Showing papers in "Archives of Pharmacal Research in 2002"

Antimicrobial activity and chemical composition of some essential oils.

Abstract: In this study the composition and antimicrobial properties of essential oils obtained fromOriganum onites, Mentha piperita, Juniperus exalsa, Chrysanthemum indicum, Lavandula hybrida, Rosa damascena, Echinophora tenuifolia, Foeniculum vulgare were examined. To evaluate thein vitro antibacterial activities of these eight aromatic extracts; theirin vitro antimicrobial activities were determined by disk diffusion testing, according to the NCCLS criteria.Escherichia coli (ATTC 25922J,Staphylococcus aureus (ATCC 25923) andPseudomonas aeruginosa (ATTC 27853 were used as standard test bacterial strains.Origanum onites recorded antimicrobial activity against all test bacteria, and was strongest againstStaphylococcus aureus. ForRosa damascena, Mentha piperita andLavandula hybrida antimicrobial activity was recorded only toStaphylococcus aureus. Juniperus exalsa, and Chrysanthemum indicum exhibited antibacterial activities against bothStaphylococcus aureus andEscherichia coli. We also examined thein vitro antimicrobial activities of some components of the essential oils and found some components with antimicrobial activity.

Protein drug oral delivery: the recent progress.

Abstract: Rapid development in molecular biology and recent advancement in recombinant technology increase identification and commercialization of potential protein drugs. Traditional forms of administrations for the peptide and protein drugs often rely on their parenteral injection, since the bioavailability of these therapeutic agents is poor when administered nonparenterally. Tremendous efforts by numerous investigators in the world have been put to improve protein formulations and as a result, a few successful formulations have been developed including sustained-release human growth hormone. For a promising protein delivery technology, efficacy and safety are the first requirement to meet. However, these systems still require periodic injection and increase the incidence of patient compliance. The development of an oral dosage form that improves the absorption of peptide and especially protein drugs is the most desirable formulation but one of the greatest challenges in the pharmaceutical field. The major barriers to developing oral formulations for peptides and proteins are metabolic enzymes and impermeable mucosal tissues in the intestine. Furthermore, chemical and conformational instability of protein drugs is not a small issue in protein pharmaceuticals. Conventional pharmaceutical approaches to address these barriers, which have been successful with traditional organic drug molecules, have not been effective for peptide and protein formulations. It is likely that effective oral formulations for peptides and proteins will remain highly compound specific. A number of innovative oral drug delivery approaches have been recently developed, including the drug entrapment within small vesicles or their passage through the intestinal paracellular pathway. This review provides a summary of the novel approaches currently in progress in the protein oral delivery followed by factors affecting protein oral absorption.

Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways.

Abstract: The action mechanisms of several chemopreventive agents derived from herbal medicine and edible plants have become attractive issues in cancer research. Tea is the most widely consumed beverage worldwide. Recently, the cancer chemopreventive actions of tea have been intensively investigated. It have been demonstrated that the active principles of tea were attributed to their tea polyphenols. Recently, tremendous progress has been made in elucidating the molecular mechanisms of cancer chemoprevention by tea and tea polyphenols. The suppression of various tumor biomarkers including growth factor receptor tyrosine kinases, cytokine receptor kinases, PI3K, phosphatases, ras, raf, MAPK cascades, N x FB, I x B kinase, PKA, PKB, PKC, c-jun, c-fos, c-myc, cdks, cyclins, and related transducing proteins by tea polyphenols has been studied in our laboratory and others. The I x B kinase (IKK) activity in LPS-activated murine macrophages (RAW 264.7 cells) was found to be inhibited by various tea polyphenols including (-) epigallocatechin-3-gallate (EGCG), theaflavin (TF-1), theaflavin-3-gallate (TF-2) and theaflavin-3,3'-digallate (TF-3). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other tea polyphenols. TF-3 inhibited both IKK1 and IKK2 activity and prevented the degradation of I x B x and I x B x in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 and other tea polyphenols could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. TF-3 and other tea polyphenols blocked phosphorylation of IB from the cytosolic fraction, inhibited NFB activity and inhibited increases in inducible nitric oxide synthase levels in activated macrophage. TF-3 and other tea polyphenols also inhibited strongly the activities of xanthine oxidase, cyclooxygenase, EGF-receptor tyrosine kinase and protein kinase C. These results suggest that TF-3 and other tea polyphenols may exert their cancer chemoprevention through suppressing tumor promotion and inflammation by blocking signal transduction. The mechanisms of this inhibition may be due to the blockade of the mitogenic and differentiating signals through modulating EGFR function, MAPK cascades, NFkappaB activation as well as c-myc, c-jun and c-fos expression.

Cytotoxic and antimutagenic stilbenes from seeds of Paeonia lactiflora.

Abstract: Cytotoxic and antimutagenic effects of a novelcis-e-viniferin and five known stilbenes,trans-resveratrol,frans-e-viniferin, gnetin H, suffruticosols A and B, isolated from the seeds ofPaeonia lactiflora Pall. (Paeoniaceae) were determined against five different cancer cell lines, and mutagenicity ofN-methyl-N'-nitro-N-nitrosoguanidine (MNNG) inSalmonella typhimurium TA100, respectively. Six stilbenes showed cytotoxic activity in a dose-dependent manner, and especially did potent cytotoxic activity against C6 (mouse glioma) cancer cell with IC50 values ranging from 8.2 to 20.5 ug/ml.trans-Resveratrol showed significant cytotoxic activity against HepG2 (liver hepatoma) and HT-29 (colon) human cancer cell lines with IC50 values of 11.8 and 25.2 g/ml, respectively. In contrast,trans-e-viniferin andcis--viniferin, and gnetin H exhibited marked cytotoxic activity against Hela (cervicse) and MCF-7 (breast) human cancer cell lines with IC50 values of 20.4, 21.5, and 12.9 μg/ml, respectively. However, suffruticosol A and B had less cytotoxic effect against all cancer cells except C6. Meanwhile, six stilbenes exerted antimutagenic activity in a dose-dependent fashion. Of them,trans-resveratrol exhibited the strongest antimutagenic effect against MNNG with IC50 value of 27.0 μg/plate, while other five resveratrol oligomers also did moderate antimutagenic activity with IC50 values ranging from 31.7 to 35.2 μg/plate.

Three new dammarane glycosides from heat processed ginseng.

Abstract: Three new dammarane glycosides were isolated from the processed ginseng (SG; Sun Ginseng). Their structure were determined to be 3β,12β-dihydroxydammar-20(21),24-diene-3-O-β-D-glucopyranosyl(1 → 2)-β-D-glucopyranoside; 3β,12β-dihydroxydammar-20(21),24-diene-3-O-β-D- glucopyranoside and 3β,6α,12β-trihydroxydammar-20(21),24-diene-6-O-β-D-glucopyr-anoside based on spectroscopic evidences. The compounds were named as ginsenoside Rk1 Rk2, and Rk3 respectively.

Airway mucus: its components and function

Abstract: The airway surface liquid (ASL), often referred to as mucus, is a thin layer of fluid covering the luminal surface of the airway. The major function of mucus is to protect the lung through mucociliary clearance against foreign particles and chemicals entering the lung. The mucus is comprised of water, ions, and various kinds of macromolecules some of which possess the protective functions such as anti-microbial, anti-protease, and anti-oxidant activity. Mucus glycoproteins or mucins are mainly responsible for the viscoelastic property of mucus, which is crucial for the effective mucociliary clearance. There are at least eight mucin genes identified in the human airways, which will potentially generate various kinds of mucin molecules. At present, neither the exact structures of mucin proteins nor their regulation are understood although it seems likely that different types of mucins are involved in different functions and might also be associated with certain airway diseases. The fact that mucins are tightly associated with various macromolecules present in ASL seems to suggest that the defensive role of ASL is determined not only by these individual components but rather by a combination of these components. Collectively, mucins in ASL may be compared to aircraft carriers carrying various types of weapons in defense of airbome enemies.

Korean mistletoe lectin-induced apoptosis in hepatocarcinoma cells is associated with inhibition of telomerase via mitochondrial controlled pathway independent of p53.

Abstract: The extract of European mistletoe(Viscum album, L) has been used in adjuvant chemotherapy of cancer and mistletoe lectins are considered to be major active components. The present work was performed to investigate the effects of Korean mistletoe lectin(Viscum album L.coloratum agglutinin, VCA) on proliferation and apoptosis of human hepatoma cells as well as the underlying mechamisms for these effects. We showed that VCA induced apoptosis in both SK-Hep-1 (p53-positive) and Hep 3B (p53-negative) cells through p53- and p21-independent pathways. VCA induced apoptosis by down-regulation of Bcl-2 and by up-regulation of Bax functioning upstream of caspase-3 in both cell lines. In addition, we observed down-regulation of telomerase activity in both VCA-treated cells. Our results provide direct evidence of the anti-tumor potential of this biological response which comes from inhibition of telomerase and consequent inducing apoptosis. VCA-induced apoptosis is regulated by mitochondrial controlled pathway independently of p53. These findings are important for the therapy with preparation of mistletoe because they show that telomerase-dependent mechanism can be targeted by VCA in human hepatocarcinoma. Taken together, our results suggest that the VCA, considered as a telomerase-inhibitor, can be envisaged as a candidate for enhancing sensitivity of conventional anticancer drugs.

Antioxidative flavonoids from leaves of Carthamus tinctorius.

Abstract: A total of eight flavonoids (1-8), including a novel quercetin-7-O-(6″-O-acetyl)-β-D-glucopyranoside (6) and seven known flavonoids, luteolin (1), quercetin (2), luteolin 7-O-β-D-glucopyranoside (3), luteolin-7-0-(6″-O-acetyl)-β-D-glucopyranoside (4) quercetin 7-O-β-D-glucopyranoside (5), acacetin 7-O-β-D-glucuronide (7) and apigenin-6-C-β-D-glucopyrano syl-8-C-β-D-glucopyranoside (8), have been isolated from the leaves of the safflower (Carthamus tinctorius L.) and identified on the basis of spectroscopic and chemical studies. The antioxidative activity of these flavonoids was evaluated against 2-deoxyribose degradation and rat liver microsomal lipid peroxidation induced by hydroxyl radicals generated via a Fenton-type reaction. Among these flavonoids, luteolin-acetyl-glucoside (4) and quercetin-acetyl-glucoside (6) showed potent antioxidative activities against 2-deoxyribose degradation and lipid peroxidation in rat liver microsomes. Luteolin (1), quercetin (2), and their corresponding glycosides (3 &5) also exhibited strong antioxidative activity, while acacetin glucuronide (7) and apigenin-6,8-di-C-glucoside (8) were relatively less active.

Anti-platelet effect of the constituents isolated from the barks and fruits of Magnolia obovata.

Abstract: In the course of our work on anti-platelet constituents from plants, five phenolic compounds, mag-nolol, honokiol, obovatol, methyl caffeate, and syringin, were isolated from the methanol extracts of the barks and fruits ofMagnolia obovata. The compounds were identified based on the spectro-scopic data. Methyl caffeate was isolated for the first time from the genusMagnolia and it showed 3 – 4-folds higher potency than ASA. The activities of obovatol and honokiol were comparable to ASA. Magnolol and syringin showed only very mild inhibitory effects to all the stimulators.

Effects of sophoraflavanone G, a prenylated flavonoid from Sophora flavescens, on cyclooxygenase-2 and in vivo inflammatory response.

Abstract: Previously, several prenylated flavonoids having a C-8 lavandulyl moiety were found to inhibit cyclooxygenase-1 (COX-1) as well as 5-lipoxygenase (5-LOX), and sophoraflavanone G was the most potent inhibitor against these eicosanoid generating enzymes among 19 prenylated flavonoids tested. In this investigation, effects of sophoraflavanone G on COX-2 induction from RAW 264.7 cells and in vivo inflammatory response were studied. Sophoraflavanone G inhibited prostaglandin E2 (PGE2) production from lipopolysaccharide (LPS)-treated RAW cells by COX-2 down-regulation at 1-50 uM. Other prenylated flavonoids including kuraridin and sanggenon D also down-regulated COX-2 induction at 10-25 uM, while kurarinone and echinoisoflavanone did not. In addition, sophoraflavanone G showed in vivo anti-inflammatory activity against mouse croton oil-induced ear edema and rat carrageenan paw edema via oral (2-250 mg/kg) or topical administration (10-250 microg/ear). Although the potencies of inhibition were far less than that of a reference drug, prednisolone, this compound showed higher anti-inflammatory activity when applied topically, suggesting a potential use for several eicosanoid-related skin inflammation such as atopic dermatitis.

Cytotoxic ergosterols from Paecilomyces sp. J300

Abstract: Seven ergosterol derivatives (1~7) were isolated from silkworm larvae infected withPaecilomyces sp. J300. On the basis of spectroscopic means, their structures have been elucidated as3β,5α-dihydroxy-ergosta-7,22-diene (1),5α,6α-epoxy-(22E,24R)-ergosta-8(14), 22-diene-3β,7α-diol (2),5α,6α-epoxy-(22E,24R)-ergosta-8,22-diene-3β,7β-diol (3),ergosta-4,6,8(14),22-tetraene-3-one (4),ergosterol (5),ergosterol endoperoxide (6),3β,5α-dihydroxy-6β-methoxyer-gosta-7,22-diene (7). Compounds3~7 showed moderate cytotoxicity against five tumor cells.

Highly sweet compounds of plant origin.

Abstract: The demand for new alternative “low calorie” sweeteners for dietetic and diabetic purposes has increased worldwide. Although the currently developed and commercially used highly sweet sucrose substitutes are mostly synthetic compounds, the search for such compounds from natural sources is continuing. As of mid-2002, over 100 plant-derived sweet compounds of 20 major structural types had been reported, and were isolated from more than 25 different families of green plants. Several of these highly sweet natural products are marketed as sweeteners or flavoring agents in some countries as pure compounds, compound mixtures, or refined extracts. These highly sweet natural substances are reviewed herein.

The radical scavenging effects of stilbene glucosides from Polygonum multiflorum.

Abstract: The extract of the root ofPolygonum multiflorum exhibited a significant antioxidant activity assessed by the DPPH radical scavenging activityin vitro. The bioassay-guided fractionation of the extract yielded a stilbene glucoside, (E)-2,3,5,4′-tetrahydroxystilbene-2-0-²-d-glucopyra-noside (1) as an active constituent responsible for the antioxidant property. Compound1 demonstrated a moderate DPPH radical scavenging activity (IC50, 40 μM), while the corresponding deglucosylated stilbene 2 exhibited a much higher activity (IC50, 0.38 μM).

In vitro antioxidant activity of some selected Prunus species in Korea.

Abstract: In the course of the investigations of natural antioxidants, we examined the antioxidant activities of the methanol (MeOH) extracts of some selectedPrunus species, includingP. buergeriana, P. davidiana, P. padus, P. pendula for.ascendens, P. sargentii, P. serrulata var. spontanea andP. yedoensis by three methods as represented by the 1,1-diphenyl-2-picrylhy-drazyl (DPPH) radical, total ROS (reactive oxygen species) and the peroxynitrite (ONOO-) scavenging activity tests. We also evaluated the activities of the organic solvent-soluble fractions, including the dichloromethane (CH2CI2), ethyl acetate (EtOAc),n-butanol (n-BuOH) fractions and the water (H2O) layer ofP. serrulata var.spontanea leaves. By means of bioassay-directed fractionation, we isolated eleven known flavonoids (1–11) from the EtOAc soluble fraction of the MeOH extract of thePrunus serrulata var.spontanea leaves, exhibiting strong antioxidant activity and characterized as prunetin (1), genistein (2), quercetin (3), prunetin 4′-O-β-glucopyranoside (4), kaempferol 3-O-β-arabinofuranoside (5), prunetin 5-O-β-glucopyranoside (6), kaempferol 3-O-β-xylopyranoside (7), genistin (8), kaempferol 3-O-β-glucopyranoside (9), quercetin 3-O-β-glucopyranoside (10) and kaempferol 3-O-β-xylopyranosyl-(1→2)-β-glucopyr-anoside (11). Compounds3 and10 showed good activities in all tested model systems. Compounds2 and8 showed scavenging activities in the DPPH and ONOCr tests, while compounds5,7,9 and11 were active in the ONOO- and ROS tests. On the other hand, compounds1,4 and6 did not show any activities in the tested model systems.

Evaluation of the immune response following exposure of mice to bisphenol A: induction of Th1 cytokine and prolactin by BPA exposure in the mouse spleen cells.

Abstract: Bisphenol A [2, 2 bis (4-hydoxyphenyl) propane; BPA] is a widely used endocrine disruptors and has estrogenic activities. Although interests on biological effect of BPA are rising, evidences of its effect on immune system are lacking. We investigated that the effect of BPA on immune parameters to postulate the mechanism, and BPA interruptions between neuroendocrine and immune system. BPA was administrated to mice by p.o. (as a drinking water) dose on 0.015, 1.5 and 30 mg/ml for 4 weeks. The BPA treatment did not result in any change in body weight, spleen weight and distribution of lymphocyte subpopulation collected from spleen. BPA induced prolactin production in spleen, and exposure of BPA increased the activity of splenocyte proliferation in response to Con A (p<0.001). The production of a strong Th-1 type cytokine (IFN-gamma) was induced while Th-2 type (IL-4) was suppressed by BPA treatment. These were consistent with RT-PCR results of transcription factor GATA-3 and IRF-1. These findings suggested that stimulation of prolactin production by estrogenic effects of BPA would affect cytokine profiles, and lead to imbalanced cellular immune response. In addition, we could speculate that prolactin and cytokine is important mediator involved in network between neuroendocrine and immune system by BPA.

Tissue factor inhibitory flavonoids from the fruits of Chaenomeles sinensis.

Abstract: Tissue factor (TF, tissue thromboplastin or coagulation factor III) accelerates the blood clotting, activating both the intrinsic and the extrinsic pathways to serve as a cofactor. In order to isolate TF inhibitors from the fruits ofChaenomeles sinensis, an activity-guided purification utilizing a bio-assay method of prothrombin time prolongation, was carried out to yield five active flavoniods such as hovetrichoside C (1) (IC50 = 14.0 μg), luteolin-7-O-β-D-glucuronide (3) (IC50 = 31.9 μg), hyperin (4) (IC50 = 20.8 μg), avicularin (6) (IC50 = 54.8 μg) and quercitrin (10) (IC50 = 135.7 μg), along with other inactive compounds such as (±)-(2E,4E)-O-α-D-glucopyranosyl-4′-hydroxy-β-ionylideneacetic acid ester (2), genistein-7-O-β-D-glucopyranoside (5), luteolin-3′-methoxy-4′-O-β-D-glucopyranoside (7), luteolin-7-O-β-D-glucuronide methyl ester (8), tricetin-3′-methoxy-4′-O-p-D-glucopyranoside (selagin-4′-O-β-D-glucopyranoside) (9), (-)-epicatechin (11), luteolin-4′-O-β-D-glucopyranoside (12) and apigenin-7-O-β-D-glucuronide methyl ester (13). The structures of the isolated compounds were elucidated through spectral analysis. Among them, compounds1 to9,12 and13 were isolated for the first time from the fruits of this plant and the compound9 is a new flavonoid.

Antimicrobial constituents of Foeniculum vulgare.

Abstract: A phenyl propanoid derivative, dillapional(1) was found to be a antimicrobial principle of the stems ofFoeniculum vulgare (Umbelliferae) with MIC values of 125, 250 and 125/ againstBacillus subtilis, Aspergillus niger andCladosporium cladosporioides, respectively A cou-marin derivative, scopoletin(2) was also isolated as marginally antimicrobial agent along with inactive compounds, dillapiol(3), bergapten(4), imperatorin(5) and psolaren(6) from this plant The isolates 1-6 were not active against the Escherichia coli

Fecal metabolic activities of herbal components to bioactive compounds.

Abstract: The herbal components should be transformed to bioactive compounds by the intestinal bacteria and then expressed the pharmacological action of herbal medicines. Human fecal enzyme activities related to the metabolism of herbal components were measured. The metabolic activities of puerarin, poncirin, glycyrrhizin, ginsenoside Rb1 and ginsenoside Rb2 to their bioactive compounds were 3.5 +/- 1.18, 333.1 +/-183.64, 95.7 +/- 107.1, 28.6 +/- 10.32 and 20.8 +/- 13.3 micromol/ h/g, respectively. The profile of these metabolic activities of glycyrrhizin and ginsenosides were not changed even if herbal extracts, water extract of Glycyrrhizae Radix and Ginseng Radix, instead of the isolated compounds were used. All the enzyme activities tested were not different between male and female, and between ages. However, the difference of these enzyme activities in individuals was significant. These results suggest that the metabolic activity of herbal components to bioactive compounds may be a factor of constitutional classification, and could be available for constitutional classifications, if the constitutional herbal medicines were used.

Recent progress in drug delivery systems for anticancer agents

Abstract: Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes, peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved dosage forms of currently marketed anticancer drugs can also enhance their therapeutic values. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems have been able to provide enhanced therapeutic activity and reduced toxicity of anticancer agents mainly by altering their pharmacokinetics and biodistribution. Furthermore, the identification of cell-specific receptor/antigens on cancer cells have brought the development of ligand- or antibody-bearing delivery systems which can be targeted to cancer cells by specific binding to receptors or antigens. They have exhibited specific and selective delivery of anticancer agents to cancer. As a consequence of extensive research, clinical development of anticancer agents utilizing various delivery systems is undergoing worldwide. New technologies and multidisciplinary expertise to develop advanced drug delivery systems, applicable to a wide range of anticancer agents, may eventually lead to an effective cancer therapy in the future.

Isoflavonoids from the rhizomes of Belamcanda chinensis and their effects on aldose reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues.

Abstract: Aldose reductase, the key enzyme of the polyol pathway, is known to play important roles in the diabetic complication. The inhibitors of aldose reductase, therefore, would be potential agents for the prevention of diabetic complications. To evaluate active principles for the inhibition of aldose reductase from the rhizomes ofBelamcanda chinensis, twelve phenolic compounds were isolated and tested for their effects on rat lens aldose reductase. As a result, isoflavones such as tectorigenin, irigenin and their glucosides were found to show a strong aldose reductase inhibition. Tectoridin and tectorigenin, exhibited the highest aldose reductase inhibitory potency, their IC50 values, being 1.08x 10-6 M and 1.12 x 10-6 M, respectively, for DL-glyceraldehyde as a substrate. Both compounds, when administered orally at 100 mg/kg for 10 consecutive days to streptozotocin-induced diabetic rats, caused a significant inhibition of sorbitol accumulation in the tissues such as lens, sciatic nerves and red blood cells. Tectorigenin showed a stronger inhibitory activity than tectoridin. From these results, it is suggested that tectorigenin is attributed to be a promising compound for the prevention and/or treatment of diabetic complications.

Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159.

Abstract: DA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of DA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the IC50 was 5.84 +/- 1.70 nM and 8.25 +/- 2.90 nM, respectively. The IC50 of DA-8159 on PDE 1, PDE 2, PDE 3 and PDE 6 were 870+/- 57.4 nM, 101 +/- 15 microM, 52.0 +/- 3.53 microM and 53.3 +/- 2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5-100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent Km value for cGMP hydrolysis but had no effect on the apparent Vmax, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly stimulated the accumulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth muscle by NO-stimulated cGMP accumulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth muscle by the NO-stimulated cGMP accumulation.

Phytochemical Constituens of Cirsium setidens Nakai and Their Cytotoxicity against Human Cancer Cell Lines

Abstract: Five terpenes (1~5), three fatty acids (6~8), two sterols (9 and 11), and a monogalactosyldiacyl glycerol (10) were isolated from the methylene chloride extract of the aerial part ofCirsium setidens. Their chemical structures were determined to be α-tocopherol (1), 25-hydroper-oxycycloart-23-en-3p-ol (2), 24-hydroperoxycycloart-25-en-3(3-ol (3), mokko lactone (4), transphytol (5), 9, 12, 15-octadecatrienoic acid (6), 9, 12-octadecadienoic acid (7), hexadecanoic acid (8), acylglycosyl β-sitosterol (9), (2R)-1, 2-0-(9z, 12z, 15z-dioctadecatrienoyl)-3-0-β-D-galactopyranosyl glycerol (10) and p-sitosterol glucoside (11) by spectral evidences. Compound3 exhibited significant cytotoxic activity against five human cancer cell lines with its ED50 values ranging from 2.66 to 11.25 μ.M.

Constituents of the fruits and leaves of Euodia daniellii.

Abstract: Four flavonoid glycosides, flavaprin (7), evodioside B (8), vitexin (11), and hesperidin (12), as well as the coumarins bergapten (1), xanthotoxin (2), and isopimpinellin (3), the lignan simplex-oside (10), the steroids β-sitosterol (4) and daucosterol (5), the limonoids isolimonexic acid (6) and limonin (9), and uracil (13) andmyo-inositol (14) have been isolated fromEuodia daniellii. The structures of these compounds were established from spectral data. Among the isolates, bergapten showed cyclooxygenase-2 inhibitory activity with an IC50 value of 6.2 μg/ml. Fla-vonoids isolated from this plant exhibited no cytotoxic activity against the human tumor cell lines, A549, SKOV-3, SKMEL-2, XF498, and HCT15.

Biological significance of essential fatty acids/prostanoids/lipoxygenase-derived monohydroxy fatty acids in the skin.

Abstract: The skin displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA), an 18-carbon (n-6) PUFA, results in characteristic scaly skin disorder and excessive epidermal water loss. Although arachidonic acid (AA), a 20-carbon (n-6) PUFA, is metabolized via cyclooxygenase pathway into predominantly prostaglandin E2 (PGE2) and PGF2α, the metabolism of AA via the 15-lipoxygenase (15-LOX) pathway, which is very active in skin epidermis and catalyzes the transformation of AA into predominantly 15S-hydroxyeicosatetraenoic acid (15S-HETE). Additionally, the 15-LOX also metabolizes the 18-carbon LA into 13S-hydroxyoctadecadienoic acid (13S-HODE), respectively. Interestingly, 15-LOX catalyzes the transformation of dihomo-γ-linolenic acid (DGLA), derived from dietary gamma-linolenic acid, to 15S-hydroxyeicosatrienoic acid (15S-HETrE). These monohydroxy fatty acids are incorporated into the membrane inositol phospholipids which undergo hydro-lytic cleavage to yield substituted-diacylglycerols such as 13S-HODE-DAG from 13S-HODE and 15S-HETrE-DAG from 15S-HETrE. These substituted-monohydroxy fatty acids seemingly exert anti-inflammatory/antiproliferative effects via the modulation of selective protein kinase C as well as on the upstream/down-stream nuclear MAP-kinase/AP-1/apoptotic signaling events.

Antithrombotic and antiallergic activities of rhaponticin from Rhei Rhizoma are activated by human intestinal bacteria.

Abstract: To evaluate the antithrombotic and antiallergic properties of rhaponticin extracted from Rhei Rhizoma, the in vitro and ex vivo inhibitory activities of rhaponticin and its metabolite, rhapontigenin, were measured. These compounds inhibited in vitro ADP- and collagen-induced platelet aggregation. Rhapontigenin was more potent, with IC50 values of 4 and 70 microg/ml, respectively. In ex vivo ADP- and collagen-induced rat platelet aggregation, these compounds also exhibited a potent inhibitory effect. The antiplatelet aggregation effects of rhaponticin and rhapontigenin were more potent than those of aspirin. Rhapontigenin showed significant protection from death due to pulmonary thrombosis in mice. Rhapontigenin also showed the strongest inhibitory activity against beta-hexosaminidase release induced by DNP-BSA. These compounds inhibited PCA reaction in mice. Rhapontigenin intraperitoneally administered showed the strongest inhibitory activity and significantly inhibited PCA at doses of 25 and 50 mg/kg, with inhibitory activities of 48 and 85%, respectively. The inhibitory activity of orally administered rhaponticin was stronger than that of intraperitoneally administered rhaponticin. These results suggest that rhaponticin, in the rhizome of Rhei Rhizoma, is a prodrug that has extensive antiallergic and antithrombotic properties.

A new phenolic amide from Lycium chinense Miller

Abstract: A new phenolic amide, dihydro-N-caffeoyltyramine (1) was isolated from the root bark ofLycium chinense Miller, along with known compounds,trans-N-caffeoyltyramine (2),cis-N-caffeoyltyramine (3), and lyoniresinol 3α-O-β-D-glucopyranoside (4). Their structures were determined by spectroscopic analysis. A NBT superoxide scavenging assay revealed that three phenolic amides showed potent antioxidative activity.

Synthesis, antimicrobial and molluscicidal activities of new benzimidazole derivatives

Abstract: A series of benzimidazole Schiff’s bases, thiosemicarbazides were synthesized, azole ring systems as 1,3,4-triazole, 1,3,4-oxadiazole were prepared. 1-Methylbenzimidazole incorporated to substituted dithio-carbamate, thiophenol, diethylamine via acetamido group were synthesized. A series of pyrimidinobenzimidazoles, triazinobenz-imidazoles, and 2-(acetonylamino)-1-methylbenzimidazole were prepared. The antimicrobial and molluscicidal activities of some newly prepared compounds were carried out.

Anti-rheumatoid arthritis effect of the Kochia scoparia fruits and activity comparison of momordin lc, its prosapogenin and sapogenin.

Abstract: MeOH extract of Kochia scoparia was fractionated into CHCl3-, EtOAc- and BuOH extracts and the last fraction were hydrolyzed by 3%-NaOH (MeOH-H2O) to compare the bioactivities on antinociceptive and anti-inflammatory effects. Silica gel column chromatography of BuOH fraction afforded a large amount of 3-O-beta-D-xylopyranosyl (1-->3)-beta-D-glucuronopyranosyl oleanolic acid (momordin lc, 4) and that of acid hydrolysate of BuOH fraction gave 3-O-beta-D-glucuronopyranosyl oleanolic acid (momordin lb, 3), its 6'-O-methyl ester (2) and oleanolic acid (1). Silica gel column chromatography of alkaline hydrolysate afforded a large amount of 4. MeOH extract and both EtOAc- and BuOH fractions were active in the rheumatoidal rat induced Freund's complete adjuvant reagent (FCA) whereas CHCl3 fraction was inactive. Compound 1 and 4 showed significant activities in the same assay but oleanolic acid 3-O-glucuronopyranoside (3) showed no activity. These fashions were also observed in carrageenan-induced edema of the rat and in the antinociceptive activity tests undertaken in hot plate- and writhing methods. These results suggest that momordin lc and its aglycone, oleanolic acid, could be active principles for rheumatoid arthritis.

The effect of linarin on LPS-induced cytokine production and nitric oxide inhibition in murine macrophages cell line RAW264.7.

Abstract: The herb,Chrysanthemum zawadskii var,latilobum commomly known as Gu-Jul-Cho in Korea, used in traditional medicine to treat pneumonia, bronchitis, cough, common cold, pharyngitis, bladder-related disorders, gastroenteric disorders, and hypertension. Linarin is the main active compound and the biological mechanisms of its activity are unclear. It is believed that effects of this herb may be exerted through the pluripotent effectors of linarin due to its ability to treat a variety of afflictions. In this study, the effects of linarin on the mouse macrophages cell line, RAW 264.7, were investigated. It was found that linarin could activate macrophages by producing cytokines. Monocytes and tissue macrophages produce at least two groups of protein mediators of inflammation, interleukin 1 (IL-1) and the tumor necrosis factor (TNF). Recent studies have shown that TNF and IL-1 modulate the inflammatory function of endothelial cells, leukocytes, and fibroblasts. TNF-α production by macrophages treated with linarin occured in a dose dependent manner. However, IL-1 production was largely unaffected by this natural product. This study demonstrated the ability of linarin to activate macrophages both directly and indirectly. Linarin also affect both cytokine production and nitric oxide inhibition, in addition to the expression of some surface molecules. Nitric oxide (NO), derived from L-argin-ine, is produced by two forms(constitutive and inducible) of nitric oxide synthase (NOS). The NO produced in large amounts by inducible NOS is known to be responsible for the vasodilation and hypotension observed in septic shock. Linarin was found to inhibit NO production in the LPS-activated RAW 264.7 cells. Linarin may be a useful candidate as a new drug for treating endotoxemia and the inflammation accompanied by NO overproduction. The linarin-treated total lymphocytes exhibited cytotoxicity in a dose dependent manner between 20 ng/ml and 40 (ug/ml. These results suggest that linarin may function through macrophage activation.

Epidermis proliferative effect of the Panax ginseng ginsenoside Rb2

Abstract: Ginseng has been used as a traditional medicine with various therapeutic effects. However, it is still unknown which component of this plant is effective at promoting wound healing. Recently, ginsenoside Rb2 has been reported to improve wound healing. In this study, to investigate the reported wound healing effect of the ginsenoside Rb2, cell morphology and protein factors involved in epidermal formation were evaluated by immunochemical and immunoblotting analysis. Rb2 stimulated epidermal cell proliferation, and the cell showed a 1.5-fold increase in thymidine uptake compared to the control (p<0.05,n=3). Furtheremore, Rb2 was found to stimulate epidermis formation in a dose-dependent manner in raft culture, and to dose dependently enhance the expressions of protein factors related to cell proliferation, namely, epidermal growth factor and its receptor, fibronectin and its receptor, keratin 5/14, and collagenase I (p<0.05,n=3~9). It is believed that ginsenoside Rb2 enhances epidermal cell proliferation by upregulating the expressions of these proliferation-related factors.