Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
29 巻 , 10 号
選択された号の論文の32件中1~32を表示しています
Review
  • Tomohiro Yano, Eriko Fujimoto, Hiromi Hagiwara, Hiromi Sato, Hiroshi Y ...
    2006 年 29 巻 10 号 p. 1991-1994
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Cellular homeostasis in many organs is maintained via gap junctions composed of connexin (Cx), a large protein family with a number of isoforms. In fact, gap junctional intercellular communication (GJIC) is actively involved in all aspects of the cellular life cycle, ranging from cell growth to cell death. It has been well known that Cx gene acts as a tumor suppressor gene due to the maintenance of cellular homeostasis via GJIC. On the other hand, recent data show that GJIC-independent function for Cx gene contributes to tumor-suppressive effect of the gene with cell certain specificity. However, the mechanistic aspect of the GJIC-independent function remains largely unknown. In this review, we briefly summarize the tumor-suppressive effects of Cx genes, refer to a new aspect of Cx32 as an anti-invasive and anti-metastatic gene against renal cell carcinoma in a GJIC-independent function and establishment of a new cancer therapy based on the new function of Cx32.
Analytical Biochemistry
Notes
  • Yasuko Mutou, Yuko Ibuki, Yoshiyasu Terao, Shuji Kojima, Rensuke Goto
    2006 年 29 巻 10 号 p. 2116-2119
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Bisphenol A (BPA) and chlorinated bisphenol A (ClBPAs) were detected in wastewater from waste paper recycling plants. In previous study, we showed the acute cytotoxicity of oxidized products of BPA and ClBPAs generated by ultraviolet (UV) irradiation. However, estrogenic activities of these photoproducts have not been studied. Therefore, we investigated change of estrogenic activities of BPA and ClBPAs [3-chlorobisphenol A (3-ClBPA), 3,3′-dichlorobisphenol A (3,3′-diClBPA) and 3,3′,5-trichlorobisphenol A (3,3′,5-triClBPA)] after UVB irradiation using yeast two-hybrid assay. The agonist activities of ClBPAs were higher than that of BPA in the absence of S9. ClBPAs irradiated with UVB lost agonist activities. The addition of S9 also completely erased the activity. The antagonist activities of BPA and ClBPAs with or without UVB irradiation were not detected both in the absence or presence of S9. UVB irradiation (0—100 J/cm2) decreased the agonist activity of 3,3′-diClBPA in proportion to increase of released chloride ion. The agonist activity was completely lost at 50 J/cm2 of UVB, of which dose could dissociated almost all chlorine. These findings suggested that UVB irradiation could decrease the estrogenic activity of chlorinated compounds, which was due to the selective release of chloride ion.
Biochemistry
Regular Articles
  • Juntipa Purintrapiban, Maitree Suttajit, Neil E. Forsberg
    2006 年 29 巻 10 号 p. 1995-1998
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Effects of extracts of a plant, which has been used as a traditional medicine for treating diabetes on glucose transport activity was evaluated in cultured L8 muscle cells. The aqueous extract of Canna indica root (CI) at doses of 0.1—0.5 mg/ml, which contains total phenolic compounds equivalent to 6—30 μg of catechin caused a dose- and time-dependent induction of 2-deoxy-[3H]glucose (2-DG) uptake activity. The induced 2-DG uptake was significantly increased within 8 h and reached a maximum by 16 h. The CI extract increased the amount of glucose transporter isoforms 1 (GLUT1) and 4 (GLUT4) at the cell surface and enhanced expression of GLUT1 protein. Cycloheximide treatment almost completely reversed CI-induced 2-DG uptake to the basal level. Exposure of muscle cells to wortmannin and SB203580 diminished CI-mediated glucose uptake by 38 and 14%, respectively. The effect of CI and insulin was partially additive. Phytochemical analysis detected the presence of flavonoids and catechol in the CI. Taken together, these data provide evidence for differential effects of CI on regulated-glucose transport in muscle cells. Our findings suggest that GLUT1 protein synthesis and the activation of phosphatidylinositol 3-kinase (PI3K) are critical for the increase in glucose transporter activity at the plasma membrane and essential for the maximal induction of glucose transport by CI in L8 muscle cells.
Molecular and Cell Biology
Regular Articles
  • Yohko Yamazaki, Yuki Hasebe, Kiyoshi Egawa, Kiyoshi Nose, Setsuko Kuni ...
    2006 年 29 巻 10 号 p. 1999-2003
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. To identify small molecule inhibitors of the HIF-1 transcriptional activation, we have established a high through-put assay system using a stable transformant of mammalian cells that express the luciferase reporter gene construct containing a HIF-1 binding site. Using this system, we screened 5000 cultured broths of microorganisms, and we found that cinerubin (1-hydroxy aclacinomycin B) showed a significant inhibition of the reporter activity induced by hypoxic conditions. In addition, we demonstrated that aclarubicin also inhibited the HIF-1 transcriptional activity under hypoxic conditions, but neither doxorubicin nor daunorubicin inhibited it. Consistent with these results, cinerubin and aclarubicin inhibited the hypoxic induction of the vascular endothelial growth factor (VEGF) protein in HepG2 cells, but neither doxorubicin nor daunorubicin affected it. Thus, our results suggested that some anthracyclines are also acting as angiogenesis inhibitors.
  • Dengfeng Gao, Xiaolin Niu, Ning Ning, Guanghua Hao
    2006 年 29 巻 10 号 p. 2004-2008
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Angiotensin (Ang) II plays a critical role in cardiovascular remodeling. Krüppel-like factor (KLF) 5 is a novel indicated mediator in Ang II-induced cardiovascular damage. However, the potential link between KLF5 and Ang II has not been well investigated. In this study, we showed that in growth-arrested vascular smooth muscle cells (VSMCs), Ang II induced cell proliferation, KLF5 mRNA and protein expression in a dose- and time-dependent fashion, whereas KLF5 mRNA stability was not affected. The AT1 antagonist losartan significantly blocked Ang II-induced KLF5 expression. Furthermore, several intracellular signals elicited by Ang II were involved in KLF5 gene upregulation, including phosphate tyrosine kinase, mitogen-activated protein kinases and reactive oxygen species. These data, for the first time, revealed the involvements of some intracellular signals in the regulation of KLF5 expression in response to Ang II in VSMCs and showed the possible role of KLF5 in Ang II-induced cell proliferation in VSMCs.
Microbiology
Notes
  • Arisa Igarashi, Satoko Ohtsu, Masashi Muroi, Ken-ichi Tanamoto
    2006 年 29 巻 10 号 p. 2120-2122
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Endocrine disrupting chemicals (EDCs) have a possibility to exacerbate infectious diseases because EDCs disturb the human immune system by interfering with endocrine balance. To assess the influence of EDCs on the innate immune function of macrophages, we investigated the effects of thirty-seven possible endocrine disruptors on lipopolysaccharide (LPS)- or bacterial lipopeptide (Pam3CSK4)-induced activation of nuclear factor kappa B (NF-κB). Alachlor, benomyl, bisphenol A, carbaryl, kelthane, kepone, octachlorostyrene, pentachlorophenol, nonyl phenol, p-octylphenol and ziram inhibited both LPS- and Pam3CSK4-induced activation of NF-κB. Simazine inhibited only LPS-induced activation. A strong inhibitory effect was observed with ziram and benomyl. On the other hand, diethylhexyl adipate and 4-nitrotoluene tended to enhance the activation induced by Pam3CSK4 and LPS, respectively. Aldicarb, amitrole, atrazine, benzophenone, butyl benzyl phthalate, 2,4-dichlorophenoxy acetic acid, dibutyl phthalate, 2,4-dichlorophenol, dicyclohexyl phthalate, diethylhexyl phthalate, diethyl phthalate, dihexyl phthalate, di-n-pentyl phthalate, dipropyl phthalate, malathion, methomyl, methoxychlor, metribuzin, nitrofen, permethrin, trifluralin, 2,4,5-trichlorophenoxyacetic acid and vinclozolin had no significant effects at 100 μM. These results indicate that some agrochemicals have the potential to inhibit macrophage function and suggest that endocrine disruptors may influence the development of bacterial infections.
Pharmacology
Regular Articles
  • Masahiko Hirata, Tetsuya Mori, Seigo Soga, Takuya Umeda, Yoshiro Ohmom ...
    2006 年 29 巻 10 号 p. 2009-2015
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    New series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-[3-(2-iodophenyl)propyl]piperazine (o-BON) and 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-[3-(3-iodophenyl)propyl]piperazine (m-BON) were evaluated as single photon emission computed tomography (SPECT) radiopharmaceuticals for mapping sigma receptors in the central nervous system (CNS) and peripheral organs. In vivo biodistribution studies of [125I] o- and m-BON in mice demonstrated high initial uptakes and prolonged retention in the brain. In contrast to high brain uptake and retention, the blood accumulations were low, resulting in good brain-blood ratios (7.9—9.2). In the other tissues, high uptake of [125I] o- and m-BON were observed in the liver, kidney, heart, lung, and pancreas. Moreover, selective interactions of [125I] o- and m-BON with sigma receptors were confirmed by pretreatment experiments with various sigma and other receptor ligands. Haloperidol posttreatment induced decreases in the accumulation of [125I] o- and m-BON. These data suggest that [125I] o- and m-BON binding to sigma receptors is reversible and competitive. Furthermore, ex vivo autoradiograms of [125I] o- and m-BON in rats showed high uptake in the parietal cortex, vestibular nucleus, and pons nucleus and moderate uptake in the thalamus, inferior colliculus, hippocampus, hypothalamus, and temporal cortex. These ex vivo autoradiograms were comparable with the histochemical distribution of sigma receptors. Furthermore, the uptake of [125I] o- and m-BON reflected quantitative amounts of sigma receptor in the brain. These results demonstrated that radiolabeled o- and m-BON have good characteristics for mapping sigma receptors in the CNS and the peripheral organs with SPECT.
  • Naoki Futakawa, Masuo Kondoh, Satoshi Ueda, Minoru Higashimoto, Masufu ...
    2006 年 29 巻 10 号 p. 2016-2020
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    We previously reported that synthesis of metallothionein (MT) was induced by mitochondrial inhibitors such as 2,4-dinitrophenol (DNP) or antimycin A (Kondoh et al., 2001), which are potent inhibitors of mitochondrial respiration. Although the inhibitors are known to be radical generators in mitochondria, the involvement of oxidative stress in the synthesis of MT induced by mitochondrial inhibitors and the biological functions of MT remain obscure. In this study, therefore, we examined the involvement of oxidative stress in MT synthesis induced by mitochondrial inhibitors and the biological functions of MT. In cultured mouse fibroblast cells, the addition of DNP increased both MT concentration and MT mRNA level. Administration of DNP to L-buthionine-SR-sulfoximine (BSO)-pretreated mice increased hepatic lipid peroxidation and induction of MT synthesis. In addition, vitamin E prevented induction of MT synthesis as well as lipid peroxidation in the liver of mice caused by administration of DNP. Administration of mitochondrial inhibitor to mice elevated the levels of lipid peroxidation in the liver and mitochondria, and MT in the liver, indicating the generation of mitochondrial oxidative stress. These data suggest that the induction of MT synthesis by mitochondrial inhibitors is correlated with generation of oxidative stress in mitochondria. Furthermore, the level of DNP-induced alanine aminotransferase (ALT) activity, reflecting hepatic damage, was greater in MT-null mice than in wild-type mice, and intracellular accumulation of reactive oxygen species (ROS) caused by the action of mitochondrial inhibitors was greater in MT-null fibloblast cells than in wild-type cells. The results suggest that MT plays a role as a radical scavenger of intracellular ROS produced in mitochondria. Taken together, the results suggest that mitochondrial oxidative stress induces the synthesis of MT, which may contribute to regulation of mitochondrial ROS production.
  • Sang Tae Kim, Jeong Do Kim, Yeoung-Su Lyu, Min-Yung Lee, Hyung-Won Kan ...
    2006 年 29 巻 10 号 p. 2021-2024
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Carboxyl-terminal fragments of APP (CT) have been found in plaques, microvessels and the neurofibrillary tangles in the brains of AD patients. These carboxyl-terminal fragments, which contain the complete Aβ sequence, appear to be toxic to neurons in culture cells. However, the possible role of other cleaved products of APP is less clear. We showed that a recombinant carboxy-terminal 105 amino acid fragment (CT105) of APP induced strong neurotoxicity in PC12 cells. We prepared alcoholic extract from Oriental herbal plants and screened their protective effects against CT105-induced cell death in PC12 cells after the treatment of these extracts. Of the 10 kinds of plant extracts, 12 kinds of extracts had considerable protective effects against CT105-induced cell death, especially, Uncariae Ramulus et Uncus (UREU), Gastrodia elata (GAE), Evodia officinalis (EO) and Panax ginseng (PAG) showed the most protective effect at the concentration of 50μg/ml. BuOH extract of UREU and GAE possessed the strongest protective effects against neurotoxicity of CT105-induced PC12 cells and showed inhibitory effect with IC50 values of 4.8 and 8.3μg/ml, respectively. These plants are promising candidates of neuroprotective effects and would be useful for the treatment of the neuronal degenerative diseases such as Alzheimer's diseases.
  • Mao-Mao An, Ke-Xing Fan, Yong-Bing Cao, Hui Shen, Jun-Dong Zhang, Lei ...
    2006 年 29 巻 10 号 p. 2025-2030
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    LIGHT is a member of the TNF superfamily, which is transiently expressed on the surface of activated T lymphocytes and immature dendritic cells. Its known receptors are herpesvirus entry mediator (HVEM) prominently in T lymphocytes, and lymphtoxin β receptor (LTβR) in stromal cells or nonlymphoid hematopoietic cells.Previous studies have shown that overexpression of LIGHT on T cells could lead to autoimmune reaction including lymphocytes activation, inflammation, and tissue destruction. To address the role of LIGHT/HVEM signaling in autoimmune hepatitis, an experimental colitis model induced by intravenous administration of concanavalin A (ConA) was given a soluble LTβR-Ig fusion protein as a competitive inhibitor of LIGHT/HVEM pathway. Marked elevation of LIGHT expression was detected in isolate intrahepatic leukocytes (IHLs) of the experimental animal. Treatment with LTβR-Ig significantly attenuated the progression and histological manifestations of the hepatic inflammation and reduced the production of inflammatory cytokines including TNF-α, IFN-γ. Moreover, LTβR-Ig treatment significantly down-regulated LIGHT expression, leading to reduced lymphocytes (particularly CD4+ T cells), infiltrating into the hepatic inflammation and inhibited NF-κB activation and expression. We postulated that blockade of LIGHT/HVEM signaling by LTβR-Ig may ameliorate hepatitis by down-regulating LIGHT expression, and therefore we envision that LTβR-Ig would prove to a promising strategy for the clinical treatment of human autoimmune hepatitis.
  • Jing-Xia Zhao, Ying-Ying Cao, Hua Quan, Chao-Mei Liu, Qiu-Qing He, Qiu ...
    2006 年 29 巻 10 号 p. 2031-2034
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The activity of HQQ-3, a new triazole antifungal agent, was evaluated and compared with those of fluconazole, ketoconazole and terbinafine in vitro and with fluconazole in vivo. HQQ-3 exhibited potent in vitro activity against clinically important fungi. The activity of HQQ-3 against Candida spp. was superior to those of fluconazole and terbinafine and comparable or superior to that of ketoconazole. HQQ-3 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC80s range, 4 to >64 μg/ml). Against Cryptococcus neoformans and filamentous fungi, the activity of HQQ-3 was superior to that of fluconazole. HQQ-3 also exhibited potent in vivo activity against murine systemic infections caused by C. albicns and C. krusei. The 50% effective doses against these infections were 0.12 to 1.9 mg/kg of body weight. These result suggest that HQQ-3 may be useful in the treatment of candidiasis.
  • Md. Ashequr Rahman, Jun Ago, Naotaka Matsumoto, Takashi Ishikawa, Chia ...
    2006 年 29 巻 10 号 p. 2035-2040
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The present study was undertaken to clarify the epileptogenic activity induced by intracerebroventricular injection (i.c.v.) of antibiotics effective in methicillin-resistant Staphylococcus aureus (MRSA) in chronically electrode implanted rats. Teicoplanin (10—100 μg, i.c.v.) caused dose-related electroencephalographic (EEG) seizure characterized by an uninterrupted high voltage and wave complex. At the same time, the rats showed forelimb clonus, head nodding, jumping and severe convulsion. At a high dose (100 μg, i.c.v.), the drug caused a severe twisting immediately after the intracerebroventricular injection (i.c.v.) followed by jumping and violent convulsion with a continuous rhythmic spike and wave complex in EEG. On the other hand, vancomycin (30—1000 μg, i.c.v.) caused no or almost no epileptogenic activity in terms of behavior and in EEG. However, at a high dose (1000 μg, i.c.v.), the drug caused an occasional spike from the hippocampus without showing any behavioral changes in the rats. Fosfomycin (30—1000 μg, i.c.v.), cefazolin (10—100 μg, i.c.v.) and penicillin G (30—300 μg, i.c.v.), used as reference drugs, caused dose-dependent epileptogenic activity in both EEG. From these findings, it was found that teicoplanin caused a potent epileptogenic activity, different to vancomycin. Therefore, it can be concluded that vancomycin may be safety on epileptogenic activity used for the clinical purpose of infections caused by MRSA.
  • Tsukasa Matsumoto, Tomoyuki Hayasaki, Yoshiko Nishimura, Masahiko Naka ...
    2006 年 29 巻 10 号 p. 2041-2045
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Recent findings have suggested that organic acids produced by anaerobic intestinal bacteria might contribute to the pathogenesis of colonic ulcers. In this study, it was shown that butyrate caused potent cytotoxicity in the murine normal colonic epithelial cells MCE301 at physiological concentrations. Several markers of apoptosis, such as phosphatidyl serine externalization, cytochrome c release, DNA fragmentation, and chromatin condensation were negative after butyrate exposure. Inhibitor of caspases failed to protect against butyrate cytotoxicity. By transmission electron microscopy, marked swollen mitochondria and vacuolization within the cytoplasm was observed by treatment of butyrate. Collective, these data indicated that butyrate-induced cell death caused through a necrosis-like process. Butyrate induced cell death was reduced partially by treatment with prednisolone or 5-aminosalicylates in a concentration dependent manner. These results suggest that (1) butyrate induces necrotic cell death but not apoptotic cell death, and (2) the necrotic cell death induced by butyrate may be useful as a novel in vitro model of ulcerative colitis to screen useful drugs for the treatment of the disease.
Notes
  • Shirou Itagaki, Wakako Ogura, Yuki Sato, Toshihiro Noda, Takeshi Hiran ...
    2006 年 29 巻 10 号 p. 2123-2125
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Lutein is a carotenoid that has antioxidant effects. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. The disposition of lutein after i.v. administration has not been investigated because lutein is now used as a supplement. The present study was undertaken to acquire additional data on the disposition of lutein after i.v. administration. After i.v. administration, lutein is preferentially distributed to the liver, spleen and lung. Intravenous administration of lutein may provide effective antioxidant activities in these tissues, not only the eye. The results of this study should provide valuable data for drug development.
Medicinal Chemistry
Regular Articles
  • Hajime Kubo, Mai Inoue, Junzo Kamei, Kimio Higashiyama
    2006 年 29 巻 10 号 p. 2046-2050
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    (−)-Multiflorine isolated from leguminous plants produces a hypoglycemic effect when administered to mice with streptozotocin-induced diabetes. (−)-Multiflorine has an enaminone-type conjugation on the A ring, which is unusual in lupine alkaloids. Proceeding on the assumption that the A–B ring is responsible for the hypoglycemic effect, several compounds bearing the quinolizidin-2-one ring system were synthesized, and their hypoglycemic effects were examined. In addition, tricyclic compounds bearing 4-pyridone were synthesized, and their hypoglycemic effects were examined. The hypoglycemic effect of a 4-pyridone-type compound was similar to that of (−)-multiflorine as measured by oral glucose tolerance testing in normal mice. No hypoglycemic effect of a 4-piperidone-type compound was observed. These results indicate that compounds possessing double bond(s) in the A ring of multiflorine may be lead compounds for a new type of diabetes drug.
Pharmacognosy
Regular Articles
  • Seung Hoon Baek, Xiang Lan Piao, Un Jo Lee, Hyun Young Kim, Jeong Hill ...
    2006 年 29 巻 10 号 p. 2051-2055
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Ginsenosides, the unique constituents and secondary metabolites of the Panax species, have been known to be the pharmacologically active ingredients of ginseng. Recently, our research group has developed a new processed ginseng, called Sun ginseng (SG), which has an increased amount of the red ginseng unique ginsenosides (RGUG). In our previous studies, this new processed ginseng reduced cisplatin-induced nephrotoxicity more than white ginseng in both in vitro and in vivo systems. In this study, we isolated and characterized active principles through activity-guided fractionation. Ginsenosides Rh4 and Rk3 significantly reduced the cisplatin-induced nephrotoxicity in LLC-PK1 cells in a dose-dependent manner. The mechanisms of function and structure–activity relationships with other ginsenosides remain for further investigation.
  • Filomena Conforti, Giancarlo Statti, Dimitar Uzunov, Francesco Menichi ...
    2006 年 29 巻 10 号 p. 2056-2064
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The chemical composition and antioxidant activities of wild and cultivated Laurus nobilis leaves and Foeniculum vulgare subsp. piperitum seeds were determined. Differences were found in the total phenolic content of fennel. GC-MS analysis of the non polar fractions showed a different composition between wild and cultivated plants. Cultivated laurel had a high content of terpenes such as linool, α-terpinol, α-terpinyl acetate, thymol, caryophyllene, aromandrene, selinene, farnesene, and cadinene, while wild laurel had a high content of eugenol and methyl eugenol, vitamin E, and sterols. The antioxidant potential of the extracts was determined using three complementary methods. Wild plants showed greater radical scavenging activity than the cultivated plants. The extracts also exhibited a significant antioxidant capacity also in the β-carotene–linoleic acid test system. A high level of antioxidant activity was observed in wild laurel (IC50=1 μg/ml). Significant antioxidant activity measured in bovine brain was observed in wild laurel.
  • Toshiaki Makino, Fumika Mizuno, Hajime Mizukami
    2006 年 29 巻 10 号 p. 2065-2069
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Herb–drug interaction has attracted attention as medicinal topics recently. However, the drug information is sometimes confusing. Previous in vitro studies revealed that schisandra fruit had strong inhibitory effect on CYP3A4 and claimed the possibilities of its herb–drug interaction. In the present study, we evaluated the inhibitory effects of schisandra fruit and shoseiryuto, an herbal formula in Japanese traditional kampo medicine containing eight herbal medicines including schisandra fruit, on rat CYP3A activity in vitro, and the effect of shoseiryuto on pharmacokinetics of nifedipine in rats, in comparison with those of grapefruit juice, a well-characterized natural CYP3A inhibitor. Shoseiryuto and its herbal constituents, schisandra fruit, ephedra herb and cinnamon bark exhibited in vitro inhibitory effect of CYP3A. Although shoseiryuto inhibited rat CYP3A activity in vitro with a degree comparable to grapefruit juice, shoseiryuto did not significantly affect a plasma concentration profile of nifedipine in rats as grapefruit juice did. These results indicate that in vivo experiments using the extract of herbal medicine prepared with the same dosage form as patients take are necessary to provide proper information about herb–drug interaction.
  • Pongpun Siripong, Jantana Yahuafai, Kosuke Shimizu, Kanae Ichikawa, Se ...
    2006 年 29 巻 10 号 p. 2070-2076
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Rhinacanthus nasutus KURZ. (Acanthaceae) has been used as Thai traditional medicine for the treatment of various cancers. Recently, we reported that rhinacanthins, active components of the plant, had antiproliferative activity against human cancer line cells. In the present study, we investigated the growth inhibitory mechanism of rhinacanthins-C, -N and -Q, three main naphthoquinone esters isolated from the roots of R. nasutus KURZ. in human cervical carcinoma (HeLaS3) cells by means of TUNEL staining, DNA fragmentation assay, flow cytometry, and cleavage assay of Asp-Glu-Val-Asp-peptide-nitroanilide, a caspase-3 substrate. After the HeLaS3 cells was exposed with different concentrations of the drugs, rhinacanthins-C, -N and -Q exhibited antiproliferative effects on HeLaS3 cells with the IC50 values of 80, 65, 73 μM; 55, 45, 55 μM; and 1.5, 1.5 and 5.0 μM for 24, 48 and 72 h time points, respectively. Morphological changes showing nuclear fragmentation of rhinacanthins-treated cells were clearly observed after 48 h exposure. Consistent with this observation, the appearance of a ladder formation was also evident with an agarose gel electrophoresis of the extracted DNA. Flow cytometric analysis revealed that rhinacanthin-N caused G2/M arrest of HeLaS3 cells after 24 h incubation, and increased the proportion of sub-G1 hypodiploid cells, apoptotic cells, in the population of HeLaS3 cells after 48 and 72 h incubation. Moreover, the drug treatment markedly elevated the activity of caspase-3. Based on these results, our findings demonstrated for the first time that the inhibitory effects of three main naphthoquinone esters isolated from the roots of R. nasutus KURZ. on the growth of HeLaS3 cells appear to arise from the induction of apoptosis, that might be associated with the activation of caspase-3 pathway.
Notes
  • Patrícia Shima Luize, Tânia Ueda-Nakamura, Benedito Prado ...
    2006 年 29 巻 10 号 p. 2126-2130
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The in vitro antiproliferative effects of 4 neolignans purified from the ethyl-acetate extract from leaves of Piper regnellii (MIQ.) C. DC. var. pallescens (C. DC.) YUNCK against Trypanosoma cruzi were investigated. These isolated compounds were identified through spectral analyses of UV, EI-MS, 1H-, 13C-NMR, H–H COSY, gNOE, HETCOR, and HMBC. The compounds eupomatenoid-5, eupomatenoid-6, and conocarpan showed considerable activity against epimastigote forms of T. cruzi, with 50% inhibition concentrations (IC50) of 7.0, 7.5, and 8.0 μg/ml respectively. After methylation, these compounds showed a lessened inhibitory activity to the growth of the protozoan, suggesting that loss of the hydroxyl group from their molecules reduces the activity. The compound eupomatenoid-3 showed lower activity than the hexane fraction. Eupomatenoid-5 was significantly more active than benznidazole, the antiparasitic drug of choice for treatment of Chagas' disease. The crude extract, hexane fraction, and eupomatenoid-5 caused no lysis in sheep blood at concentrations which inhibit the growth of epimastigote forms. The compound eupomatenoid-5 showed low cytotoxic effects against Vero cells. These results provide new perspectives on the development of novel drugs obtained from natural products with trypanocidal activity. However, the extracts and active compound isolated from P. regnellii var. pallescens should be further studied in animal models for in vivo efficacy.
  • Sung-Jin Lee, Hak-Kyo Lee, Min-Kyung Jung, Woongchon Mar
    2006 年 29 巻 10 号 p. 2131-2134
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    This study examined the antiviral activity of the root of Paeonia lactiflora PALL. Among the solvent fractions of the crude drug, the ethyl acetate fraction showed anti-hepatitis B virus (HBV) activity (IC50, 8.1 μg/ml) in an HBV-producing HepG2.2.15 cell culture system. The active anti-HBV principle was isolated and identified as 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) from the crude drug by activity-guided fractionation. PGG isolated from P. lactiflora was examined for the inhibition of HBV multiplication by measurement of HBV DNA and hepatitis B surface antigen (HBsAg) levels in the extracellular medium of HepG2.2.15 cells after 8-d treatment. PGG decreased the level of extracellular HBV (IC50, 1.0 μg/ml) in a dose-dependent manner. PGG also reduced the HBsAg level by 25% at a concentration of 4 μg/ml. The gallate structure of PGG may play a critical role in the inhibition of anti-HBV activity. These results suggest that PGG could be a candidate for developing an anti-HBV agent.
  • Jung-Bum Lee, Kyoko Hayashi, Megumi Hirata, Eiko Kuroda, Eiko Suzuki, ...
    2006 年 29 巻 10 号 p. 2135-2139
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    A sulfated polysaccharide named naviculan was isolated from a diatom, Navicula directa (W. SMITH) RALFS, collected in deep sea water from Toyama Bay. The polysaccharide consisted of fucose, xylose, galactose, mannose, rhamnose and sulfate with an apparent molecular weight of 220000. It showed antiviral activities against herpes simplex viruses type 1 and 2, and influenza A virus with selectivity indices (CC50/IC50) of 270, 510 and 32, respectively. Naviculan also showed an inhibitory effect on cell–cell fusion between CD4-expressing and human immunodeficiency virus (HIV) gp160-expressing cells that was used as a model system of infection with HIV.
  • Young Ho Kim, Eun Jung Park, Mi Hyun Park, Uranchimeg Badarch, Girma M ...
    2006 年 29 巻 10 号 p. 2140-2142
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    In a search for natural product inhibitors of hypoxia inducible factor-1 (HIF-1) function, crinamine (1), a crinane type alkaloid, showed potent dose dependent inhibition (IC50=2.7 μM) of HIF-1α in a cell-based reporter gene assay. Crinamine (1) was isolated from the aerial parts of Crinum asiaticum var. japonicum together with lycorine (2), norgalanthamine (3) and epinorgalanthamine (4). The other components (2—4) showed no significant inhibition of HIF-1α induced transcriptional activity.
Biopharmacy
Regular Articles
  • Noriaki Nagai, Ying Liu, Takashi Fukuhata, Yoshimasa Ito
    2006 年 29 巻 10 号 p. 2077-2081
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    We previously found that Ca2+ concentrations, inducible nitric oxide synthase (iNOS) mRNA, and protein expression in lenses of the Shumiya cataract rat (SCR) increase with the development of cataracts. In this study, we investigated the change in Ca2+-ATPase activities and ATP levels in the human lens epithelial cell line SRA 01/04 (HLE cells) with the stimulation of interferon-gamma (IFN-γ) and lipopolysaccharide (LPS). Expression levels of iNOS mRNA in HLE cells, which were determined using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time RT-PCR methods, increased during stimulation with IFN-γ (1000 IU) and LPS (100 ng/ml). NO release from HLE cells, expressed as the sum of NO2 and NO3 levels, increased with the increase in iNOS expression levels. Ca2+-ATPase activities increased and ATP levels decreased in HLE cells stimulated with the combination of IFN-γ and LPS. Furthermore, both diethyldithiocarbamate and aminoguanidine attenuated the increase in Ca2+-ATPase activities and the decrease in ATP levels. These results suggest that excessive production of NO may cause mitochondrial damage, resulting in an increased Ca2+ concentration in the lens. The increase in Ca2+ concentration in the lens may increase Ca2+-ATPase activities.
  • Junzo Nakamura, Shintaro Fumoto, Keiko Shoji, Yukinobu Kodama, Junya N ...
    2006 年 29 巻 10 号 p. 2082-2086
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The purpose of the present study was to achieve a stomach-selective gene transfer following the administration of naked plasmid DNA (pDNA) onto the gastric serosal surface in mice. Gene expression in the stomach and other tissues was evaluated by firefly luciferase activity. Six hours after gastric serosal surface instillation of naked pDNA, high gene expression in the stomach was observed. On the contrary, intravenous and intraperitoneal injection of naked pDNA exhibited no detectable gene expression. Following instillation of naked pDNA onto the gastric serosal surface, gene expression in the stomach was significantly higher than in other tissues. Gene expression in the stomach was highest 12 h after the instillation and thereafter decreased gradually. Utilizing a glass-made diffusion cell that is able to limit the contact dimension between the gastric serosal surface and the naked pDNA solution administered, site-specific gene expression in the stomach was achieved. This novel gene transfer method is expected to be a safe and effective treatment against serious stomach diseases.
  • Mariko Tanaka, Yoshihiko Fujisaki, Kazunori Kawamura, Kiichi Ishiwata, ...
    2006 年 29 巻 10 号 p. 2087-2094
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    11C-Labeled analogs of 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole ([11C]1), 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide ([11C]2) and 2-(4-aminosulfonylphenyl)-3-(4-methoxyphenyl)indole ([11C]3), which have been shown to have excellent potency and high selectivity for cyclooxygenase isoform 2 (COX-2) inhibiting activity, were prepared and evaluated in rats as potential radiopharmaceuticals for imaging the COX-2 enzyme by positron emission tomography. These 11C-labeled COX-2 inhibitors were synthesized in high radiochemical yields by O-[11C]methylation of phenolic precursors with [11C]methyl triflate in acetone containing NaOH as a base. In vivo evaluation in rats bearing AH109A hepatoma showed no specific binding of any tracer to COX-2 in any tissue such as the brain, heart, lung, kidney, and AH109A hepatoma. In ex vivo autoradiography, [11C]1 showed regionally different distribution in the brain, while [11C]2 and [11C]3 were not substantially taken up by the brain. In in vitro monolayer efflux assays, compound 3 was found to be a substrate for the P-glycoprotein (P-gp) efflux pump, but pretreatment of rats with the potent P-gp inhibitor, cyclosporine A, did not have any significant influence on the cerebral uptake of [11C]3. These results indicate that all three tracers were not suitable for in vivo imaging of COX-2. There seem to be some obstacles to finding a useful candidate for in vivo imaging application of COX-2 selective inhibitors only by standard consideration of in vitro affinity and selectivity, and the lipophilicity of the compound.
  • Tetsuo Adachi, Taisuke Toishi, Eiji Takashima, Hirokazu Hara
    2006 年 29 巻 10 号 p. 2095-2098
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Extracellular-superoxide dismutase (EC-SOD) is the major SOD isozyme in blood vessel walls, normal cartilage and synovial fluid and may be important for the antioxidant capability of these tissues. We have reported that EC-SOD gene transferred mice exhibited significant suppression of clinical symptoms of type II collagen induced arthritis [Iyama, et al., Arthritis Rheum., 44, 2160—2167 (2001)] and plasma EC-SOD levels in type 2 diabetic patients were significantly negatively related to indices of insulin resistance [Adachi, et al., J. Endocrinol., 181, 413—417 (2004)]. Tumor necrosis factor-α (TNF-α) has been implicated in the pathological conditions of the above diseases and is a major therapeutic target, based on clinical studies with anti-TNF-α monoclonal antibodies such as infliximab. In this report, we investigated the effect of TNF-α on the expression of EC-SOD in cultured cells and the cooperating effect of infliximab. In the in vitro assays examined, expression of EC-SOD, but not other SOD isozymes, in smooth muscle and fibroblast cells were suppressed by the addition of TNF-α. Simultaneous addition of infliximab dose-dependently and significantly prevented the suppressive effects of TNF-α. p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, prevented significantly the suppressive effect of TNF-α suggesting that p38 MAPK is an important signaling molecule downstream of TNF-α to inhibit the EC-SOD expression. From the results, it is speculated that the decline in TNF-α activity by the administration of infliximab results in the liberation of EC-SOD from the suppressed state of gene expression. This reveals a potential usefulness of infliximab on TNF-α related pathological conditions such as arthritis and insulin resistance.
  • Nobuyuki Sugioka, Takayuki Sasaki, Takatoshi Kokuhu, Yukako Ito, Nobuh ...
    2006 年 29 巻 10 号 p. 2099-2105
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Mycophenolate mofetil (MMF), a morpholinoethyl ester of mycophenolic acid (MPA), is currently widely used in organ transplantation as an immunosuppressant. The usefulness of therapeutic drug monitoring (TDM) of MPA after MMF dosing is not clear in Japanese renal transplant patients. In this study, to obtain more information for TDM of MPA, the association between MPA pharmacokinetic characteristics and the development of the side effects, and the effect of other concomitant immunosupressants such as cyclospoline A (CyA), tacrolimus (FK) and predonisolone (PSL) on MPA pharmacokinetics were investigated in detail. Moreover, the effects of enterohepatic recirculation (EHRA) on pharmacokinetic characteristics of MPA and the development of the side effects were also investigated. AUCMPA0—9 with FK medication was 1.3—1.9 times higher than that with CyA medication, and the contribution to the plasma level of MPA of FK might be smaller than that of CyA, because EHRA inhibition by CyA was 2 times greater than that by FK. AUCMPA0—9 was not influenced by PSL. The association between AUCMPA0—9 and the development of the side effects was not observed; however, the development of side effects (leukopenia and diarrhea) in the EHRA group was 2 times higher than that in the non-EHRA group. These results suggested that TDM for MPA after MMF dosing was desirable in Japanease transplant patients. However, though not frequently, AUC obtained by multiple blood sampling after MMF dosing was needed. In addition, EHRA has led to increasing interest in MMF medication.
  • Mayumi Ikeuchi, Tomoyuki Koyama, Jiro Takahashi, Kazunaga Yazawa
    2006 年 29 巻 10 号 p. 2106-2110
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The present study was designed to determine the effect of astaxanthin on endurance capacity in male mice aged 4 weeks. Mice were given orally either vehicle or astaxanthin (1.2, 6, or 30 mg/kg body weight) by stomach intubation for 5 weeks. The astaxanthin group showed a significant increase in swimming time to exhaustion as compared to the control group. Blood lactate concentration in the astaxanthin groups was significantly lower than in the control group. In the control group, plasma non-esterfied fatty acid (NEFA) and plasma glucose were decreased by swimming exercise, but in the astaxanthin group, NEFA and plasma glucose were significantly higher than in the control group. Astaxanthin treatment also significantly decreased fat accumulation. These results suggest that improvement in swimming endurance by the administration of astaxanthin is caused by an increase in utilization of fatty acids as an energy source.
Notes
  • Koji Sakanaka, Kouichi Kawazu, Koyo Nishida, Junzo Nakamura, Mikiro Na ...
    2006 年 29 巻 10 号 p. 2143-2147
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The purpose of this study is to characterize the transport of tilisolol and timolol through the corneal epithelium, which is believed to be a tight barrier of ocular drug absorption. Cultured normal rabbit corneal epithelial cells (RCEC) were used to investigate drug transport. Primary RCEC were seeded on a filter membrane of Transwell-COL® insert coated with fibronectin and grown in Dulbecco's modified Eagle's medium/nutrient mixture F-12 with various supplements. Beta-blocker permeability through the RCEC layer was measured to assess the transcellular permeability coefficient (Ptranscell) in the absence or presence of inhibitors. The transcellular permeability of tilisolol was dependent on drug concentration although timolol showed no concentration dependency. Tilisolol flux from the apical to the basal side was larger than in the opposite direction although timolol showed no direction dependency. The transcellular permeability of tilisolol from the apical to the basal side was inhibited by sodium azide, tetraethylammonium, quinidine, taurocholic acid, guanidine and carnitine. Tilisolol had an active mechanism in uptake to the corneal epithelium, probably by the organic cation transporter family, although timolol predominantly permeated via passive diffusion. This RCEC system was useful to characterize the ocular permeation mechanism of drugs.
  • Akito Minamizono, Masatoshi Tomi, Ken-ichi Hosoya
    2006 年 29 巻 10 号 p. 2148-2150
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    Vitamin C is mainly transported across the blood–retinal and –brain barriers as dehydroascorbic acid (DHA) via a facilitative glucose transporter, GLUT1, and accumulates as ascorbic acid in the retina and brain. To investigate whether DHA transport to the retina and brain is changed by hyperglycemia, [14C]DHA transport across the blood–retinal and –brain barriers was examined using in vivo integration plot analysis in streptozotocin-induced diabetic rats with a 3-week duration of diabetes and in normal rats. Blood-to-retina and -brain transport of [14C]DHA was reduced by 65.5% and 84.1%, respectively, in diabetic rats compared with normal rats, whereas there was no major difference in the heart. Therefore, we propose that hyperglycemia reduces the supply of vitamin C to the retina and brain.
Miscellaneous
Regular Articles
  • Jeong-Ryae Jeon, Jong-Yeon Kim
    2006 年 29 巻 10 号 p. 2111-2115
    発行日: 2006年
    公開日: 2006/10/01
    ジャーナル フリー
    The present study examined the anti-obesity effects of pine needle extract (PNE) in 3T3-L1 preadipocytes and in vivo studies. PNE treatment suppressed both glycerol-3-phosphate dehydrogenase activity and expression of peroxisome proliferator-activated receptor (PPAR) γ in cultured 3T3-L1 adipocytes. To investigate the effect of PNE on obesity in rats fed high-fat diet, four types of diet, which included a normal diet (ND), high-fat diet (HFD), ND+PNE, and HFD+PNE diets, were fed to the rats ad libitum for 6 weeks. The PNE supplement significantly decreased body weight gain and visceral fat mass compared to the HFD group. The total cholesterol, TG, and leptin levels in the plasma were significantly reduced by PNE supplementation compared with those of the HFD group. Histological findings in liver tissue showed that PNE supplementation alleviated steatosis induced by HFD. In conclusion, PNE treatment suppressed differentiation of 3T-L1 adipocytes, in part by down-regulating expression of PPAPγ mRNA, and reduced adipose tissue mass, hyperlipidemia, and hepatic steatosis in obese rats fed HFD. Therefore, pine needle water extract may be considered for use in therapy to control obesity.
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