-Go-Go/genética , Estereoisomerismo , Triazoles/química , Sitios de Unión , Simulación por Computador , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Células HEK293 , Humanos , Técnicas de Placa-Clamp , Piperazinas , Conformación ProteicaRESUMEN
Three new guaiane-type sesquiterpene lactones (1-3), together with nine related sesquiterpenes (4-12), were isolated from the whole extract of Ixeris dentata (Asteraceae). The chemical structures of isolates 1-12 were established by spectroscopic analyses as 3 ß,8 ß-dihydroxy-guaia-10(14)-en-1 α,4 α,5 α,6 ß,7 α,11 ßH-12,6 α-olide (1), ixerin N 6'- O-acetate (2), ixerisoside A 6'- O-acetate (3), ixerin N ( 4), ixerisoside A (5), ixerin M (6), tectroside (7), 8-epidesacylcynaropicrin glucoside (8), 8-epiisolipidiol (9), 11 ßH-11,13-dihydrointegrifolin (10) 8 ß-hydroxy-4 ß,15-dihydrozaluzanin C (11), and integrifolin (12). Compounds 1-12 were evaluated for their inhibitory effect on the proliferation of the cultured human tumor cell lines MES-SA, MES-SA/DX5, HCT-15, and HCT15/CL02 in vitro.
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Antineoplásicos Fitogénicos/aislamiento & purificación , Asteraceae/química , Lactonas/aislamiento & purificación , Extractos Vegetales/química , Sesquiterpenos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Humanos , Lactonas/química , Lactonas/farmacología , Estructura Molecular , Neoplasias/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Sesquiterpenos/química , Sesquiterpenos/farmacologíaRESUMEN
Three new triterpenoid saponins, platyconic acid B lactone (1), deapio-platyconic acid B lactone (2), and deapio-platycodin D(2) (3), together with 17 known triterpenoid saponins, were isolated from a root extract of Platycodon grandiflorum. The structures of 1-3 were determined on the basis of spectroscopic data interpretation and chemical transformation. Saponins with a platycodigenin or polygalacic acid unit as a sapogenin demonstrated significant inhibitory effects on the proliferation of a small panel of cultured human tumor cells.
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Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Platycodon/química , Saponinas/aislamiento & purificación , Saponinas/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Raíces de Plantas/química , Saponinas/química , Triterpenos/química , Células Tumorales CultivadasRESUMEN
In the course of searching for new classes of α-glucosidase inhibitors originated from natural resources, 11 kinds of isoflavones, i.e., medicarpin (1), formononetin (2), mucronulatol (3), (3R)-calussequinone (5), (3R)-5'-methoxyvestitol (6), tectorigenin (7), biochanin A (8), tuberosin (9), calycosin (10), daidzein (11), and genistein (12), as well as a flavone, liquritigenin (4), were isolated as active principles responsible for the yeast α-glucosidase inhibitory activity from two leguminous plant extracts, i.e., the heartwood extract of Dalbergia odorifera and the roots extract of Pueraria thunbergiana. Each components (1-12) demonstrated a significantly potent inhibition on yeast α-glucosidase in a dose dependent manner when the p-nitrophenyl-α-D-glucopyranoside was used as a substrate in vitro. The concentration required for 50% enzyme inhibition (IC50) were calculated as 2.93 mM (1), 0.51 mM (2), 3.52 mM (7) 0.35 mM (8), 3.52 mM (9), 0.85 mM (11), and 0.15 mM (12) when that of reference drug acarbose was evaluated as 9.11 mM, in vitro. However, isoflavone glycosides, i.e., puerarin (13), daidzin (14), formononetin-7-O-ß-glucopyranoside (15), and genistin (16), exhibited a relatively poor inhibitory activity on yeast α-glucosidase as compared with the corresponding isoflavone (2, 11, 12), respectively.
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Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Fabaceae/química , Inhibidores de Glicósido Hidrolasas , Isoflavonas/química , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Saccharomyces cerevisiae/enzimología , Acarbosa/química , Inhibidores Enzimáticos/aislamiento & purificación , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Isoflavonas/aislamiento & purificación , Cinética , Extractos Vegetales/químicaRESUMEN
The ginsenoside content of berries and roots of three cultivars of Korean ginseng have been investigated. For all cultivars, ginsenoside Re was the most abundant ginsenoside in roots and berries. However, berries produced more total ginsenosides, and berry the ginsenoside profile differed from that of roots. The ginsenoside Re content of berries was 4-6 times more than that of roots. Averaged across all cultivars, the amounts of the five ginsenosides in berries was Re > Rc approximately = Rg1 approximately = Rb1 approximately = Rd. For roots, the amounts were Re > Rg1 > Rb1 > Rc > Rd. Roots of the Yunpoong cultivar had the greatest ginsenoside content, followed by roots of the Chunpoong cultivar and the Gumpoong cultivar. The total amount of ginsenosides (especially Rb1, Re, and Rg1) was greatest in the Yunpoong cultivar.
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Ginsenósidos/química , Panax/química , Calibración , Cromatografía Líquida de Alta Presión , Frutas/química , Ginsenósidos/aislamiento & purificación , Corea (Geográfico) , Raíces de Plantas/química , Reproducibilidad de los ResultadosRESUMEN
A genuine triterpenoid saponin, platyconic acid A (1) was isolated from the roots extract of Platycodon grandiflorum, together with five known saponins: deapioplatycoside E (2), platycoside E (3), platycodin D(3) (4), platycodin D(2) (5) and platycodin D (6). The structure of 1 was determined on the basis of spectral analysis and chemical evidence.
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Platycodon/química , Saponinas/química , Saponinas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Raíces de Plantas/químicaRESUMEN
A new isoflavone, neocorylin ( 1) was isolated from the seeds extract of Psoralea corylifolia L. (Fabaceae), together with eight known constituents ( 2 - 9), i. e., bakuchiol ( 2), psoralen ( 3), bavachromene ( 4), isobavachromene ( 5), bavachalcone ( 6), isobavachalcone ( 7), 7,8-dihydro-8-(4-hydrophenyl)-2,2-dimethyl-2 H,6 H-[1,2- B:5,4- B']dipyran-6-one ( 8), and bavachinin ( 9). The structure of the new isoflavone 1 was elucidated as 7-hydroxy-3-[2-methyl-2-(4-methylpenten-3-yl)-2 H-chromen-6-yl]-4 H-chromen-4-one by spectroscopic analyses. Neocorylin ( 1) as well as related compounds 2, 4 - 6, 8 and 9 exhibited a significant inhibitory effect on baculovirus-expressed BACE-1 in vitro.