Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract.
(9/91)
Schisandra fruit, a Schisandraceae family herb, is used as a component in Kampo medicines (developed from Chinese medicines, but established in Japan). It can act as a sedative and antitussive, improve hepatic function, and give a general tonic effect. An extract of Schisandra fruit has been shown with a potent inhibitory effect on human liver microsomal erythromycin N-demethylation activity mediated by cytochrome P450 3A4 (CYP3A4). The present study was conducted to identify Schisandra fruit components having inhibitory effects on CYP3A4 by surveying the effect on human liver microsomal erythromycin N-demethylation activity. Known components of Schisandra fruit, gomisins B, C, G, and N and gamma-shizandrin, showed inhibitory effects on N-demethylation activity. Among these components, gomisin C displayed the most potent and competitive inhibitory effect, with a Ki value of 0.049 microM. Furthermore, the inhibitory effect of gomisin C was stronger than that of ketoconazole (Ki = 0.070 microM), a known potent CYP3A4 inhibitor. Gomisin C, however, inhibited CYP1A2-, CYP2C9-, CYP2C19-, and CYP2D6-dependent activities only to a limited extent (IC50 values >10 microM). Moreover, gomisin C inactivated human liver microsomal erythromycin N-demethylation activity in a time- and concentration-dependent manner. The inactivation kinetic parameters k(inact) and K(I) were 0.092 min(-1) and 0.399 microM, respectively. The human liver microsomal erythromycin N-demethylation activity inactivated by gomisin C did not recover on dialysis of the microsomes. Spectral scanning of CYP3A4 with gomisin C yielded an absorbance at 455 nm, suggesting that gomisin C inactivated the cytochrome P450 via the formation of a metabolite intermediate complex. This pattern is consistent with the metabolism of the methylenedioxy substituent in gomisin C. These results indicate that gomisin C is a mechanism-based inhibitor that not only competitively inhibits but irreversibly inactivates CYP3A4. (+info)
Down-modulation of heat shock protein 70 and up-modulation of Caspase-3 during schisandrin B-induced apoptosis in human hepatoma SMMC-7721 cells.
(10/91)
AIM: To investigate the effect of schisandrin B (Sch B) on proliferation and apoptosis of human hepatoma SMMC-7721 cells in vitro and regulation of Hsp70 and Caspases-3, 7, 9 expression by Sch B. METHODS: Human hepatoma cell line SMMC-7721 was cultured and treated with Sch B at various concentrations. Growth suppression was detected with MTT colorimetric assay. Cell apoptosis was confirmed by DNA ladder detection and flow cytometric analysis. The expression of Hsp70, Caspases-3, 7, 9 were analyzed by Western blot analysis. RESULTS: Sch B inhibited the growth of hepatoma SMMC-7721 cells in a dose-dependent manner, leading to a 50% decrease in cell number (LC50) value of 23.50 mg/L. Treatment with Sch B resulted in degradation of chromosomal DNA into small internucleosomal fragments, evidenced by the formation of a 180-200 bp DNA ladder on agarose gels. FCM analysis showed the peak areas of subdiploid at the increased concentration of Sch B. The results of Western bolt analysis showed that Hsp70 was down-regulated and Caspase-3 was up-regulated, while the activity of Caspases-7, -9 had no significant change. CONCLUSION: Sch B is able to inhibit the proliferation of human hepatoma SMMC-7721 cells and induce apoptosis, which goes through Caspase-3-dependent and Caspase-9-independent pathway accompanied with the down-regulation of Hsp70 protein expression at an early event. (+info)
Photoinduced plasticity in cross-linked polymers.
(11/91)
Chemically cross-linked polymers are inherently limited by stresses that are introduced by post-gelation volume changes during polymerization. It is also difficult to change a cross-linked polymer's shape without a corresponding loss of material properties or substantial stress development. We demonstrate a cross-linked polymer that, upon exposure to light, exhibits stress and/or strain relaxation without any concomitant change in material properties. This result is achieved by introducing radicals via photocleavage of residual photoinitiator in the polymer matrix, which then diffuse via addition-fragmentation chain transfer of midchain functional groups. These processes lead to photoinduced plasticity, actuation, and equilibrium shape changes without residual stress. Such polymeric materials are critical to the development of microdevices, biomaterials, and polymeric coatings. (+info)
A new triterpene and dibenzocyclooctadiene lignans from Schisandra propinqua (WALL.) BAILL.
(12/91)
A new triterpene and two new natural dibenzocyclooctadiene lignans were isolated from the stems of Schisandra propinqua. In addition, three known lignans, octadecanoic acid, 2,3-dihydroxypropyl ester and beta-sitosterol were isolated. The structures of the new triterpene and new natural products were elucidated base on spectral analysis, including 1D and 2D NMR experiments. The isolates were tested for their cytotoxic effects against several tumor cell lines by MTT assay. (+info)
Bioactivity of neolignans from fructus Schizandrae.
(13/91)
Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products. (+info)
Four new nonaoxygenated C18 dibenzocylcooctadiene lignans from Kadsura philippinensis.
(14/91)
Four new nona-oxygenated C18 dibenzocyclooctadiene lignans, kadsuphilins C-F (1-4), were isolated from the EtOAc soluble portion of the alcoholic extract of the aerial parts of Kadsura philippinensis. The structures of 1-4 were elucidated on the basis of extensive spectroscopic analyses, including 2D NMR (HMQC, HMBC, and NOESY) experiments, comparison of the spectral data with those of the related metabolites. The stereochemistries of the biphenyl and octadiene moieties were deduced from circular dichorism (CD) and the NOESY spectra, respectively. The in vitro antiplatelet aggregation activity of metabolites 1-4 also have been evaluated. (+info)
Amyloid-beta-induced cytotoxicity of PC-12 cell was attenuated by Shengmai-san through redox regulation and outgrowth induction.
(15/91)
Neurodegenerative brain disorders such as Alzheimer's disease (AD) have been well investigated. However, significant methods for the treatment of the promotion and progression of AD are unavailable to date. Recent studies suggested that the redox imbalance and the accumulation of amyloid-beta (Abeta) peptide occurring in the brain of AD patients lead to oxidatively-induced apoptotic cell death. Here, we show the effects of Shengmai-san (SMS) on Abeta-induced cytotoxicity in PC-12 cells. SMS dose-dependently attenuated the cytotoxicity by Abeta incubation and also prevented the morphological damage in neurites of the PC-12 cells. Hemeoxygenase-1 and glutathione peroxidase-1 expressions were increased by SMS pretreatment. SMS decreased the phosphorylation level of c-jun amino-terminal kinase (JNK) and the activity of caspase-3, which were enhanced by Abeta incubation. Of importance, SMS treatment promoted neurite outgrowth. These data demonstrated dual roles of SMS in PC-12 cells. SMS prevents the apoptosis through the enhancement of anti-oxidant enzymes and inhibition of the JNK signaling pathway with the promotion of nerve cell maturation, thus suggesting benefits of SMS for the treating of neurodegenerative diseases. It may also be beneficial not only for the treatment of brain disorders but also for other diseases caused by oxidative stress. (+info)
Schisandrin B decreases the sensitivity of mitochondria to calcium ion-induced permeability transition and protects against carbon tetrachloride toxicity in mouse livers.
(16/91)
Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against carbon tetrachloride (CCl4) hepatotoxicity in mice. In order to elucidate the molecular mechanism underlying the hepatoprotection afforded by Sch B, the effect of Sch B treatment on the sensitivity of mitochondria to Ca2+-stimulated permeability transition (PT) was investigated in mouse livers under normal and CCl4-intoxicated conditions. CCl4 hepatotoxicity caused an increase in the sensitivity of mitochondria to Ca2+-stimulated PT in vitro. The enhanced sensitivity to mitochondrial PT was associated with increases in mitochondrial Ca2+ content as well as the extent of reactive oxidant species (ROS) production and cytochrome c release. The hepatoprotection afforded by Sch B pretreatment against CCl4 toxicity was paralleled by the decrease in the sensitivity of hepatic mitochondria to Ca2+-stimulated PT as well as the attenuations of mitochondrial Ca2+ loading, ROS production and cytochrome c release under CCl4-intoxicated condition. In conclusion, the results suggest that the hepatoprotection afforded by Sch B pretreatment against CCl4 toxicity may be related to the increase in the resistance of hepatic mitochondria to Ca2+-stimulated PT. (+info)