Hypocholesterolemic property of<Emphasis Type="Italic">Yucca schidigera</Emphasis> and<Emphasis Type="Italic">Quillaja saponaria</Emphasis> extracts in human body

This study was undertaken to observe the effects of the blend of partially purified Yucca schidigera and Quillaja saponaria extracts on cholesterol levels in the human's blood and gastrointestinal functions, and to determine if a new cholesterol-lowering drug can be developed by the further purification of the extracts. Ultrafiltration and sequential diafiltration increased the amounts of steroidal saponin in aqueous yucca extract and terpenoid saponin in aqueous quillaja extract from 9.3% and 21.4% to 17.2% and 61.8%, respectively. Taking 0.9 mg of the blend (6:4, v:v) of the resulting filtrates a day for 4 weeks resulted in the decreases in total and LDL cholesterol levels in blood plasma of hyper-cholesterolemic patients with enhancement in gastrointestinal symptoms of patients.     

<Emphasis Type="Italic">In vivo</Emphasis> anti-inflammatory effect of a new steroidal saponin,mannioside A,and its derivatives isolated from <Emphasis Type="Italic">Dracaena mannii</Emphasis>

A new steroidal saponin, mannioside A (1), was isolated from the stem bark of Dracaena mannii, together with the known pennogenin (2), pennogenin-3-O-beta-D-glucopyranoside (3) and pennogenin-3-O-alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-beta-D-glucopyranoside (4). Their structures were determined using 1D-and 2D-NMR spectroscopy and mass spectrometry. Compounds 1 and 3 significantly inhibited carrageenan-induced paw edema in the rat; compound 4 was moderately active whereas 2 showed very weak activity.     

Paridis saponins inhibiting carcinoma growth and metastasis <Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>

Paris polyphylla Smith var. yunnanensis extracts, Rhizoma Paridis saponins (RPS) have been found to show strong antitumor activity. However, few studies have yet investigated pulmonary metastasis treatment with this herb. To detail the effective components in RPS and discuss the preliminary mechanism of antitumor effects in vivo and in vitro, a mixture isolated from RPS was investigated. The main constituents were identified as polyphyllin D, formosanin C, dioscin, Paris H, Paris VII and pennogennin 3-O-α-L-rhamnopyranosyl (1→4)-[β-L-rhamnopyranosyl (1→2)]-β-D-glucopyranoside. In our experiments, LA795 cells were exposed to the mixed compounds. Migration inhibition was evaluated by wound healing assay and migration assay in non-cytotoxic dose which was determined by MTT assay. The results demonstrated that the constituent in varying degrees inhibited the migration of the tumor cells in vitro. The mixture also showed antitumor effects on carcinoma in vivo. In conclusion, the mixture is a potent anticancer agent that elicits programmed cell death and inhibits the migration in murine lung adenocarcinoma, both in vitro and in vivo.     

Antiangiogenic activity of<Emphasis Type="Italic">Bupleurum longiradiatum</Emphasis> on human umbilical venous endothelial cells

The ethyl acetate fraction of Bupleurum longiradiatum was found to have an inhibitory effect on the tube-like formation of human umbilical venous endothelial (HUVE) cells. The active compounds, isolated from the fraction, were identified as acetylbupleurotoxin (P1) and bupleurotoxin (P2). The compounds P1 and P2 completely inhibited the tube-like formation of HUVE cells at 30 microg/ml, below the cytotoxic concentration. But, they did not exhibit antitumor activity on BDF1 mice bearing Lewis lung carcinoma cells despite their antiangiogenic activity.     

<Emphasis Type="Italic">In Vitro</Emphasis> antioxidant and anti-inflammatory activities of Jaceosidin from <Emphasis Type="Italic">Artemisia princeps</Emphasis> Pampanini <Emphasis Type="Italic">cv.</Emphasis> Sajabal

Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu²⁺-mediated LDL oxidation with IC₅₀ values of 10.2 μM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-κB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-κB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.     

Inhibitory effect of<Emphasis Type="Italic">Trans-N-p</Emphasis>-coumaroyl tryamine from the twigs of<Emphasis Type="Italic">Celtis chinensis</Emphasis> on the acetylcholinesterase

The methanolic extract of the twigs of Celtis chinensis was found to show inhibitory activity on acetylcholinesterase (AChE), an enzyme that plays a role in the metabolic hydrolysis of ACh. Bioassay-guided fractionation of the methanolic extract resulted in the isolation of N-p-coumaroyl tyramine, as an inhibitor on AChE. This compound inhibited AChE activity in a dose-dependent manner, and the IC50 value of trans-N-p-coumaroyl tyramine was 34.5 microg/mL (122 microM).     

<Emphasis Type="Italic">In Vitro</Emphasis> hepatoprotective compounds from <Emphasis Type="Italic">Suaeda glauca</Emphasis>

Bioassay-guided fractionation of the MeOH extract of Suaeda glauca yielded four phenolic compounds, methyl 3,5-di-O-caffeoyl quinate (1) and 3,5-di-O-caffeoyl quinic acid (2), isorhamnetin 3-O-beta-D-galactoside (3), and quercetin 3-O-beta-D-galactoside (4). Compounds 1 and 2 were hepatoprotective against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells with the EC(50) values of 72.7+/-6.2 and 117.2+/-10.5 microM, respectively. Silybin as a positive control showed an EC(50) value of 82.4+/-4.1 microM.     

<Emphasis Type="Italic">Perilla frutescens</Emphasis> var. <Emphasis Type="Italic">frutescens</Emphasis> in northern Laos

Twenty-eight samples of mericarps of Perilla frutescens var. frutescens were collected through fieldwork performed in Phongsali and Xieng Khouang provinces in northern Laos. No perilla samples were collected from Savannakhet province in the south although more than 20 sites were investigated. Perilla plants are mostly grown mixed with dry-paddy rice by slash-and-burn cultivation in Laos. The most popular local name for perilla mericarps in the area was “Ma Nga Chan”. Weight of 1,000 grains and hardness of the mericarps were measured, and all mericarps were found to be large (weight of 1,000 grains around 2 g) and soft (limit load weight under 300 g), which were preferred for culinary use in Laos. The composition of the essential oils obtained from the herbaceous plants raised from the mericarps was divided into five types, perillaketone, elemicine plus myristicine, shisofuran, piperitenon, and myristicine, and GC–MS analysis of these Laotian perilla samples showed that they were similar to those of corresponding types of known Japanese perilla strains. One of the shisofuran-type perilla contained large amounts of putative α-naginatene, which is likely to be an intermediate of the biosynthesis of naginataketone. The farmers' indifference to the oil type of the leaf seems to leave Laotian perilla as a good genetic resource for studies of the biosynthesis of oil compounds.     

Antioxidative constituents from<Emphasis Type="Italic">Buddleia officinalis</Emphasis>

Four flavonoids (1-4), a phenylethyl glycoside (5), and a phenylpropanoid glycoside (6) were isolated from the flowers of Buddleia officinalis (Loganiaceae). Their structures were determined by chemical and spectral analysis. Among the isolated compounds, luteolin (1) and acteoside (6) exhibited the most potent antioxidative activity on the NBT superoxide scavenging assay. In addition, compounds 1-6 revealed weak antifungal activity, and no hemolytic activity.     

A new <Emphasis Type="Italic">Erythrina</Emphasis> alkaloid from <Emphasis Type="Italic">Erythrina herbacea</Emphasis>

A new Erythrina alkaloid, 10-hydroxy-11-oxoerysotrine (1), has been isolated from the flowers of Erythrina herbacea together with five known compounds: erytharbine (2), 10,11-dioxoerysotrine (3), erythrartine (4), erysotramidine (5) and erysotrine-N-oxide (6). The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass (MS) spectra. The new compound is a rare C-10 oxygenated Erythrina alkaloid. The antioxidant activities of the isolated compounds 1–6 were evaluated by scavenging with peroxynitrite.     

Low glutathione<Emphasis Type="Italic"> S</Emphasis>-transferase dogs

Liver and kidney glutathione S-transferase (GST) activities to 1,2-dichloro-4-nitrobenzene (DCNB) as a substrate (GST-D activities) were measured in 280 dogs from five different breeders, and significant individual differences in this activity were observed in both organs. Interestingly, 34 out of the 280 dogs (i.e. 12.1%) were those in which liver GST-D activities were less than 10 nmol/min per mg cytosolic protein, low GST dogs, and the other dogs were classified as middle and high GST dogs for which the liver GST-D activities were 10–80 and >80 nmol/min per mg protein, respectively, and occurred at similar percentages (41.4% for the middle GST dog and 46.4% for the high GST dog). Furthermore, the existence of the low GST dogs was not limited to one particular breeder. There was a good correlation (r=0.910) between the liver and kidney GST-D activities, showing low activity in not only the liver but also the kidney in the low GST dogs. Although liver GST activity to 1-chloro-2,4-dinitrobenzene as a substrate (GST-C activity), catalyzed by various GST isozymes in dogs, was significantly correlated with liver GST-D activity, GST-C activity showed more than 450 nmol/min per mg protein even in the low GST dogs. There was no significant difference in cytochrome P450 content, 7-ethoxycoumarin O-deethylase activity or UDP-glucuronosyltransferase activity to p-nitrophenol as a substrate between low GST dogs and the other dogs. Finally, remarkably high plasma concentrations of DCNB were observed in the low GST dogs after single doses of DCNB at 5 or 100 mg/kg. The individual differences in GST-D activity are probably attributable to the content and/or activity of the theta class GST isozyme Yd_fYd_f since it has been reported that glutathione conjugation of DCNB is specifically catalyzed by GSTYd_fYd_f in dogs. In conclusion, we identified a number of low GST dogs in which the GST-D activities were not observed either in vivo or in vitro. The feasibility of using a single low dose of DCNB to phenotype dogs based on GST-D activity was confirmed. It was also suggested that low GST dogs have high susceptibility, including unexpected toxicity or abnormal exposure, to chemicals metabolized by GSTYd_fYd_f.     

Enhanced Intracellular Uptake of Sterically Stabilized Liposomal Doxorubicin <Emphasis Type="Italic">in Vitro</Emphasis> Resulting in Improved Antitumor Activity <Emphasis Type="Italic">in Vivo</Emphasis>

Purpose To investigate the correlation between the in vitro intracellular uptake and the in vivo antitumor activity of anticancer drugs delivered by sterically stabilized liposomes (SSL).Methods Arginine-glycine-aspartic acid (RGD) peptide or RGD mimetic (RGDm) was coupled onto the surface of SSL to obtain the cell-binding carrier to facilitate the intracellular delivery of the encapsulated drugs. DOX-loaded SSL (SSL-DOX), DOX-loaded RGD-modified SSL (RGD-SSL-DOX) and DOX-loaded RGDm-modified SSL (RGDm-SSL-DOX) were prepared by lipid film dispersion followed by remote loading of DOX. The intracellular uptake of DOX from the various liposomal formulations was evaluated in vitro with melanoma B16 cells, and the pharmacokinetics, biodistribution, and antitumor activity were compared in C57BL/6 mice carrying melanoma B16 tumors.Results In vitro intracellular uptake of DOX by B16 cells and in vivo antitumor activity in terms of tumor growth inhibition and mice survival time prolongation for various liposomal DOX were in the following order: RGD-SSL-DOX > RGDm-SSL-DOX > SSL-DOX. The mean survival time of the mice treated with RGD-SSL-DOX, RGDm-SSL-DOX, and SSL-DOX was 55, 49, and 44 days, respectively. The three liposomal DOX formulations produced very close DOX accumulation in tumor, which is significantly higher than that of free DOX. RGD- or RGDm-SSL-DOX demonstrated prolonged circulation time similar to that of SSL-DOX, whereas they showed significantly lower DOX level in blood and remarkably higher uptake by spleen than SSL-DOX.Conclusions Enhanced intracellular uptake of DOX encapsulated in SSL could produce an improved therapeutic effect for the melanoma B16 tumors. Enhancing intracellular delivery of the anticancer drugs encapsulated in SSL may be a promising strategy to improve their therapeutic efficacy for solid tumors.     

Diphenyl diselenide supplementation delays the development of <Emphasis Type="Italic">N</Emphasis>-nitroso-<Emphasis Type="Italic">N</Emphasis>-methylurea-induced mammary tumors

The effect of dietary diphenyl diselenide (1 ppm) on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis was examined in female Wistar rats. Beginning at 5 weeks of age, the animals were fed with either control or diphenyl-diselenide-supplied diets until the end of the study (210 days). At 50 days of age, mammary tumor was induced by the administration of three doses of NMU (50 mg/kg body wt, intraperitoneally) once a week for 3 weeks. In experimental trials, latency to tumor onset was extended in rats fed with diet supplemented with diphenyl diselenide (P < 0.05). The incidence and frequency of tumors were significantly small in animals supplemented with diphenyl diselenide. However, the multiplicity of tumors was not altered by dietary diphenyl diselenide. Diphenyl diselenide supplementation also restored superoxide dismutase (SOD) activity and vitamin C levels altered in the NMU group (P < 0.05). Our results suggest that diphenyl diselenide can be considered a chemopreventive agent, even when supplemented at a relatively low concentration.     

Two new antibacterial norabietane diterpenoids from cyanobacteria, <Emphasis Type="Italic">Microcoleous </Emphasis><Emphasis Type="Italic">lacustris</Emphasis>

Two abietane diterpenes were isolated from cyanobacteria Microcoleous lacustris, 20-nor-3α-acetoxyabieta-5,7,9,11,13-pentaene and 20-nor-3α-acetoxy-12-hydroxy-abieta-5,7,9,11,13-pentaene. These compounds were assayed against Staphylococcus aureus, Staphylococcus epidermidis, Salmonella typhi, Vibrio cholerae, Bacillus subtilis, Bacillus cereus, Escherichia coli, and Klebsiella pneumoniae. Both compounds showed activity against S. aureus, S. epidermidis, S. typhi, and V. cholerae, but not against the other bacteria.     

Norisoprenoids and hepatoprotective flavone glycosides from the aerial parts of<Emphasis Type="Italic">Beta vulgaris</Emphasis> var.<Emphasis Type="Italic">cicla</Emphasis>

(+)-Dehydrovomifoliol (1), 3-hydroxy-5alpha,6alpha-epoxy-beta-ionone (2), vitexin 7-O-beta-D-glucopyranoside (3), and vitexin 2'-O-beta-D-glucopyranoside (4) were isolated as new constituents from the aerial parts of Beta vulgaris var. cicla. Compounds 3 and 4 demonstrated hepatoprotective activity with values of 65.8 and 56.1%, respectively, in primary cultured rat hepatocytes with CCl4-induced cell toxicity, compared to controls. This was comparable to that of silibinin (69.8 %) which was used as a positive control.     

Synthesis and antitumor evaluation of some 1,3,4-oxadiazole-2(3<Emphasis Type="Italic">H</Emphasis>)-thione and 1,2,4-triazole-5(1<Emphasis Type="Italic">H</Emphasis>)-thione derivatives

A series of 1,3,4-oxadiazole-2-thione and 1,2,4-triazole-5-thione derivatives have been successfully synthesized and studied for their antitumor activity. These compounds were prepared from carboxylic acids and chiral aminoacid esters. The prepared compounds were evaluated for their cytotoxicity against cancer in vitro using hydroxyurea (HU) as positive control. A fair number of compounds were found to have significant antitumor activity. To study the molecular basis of interaction and affinity of binding of the target molecules, all the compounds were docked into the ATPase domain of TP-II and tubulin using Schrödinger.     

Extract from <Emphasis Type="Italic">Calotropis procera</Emphasis> latex activates murine macrophages

Calotropis procera latex has long been used in traditional medicines. Extracts from C. procera latex have been reported to have various pharmacological actions, including protection from myocardial infarction, hepatoprotective action, antitumor activity, antinociceptive, and pro- and anti-inflammatory actions. To evaluate the immunomodulatory functions of the water-soluble C. procera extract (CPE), we investigated its ability to activate macrophages—effector cells in inflammatory and immune responses. Intraperitoneal injection of CPE in mice (2 mg/mouse) induced migration of macrophages to the intraperitoneal cavity, confirming the proinflammatory effects of water-soluble CPE. The direct effects of CPE on macrophages were then assessed by measuring the production of nitric oxide (NO) as an indicator for macrophage activation. Addition of CPE (1–10 μg/ml) to the culture medium of the murine monocyte/macrophage cell line RAW264.7 caused an increase in NO production in a time- and dose-dependent manner. CPE-elicited NO production was blocked by application of an inhibitor of inducible nitric oxide synthase (iNOS). Expression of iNOS mRNA was induced by treatment of cultured macrophages with CPE. Injection of CPE in mice also resulted in an increase in plasma NO level. The results suggest that CPE activates macrophages and facilitates NO production via up-regulation of iNOS gene expression. A. l. S. Seddek and M. Elsayed Mahmoud contributed equally to this work.     

Anti-Inflammation activity of<Emphasis Type="Italic">Actinidia polygama</Emphasis>

The fruit of Actinidia polygama (AP) has long been used as a folk medicine in Korea for treating pain, rheumatic arthritis and inflammation. The present investigation was carried out to determine the in vivo and in vitro anti-inflammatory activity of AP using several animal models of inflammation. The 70% ethanol extract of the fruit of AP significantly inhibited acetic acid-induced, vascular permeability in a dose dependent manner (23%, 38%, and 41% inhibition at doses of 200 mg/kg, 500 mg/kg and 1000 mg/kg, respectively). This effect was maintained in AP water-soluble fraction (APW). The APW fraction also showed significant inhibitory activity against the rat paw edema induced by a single treatment of carrageenan. In vitro experiments were performed to demonstrate the inhibitory activities of APW (100 microg/ml) on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. The results showed that APW dose-dependently suppressed LPS-induced NO production in RAW 264.7 macrophages without a notable cytotoxic effect and also decreased inducible NO synthase (iNOS) protein expression. APW also showed a significant inhibitory effect in LPS-induced PGE2 production and cyclooxygenase-2 (COX-2) expression.     

A new steroidal saponin,yuccalan, from the leaves of<Emphasis Type="Italic">Yucca smalliana</Emphasis>

An extract of the leaves of Yucca smalliana Fern. (Agavaceae) showed potential antimicrobial activity. Employing a bioassay linked fractionation method, one of the active principles, namely yuccalan, was isolated as a new steroidal saponin. The structure of the new steroidal saponin was elucidated as 3-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(3beta, 5alpha, 6alpha, 25S)-spirostan-3,6,27-triol (1) using various spectroscopic techniques, including IR, MS, 1D and 2D 1H-NMR, and 13C-NMR. The purified yuccalan showed antifungal activities against both Rhizoctonia solani and Fusarium oxysporum.     

DNA interstrand cross-linking and <Emphasis Type="Italic">in vivo</Emphasis> antitumor activity of the extended pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzodiazepine dimer SG2057

The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. SG2000 is a propyldioxy linked PBD dimer which binds sequence selectively in the minor groove of DNA forming DNA interstrand and intrastrand cross-linked adducts, and also mono-adducts depending on sequence. SG2057 is the corresponding dimer containing a pentyldioxy linkage. SG2057 has multilog differential in vitro cytotoxicity against a panel of human tumour cell lines with a mean GI₅₀ of 212 pM. The agent is highly efficient at producing DNA interstrand cross-links in cells which form rapidly and persist over a 48 h period. Significant antitumor activity was demonstrated in several human tumor xenograft models. Cures were obtained in a LOX-IMVI melanoma model following a single administration and dose-dependent activity, including regression responses, observed in SKOV-3 ovarian and HL-60 promyelocytic leukemia models following repeat dose schedules. In the advanced stage LS174T model, SG2057 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. SG2057 is therefore a highly active antitumor agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development.