Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 32 , Issue 12
Showing 1-26 articles out of 26 articles from the selected issue
Biochemistry
Regular Articles
  • Hiroshi Izuta, Yukimi Narahara, Masamitsu Shimazawa, Satoshi Mishima, ...
    Type: Regular Articles
    Subject area: Biochemistry
    2009 Volume 32 Issue 12 Pages 1947-1951
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    The aim of this work was to investigate the antioxidant property of honeybee products and their constituents using an ESR method. Antioxidative activity was evaluated as the scavenging activity of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. The DPPH radical scavenging activities, in descending order, were: ethanol extract of Chinese red propolis>ethanol extract of Brazilian green propolis>water extract of Brazilian green propolis>ethanol extract of bee pollen. Many natural compounds are included in Brazilian green propolis, such as caffeoylquinic acid derivatives [3,4-di-caffeoylquinic acid (3,4-CQA), 3,5-di-caffeoylquinic acid (3,5-CQA), and chlorogenic acid (ChA)] and cinnamic acid derivatives [artepillin C, baccharin, ρ-coumaric acid, and drupanin]. Caffeoylquinic acid derivatives exhibited DPPH radical scavenging activity as strong as that of ascorbic acid and trolox. Among the cinnamic acid derivatives, artepillin C exhibited relatively strong DPPH radical scavenging activity. Caffeic acid phenethyl ester (CAPE), a constituent of Chinese red propolis, exhibited potent DPPH radical scavenging activity, stronger than that of ascorbic acid and trolox. Caffeic acid, a metabolite of caffeoylquinic acid, exhibited powerful DPPH radical scavenging activity, while quinic acid, another metabolite of caffeoylquinic acid, had no such activity. Both Brazilian and Chinese propolis and their constituents (caffeoylquinic acid derivatives and CAPE) therefore appear to be powerful scavengers of DPPH radical, and the effects may be partly dependent on the nature of their caffeoyl groups.
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  • Bui Huu Tai, Bong Yong Jung, Nguyen Manh Cuong, Pham Thuy Linh, Nguyen ...
    Type: Regular Articles
    Subject area: Biochemistry
    2009 Volume 32 Issue 12 Pages 1952-1956
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Nine compounds, including six phenylethanoid glycosides: acteoside (1); bioside (2); echinacoside (3); poliumoside (4); phenylethyl glycoside (5); salidroside (6) and three flavonoids; linarin (7); apigenin (8); isorhoifolin (9), were isolated from the flowers of Buddleja officinalis MAXIM. (Buddlejaceae). Chemical structures were confirmed by 1H-, and 13C-NMR, and MS spectral methods and compared with those reported in the literature. Antioxidant activities of the methanol and water extracts, and all isolated compounds were evaluated using the total oxidant scavenging capacity (TOSC) assay against peroxynitrite. Results of the assay showed that the phenylethanoid glycosides, a major class of compounds of the flowers of B. officinalis, possess strong antioxidant activity. Of these, acteoside, echinacoside and poliumoside have 9.9-, 9.8- and 9.5-fold TOSC value, respectively, compared with the positive control, Trolox.
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  • Masaru Doshi, Yudai Kuwatori, Yoko Ishii, Masakiyo Sasahara, Yutaka Hi ...
    Type: Regular Articles
    Subject area: Biochemistry
    2009 Volume 32 Issue 12 Pages 1957-1961
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    C57BL/6J mice are widely used as a background strain for genetic alterations and have been valuable for investigating the molecular mechanism of selective neuronal death following transient forebrain ischemia, which was induced by occlusion of bilateral common carotid arteries (BCCA). Hypothermia (HT) during ischemia has been shown to protect against neuronal death in several experimental models of cerebral ischemia including that induced by BCCA occlusion in C57BL/6J mice. In this study, we demonstrated that brain edema, one of the most important disorders following cerebral ischemia, occurred in the forebrain before neuronal death in the hippocampus and was not prevented by HT during cerebral ischemia induced by BCCA occlusion in C57BL/6J mice. Our results indicate that neuronal death and acute brain edema were induced by different mechanisms in the BCCA occlusion and reperfusion C57BL/6J mouse model, suggesting that our model with and without HT during cerebral ischemia may be a useful tool for the investigation of the specific mechanism of brain edema and neuronal death, respectively.
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Notes
  • Masaki Okawara, Hiroyuki Seki, Kikumi Matsuoka, Fumie Hashimoto, Hiden ...
    Type: Notes
    Subject area: Biochemistry
    2009 Volume 32 Issue 12 Pages 2053-2056
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Objectives: The purpose of this paper is to elucidate the roles of phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin I2 (PGI2) synthase in pregnancy induced hypertension (PIH). Methods: In placentas from normal pregnant women and pregnant women with severe PIH, the enzyme expression of PLA2, COX-2, and PGI2 synthase was measured using real time reverse transcription-polymerase chain reaction (RT-PCR). Results: The expression of each enzyme was compared between normal (n=12) and PIH (n=12) groups. The expression levels of COX-2 and PGI2 synthase during PIH pregnancy were significantly decreased to about 51% and 68%, respectively, of their values in normal pregnancy. However, the expression of PLA2 was hardly changed by PIH. Conclusions: The decreases in COX-2 and PGI2 synthase expression in severe PIH placentas may be causal factors in the disruption of the PGI2–thromboxane A2 (TXA2) balance in favor of TXA2. The decrease in COX-2 was more marked than that of PGI2 synthase.
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Molecular and Cell Biology
Regular Articles
  • Ami Oguro, Koichi Sakamoto, Sachiko Suzuki, Susumu Imaoka
    Type: Regular Articles
    2009 Volume 32 Issue 12 Pages 1962-1967
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Soluble epoxide hydrolase (sEH) is an important pharmacological target because it metabolizes potent bioactive substrates, epoxyeicosatrienoinc acids (EETs) and other lipid epoxide. EETs have a variety of biological functions including angiogenesis and cancer metastasis. However, the regulation and physiological function of sEH is not well understood. In this study, we found that hypoxia significantly suppressed the expression of sEH in mouse liver and a human hepatoma cell line, Hep3B. Hypoxia promotes the proliferation of vascular endothelial cells or carcinoma cells. Knockdown of sEH in Hep3B cells induced vascular endothelial growth factor (VEGF) mRNA and cell growth, both of which were suppressed by overexpression of sEH. sEH has phosphatase activity as well as epoxide hydrolase (EH) activity. We prepared mutant clones which lacking EH or phosphatase activity using the amino acid change Asp335Ser or Asp9Ala, respectively. The effects of WT sEH on cell growth were lost by mutation of either the EH domain or phosphatase domain. However, mutation of the phosphatase domain but not EH domain did not influence the expression of VEGF. These results suggest that sEH plays an important role in the physiology of cells including proliferation and that the epoxide hydrolase and phosphatase domains of sEH have different biological functions.
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  • Paranee Meetam, Chutima Srimaroeng, Sunhapas Soodvilai, Varanuj Chatsu ...
    Type: Regular Articles
    Subject area: Molecular and Cell Biology
    2009 Volume 32 Issue 12 Pages 1968-1972
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    This study examined the effect of estrogen (17β-estradiol) on renal handling of organic cation, tetraethylammonium (TEA), both in vivo and in vitro. Clearance of TEA in ovariectomized (OVX) mice was increased by 38% above intact animals, which was able to be returned to control level by estrogen supplementation. The mechanism of this effect was examined in isolated mouse renal proximal tubules (mRPT), showing that [3H]-TEA uptake was higher in OVX mice than control, and estrogen supplementation returned uptake to normal level. Kinetics analysis of [3H]-TEA uptake indicated an increase in numbers of organic cation transporters in OVX mice but no change in substrate affinity. However, mRNA levels determined by quantitative real time polymerase chain reaction of the relevant transporters at basolateral (organic cation transporter (OCT)1, OCT2 and OCT3) and apical (organic cation/carnitine transporter (OCTN)1, OCTN2 and multidrug and toxin extrusion (MATE)1) membranes of OVX mice were not significantly changed, with only MATE2 mRNA of OVX mice being significantly decreased. The realization that estrogen status affects renal clearance of organic cations will be of importance when assessing the susceptibility of an individual to drug-induced toxicity.
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  • Yoko Nemoto-Sasaki, Ken-ichi Kasai
    Type: Regular Articles
    Subject area: Molecular and Cell Biology
    2009 Volume 32 Issue 12 Pages 1973-1977
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Galectins are a family of β-galactoside-binding lectins. They are involved in the regulation of a variety of biological phenomena in mammals. However, little is known about their roles in invertebrates. Caenorhabditis elegans is a well-characterized model organism whose complete genome has been sequenced. C. elegans is now being studied extensively in various fields of medical sciences. In this study, we examined the phenotypes of a mutant strain of C. elegans (tm1262) lacking lec-10, a galectin-encoding gene. We observed no difference in the rates of embryonic lethality and larval arrest/slow growth between this mutant strain and the wild-type strain. No apparent morphological defect was observed in the lec-10-deletion mutant (tm1262). Moreover, the life-spans of this mutant and the wild-type strain were equivalent. However, this mutant showed significantly greater susceptibility to paraquat and hydrogen peroxide than the wild type did. The lec-10-deletion mutants (tm1262) were as susceptible as the daf-16-deletion mutants (mu86) to paraquat and hydrogen peroxide. These results suggest that the deletion of lec-10 does not have a notable effect on the worm's survival under laboratory conditions. However, this study indicates that lec-10 does confer some protection against oxidative stress.
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Notes
Microbiology
Notes
  • Yun-Ju Kwon, Yi Fang, Guang-Hua Xu, Won-Gon Kim
    Type: Notes
    Subject area: Microbiology
    2009 Volume 32 Issue 12 Pages 2061-2064
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In this study, we determined that a fungal metabolite from Sporothrix sp. FN611 potently inhibited the enoyl-ACP reductase (FabI) of Staphylococcus aureus. Its structure identified the metabolite as aquastatin A by the MS and NMR data. Aquastatin A inhibited S. aureus FabI with an IC50 of 3.2 μM. It also prevented the growth of S. aureus and methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration of 16—32μg/ml. Aquastatin A also exerted an inhibitory effect against the FabK isoform, an enoyl-ACP reductase of Streptococcus pneumoniae, with an IC50 of 9.2 μM. The degalactosylation of aquastatin A did not affect the FabI and FabK-inhibitory or antibacterial activities, thereby suggesting that the sugar moiety within its molecular structure was not involved in these activities. The inhibitory effects of aquastatin A and its degalactosylated derivative on enoyl-ACP reductases and bacterial viability are reported for the first time in this study; these effects point to the potential that aquastatin A may be developed into a new broad-spectrum antibacterial and anti-MRSA agent.
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Pharmacology
Regular Articles
  • Eva Brcakova, Leos Fuksa, Jolana Cermanova, Gabriela Kolouchova, Milos ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 1978-1985
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Methotrexate (MTX), an important anticancer and immunosuppressive agent, has been suggested for the treatment of primary biliary cirrhosis. However, the drug's pharmacodynamics and toxicity is dependent on its concentrations in plasma which in turn are directly related to MTX's elimination in the liver and kidney. Therefore, the aim of this study was to evaluate changes in MTX biliary and renal excretion during either intrahepatic or obstructive cholestasis in rats. The steady state pharmacokinetic parameters of MTX were evaluated in rats one (BDO1) or seven (BDO7) days after bile duct obstruction (BDO) or 18 h after administration of lipopolysaccharide (LPS). In comparison to the respective control groups, biliary and total clearances of MTX were decreased to 12% and 49% in the BDO1 group, to 5% and 56% in the BDO7 animals, and to 42% and 43% in the LPS group, respectively. Renal clearance of MTX was unchanged in BDO groups, but decreased to 23% of controls in the LPS animals. The serum biochemistry and expression of main hepatic MTX transporters (Mrp2, Mrp3, Mrp4, Bcrp, Oatp1a1, Oatp1a4 and Oatp1b2) confirmed the pathological cholestatic changes in the liver and partly elucidated the cause of changes in MTX pharmacokinetic parameters. In conclusion, this study is the first describing marked alteration of MTX hepatic and renal elimination induced by cholestasis in rats. Moreover, the reported changes in MTX pharmacokinetics and respective transporter expression suggest important mechanistic differences between the two widely used cholestatic models.
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  • Xiao-ping Zhou, Mu-xin Zhang, Wei Sun, Xiao-hong Yang, Guang-shu Wang, ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 1986-1990
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    A series of 4,5-diaryloxazole analogs were designed and the interaction between oxaprozin and cyclooxygenase-2 studied by the docking method to improve the biological activity and reduce the gastrointestinal side effects of oxaprozin. Finally, 3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid (NC-2142), the best candidate, was selected for synthesis and bioassay based on the screening result. NC-2142 could lower the tumefaction rates of back metatarsus in rats, as well as reduce the writhing times in mice. NC-2142 produced fewer gastric lesions than oxaprozin. After the aminosulfonyl group was introduced into the benzene ring of oxaprozin, its analgesic and anti-inflammatory activities remained unchanged, and it reduced the number of gastric lesions. This provided a feasible method for further structure modification and optimization of oxaprozin.
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  • Tsuyoshi Tsujimura, Jun Nagamine, Eiji Sugaru, Michiko Ono-Kishino, Te ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 1991-1996
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    The number of patients with chronic kidney disease (CKD) has continuously grown worldwide. Treatment with antihypertensive agents reduces the rate of progression of CKD, however, there is still a large unmet need to develop strategies for the treatment of CKD. Although we have previously reported that the antifibrotic agent, SMP-534 inhibits the progression of CKD, it is unknown whether combination therapy with SMP-534 and antihypertensive agent shows additive effects on CKD. In present study, we examined whether combination therapy with SMP-534 and the antihypertensive agent, lisinopril is more effective than single therapy with SMP-534 or lisinopril on five-sixths nephrectomized (5/6Nx) rat model. Combination therapy with SMP-534 (50 mg/kg) and lisinopril (5 mg/kg) significantly decreased urinary albumin excretion, blood urea nitrogen (BUN) and serum creatinine and increased creatinine clearance in 5/6Nx rats. On the other hands, single treatment with SMP-534 or lisinopril did not improve renal function at this dose. In addition, combination therapy with SMP-534 and lisinopril significantly decreased extracellular matrix (ECM) accumulation in renal glomeruli and tubulointerstitial injury. These data suggest that combination therapy with an antifibrotic agent and an antihypertensive agent may offer a new therapeutic option for suppressing the progression of CKD.
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  • Megumi Sugitani, Rieko Abe, Nobutomo Ikarashi, Kiyomi Ito, Hideaki Mur ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 1997-2001
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Recently, a new compound IT-M-07000 was designed as a prodrug of tamibarotene, one of the therapeutic agents for acute promyelocytic leukemia. In the present study, IT-M-07000 was administered to mice to investigate whether it is actually metabolized to tamibarotene. Its metabolic pathway and the utility as a tamibarotene prodrug were also evaluated. After oral administration of IT-M-07000, IT-M-07000, tamibarotene and two compounds that were supposed to be metabolic intermediates in a β-oxidation pathway of IT-M-07000 to tamibarotene were detected in mouse plasma. It was thus shown that IT-M-07000 is probably β-oxidized to tamibarotene in mice. Comparison of tamibarotene concentration profiles after oral administration of IT-M-07000 or tamibarotene showed that the plasma tamibarotene concentration increased slower and was retained stable, and the area under the plasma concentration–time curve (AUC) of tamibarotene was larger in mice administered IT-M-07000 than tamibarotene. These results indicate that IT-M-07000 is possibly useful as a prodrug of tamibarotene.
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  • Upal Roy, Geetika Chakravarty, Kerstin Honer Zu Bentrup, Debasis Monda ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 2002-2009
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    The ATP binding cassette (ABC)-transporters are energy dependent efflux pumps which regulate the pharmacokinetics of both anti-cancer chemotherapeutic agents, e.g. taxol, and of human immunodeficiency virus-1 (HIV-1) protease inhibitors (HPIs), e.g. saquinavir. Increased expression of several ABC-transporters, especially P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), are observed in multidrug resistant (MDR) tumor cells and on HIV-1 infected lymphocytes. In addition, due to their apical expression on vascular endothelial barriers, both P-gp and MRP2 are of crucial importance towards dictating drug access into sequestered tissues. However, although a number of P-gp inhibitors are currently in clinical trials, possible inhibitors of MRP2 are not being thoroughly investigated. The experimental leukotriene receptor antagonist (LTRA), MK-571 is known to be a potent inhibitor of MRP transporters. Using the MRP2 over-expressing Madin-Darby canine kidney cell line, MDCKII-MRP2, we evaluated whether the clinically approved LTRAs, e.g. montelukast (Singulair™) and zafirlukast (Accolate™), can similarly suppress MRP2-mediated efflux. We compared the efficacy of increasing concentrations (20—100 μM) of MK-571, montelukast, and zafirlukast, in suppressing the efflux of calcein-AM, a fluorescent MRP substrate, and the radiolabeled [3H-] drugs, taxol and saquinavir. Montelukast was the most potent inhibitor (p<0.01) of MRP2-mediated efflux of all three substrates. Montelukast also increased (p<0.01) the duration of intracellular retention of both taxol and saquinavir. More than 50% of the drugs were retained in cells even after 90 min post removal of montelukast from the medium. Our findings implicate that montelukast, a relatively safe anti-asthmatic agent, may be used as an adjunct therapy to suppress the efflux of taxol and saquinavir from MRP2 overexpressing cells.
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  • Keiichi Ito, Kazuya Kinoshita, Naotoshi Yamamura, Atsuyuki Tomizawa, F ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 2010-2017
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    In the present study, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) on the intragastric acidity of cynomolgus monkeys. The study was performed in a crossover manner with five male animals. CS-526 was administered orally or intravenously at doses of 3.0, 10 and 30 mg/kg, or 0.3, 1.0 and 3.0 mg/kg, respectively. The time period in which the intragastric pH was 4.0 or more (TimepH≥4.0) and the median pH were calculated for 24 h after the administration. The intragastric pH was elevated after CS-526 treatment. The TimepH≥4.0 was increased in a dose-dependent manner (p=0.0292) in the oral administration, and the median pH was also increased in a dose-dependent fashion (p=0.0491) in the intravenous administration. The plasma concentration of CS-526 and its metabolite R-130185 was increased after oral and intravenous administration of CS-526, except for one animal which did not show any detectable amount of R-130185 after intravenous administration at the lowest dose. The area under the time–concentration curve of the active component was increased in the dose proportional manner after oral and intravenous administration. The absolute bioavailability of the active component was estimated to be approximately 1%. Correlation between the pharmacodynamic parameters and the pharmacokinetic parameters was observed in oral (p=0.0029—0.0745), but not in intravenous administration (p=0.0558—0.2789). In conclusion, oral and intravenous administration of CS-526 showed inhibition on gastric acidity in cynomolgus monkeys using intragastric pH-metry and some pharmacokinetic and pharmacodynamic parameters were well correlated.
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  • Toshiyuki Satoh, Yuka Watanabe, Nobutomo Ikarashi, Kiyomi Ito, Kiyoshi ...
    Type: Regular Articles
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 2018-2021
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    The Kampo medicines are more and more often used in recent years, usually together with the western drugs. The need for the investigation of drug interactions between Kampo medicines and western drugs are, therefore, widely recognized. Among the various possible causes for the drug–drug interactions, those related to pharmacokinetics such as drug metabolism and transport are regarded as most frequent and clinically important. In the present study, the effects of Kampo medicines on the P-glycoprotein (P-gp), one of the major drug transporters, were investigated in in vitro studies using human P-gp membranes. The P-gp activity in the presence and absence of commonly used 50 Kampo medicines was evaluated by the ATPase assay detecting the inorganic phosphate produced by the ATP hydrolysis. The ATPase activity was inhibited by most of the Kampo medicines studied, indicating the possibility of their inhibiting the P-gp. The degree of inhibition in the presence of verapamil, a P-gp substrate, showed a significant correlation with that in the absence of verapamil. Furthermore, the inhibitory effect of the Kampo medicines on the ATPase activity correlated with their licorice root (kanzo) content, suggesting the contribution of licorice root in the P-gp inhibition. Because licorice root is one of the most common ingredients in the Kampo medicines and is also often used in the food as a sweetener, it might be necessary to pay attention on the interaction between the licorice root-containing drug/food and the number of drugs transported by P-gp.
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Notes
  • Kazunori Sano, Emi Koushi, Keiichi Irie, Sei Higuchi, Ryota Tsuchihash ...
    Type: Notes
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 2065-2067
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    The present study was designed to determine the effect of delta(9)-tetrahydrocannabinol (THC) on susceptibility to stress. We reported that THC significantly prolonged the immobility time during the forced swim-stress. The selective cannabinoid CB1 receptor antagonist O-2050 significantly reduced the enhancement of immobility by THC. We investigated the effect of THC on levels of stress hormone corticosterone under non-stress and forced swim-stress conditions. THC did not affect plasma corticosterone levels under non-stress conditions. However, THC, together with forced swim-stress, significantly increased plasma corticosterone levels. This effect was inhibited by O-2050. This evidence suggests that THC, under stressful conditions, enhances the susceptibility of the hypothalamus-pituitary-adrenal-axis to stress via the CB1 receptor, thereby increasing the risk of depression.
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  • Masahiro Noguchi, Asami Mori, Kenji Sakamoto, Tsutomu Nakahara, Kunio ...
    Type: Notes
    Subject area: Pharmacology
    2009 Volume 32 Issue 12 Pages 2068-2071
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    The aim of this study was to investigate the effects of intravenous administration of flunarizine on the diameter of retinal blood vessels and blood pressure in anesthetized rats and to compare the effects of this antagonist with those of nicardipine and nifedipine. Retinal vascular images were captured with a fundus camera system for small animals and the diameter of retinal blood vessels contained in the images was measured using image-processing softwares on a personal computer. Blood pressure was continuously measured. Flunarizine [1—30 μg/kg, intravenously (i.v.)] dose-dependently increased the diameter of retinal blood vessels without significantly changing systemic blood pressure. Nicardipine (1—30 μg/kg, i.v.) increased the retinal blood vessel diameter but decreased blood pressure in a dose-dependent manner. Nifedipine (10—100 μg/kg, i.v.) failed to dilate the retinal blood vessels, although it produced comparable depressor responses as those to nicardipine. These results suggest that flunarizine selectively acts on the retinal blood vessels rather than on the peripheral resistance vessels. Flunarizine could therefore be considered as a candidate for therapeutic drugs to treat diseases associated with disorders of retinal circulation without severe cardiovascular side-effects.
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Medicinal Chemistry
Notes
  • Jiepeng Chen, Xuelian Qiu, Ronghua Wang, Lili Duan, Shouxian Chen, Jia ...
    Type: Notes
    Subject area: Medicinal Chemistry
    2009 Volume 32 Issue 12 Pages 2072-2074
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Cladosporol was isolated from the fermentation broth of Alternaria alternata var. monosporus obtained from the inner bark of the yew tree and mutated for many generations. We investigated the antitumor effects of cladosporol in vitro and in vivo. The growth-inhibitory effects of cladosporol in vitro against six human cancer cell lines were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The results showed that cladosporol selectively killed cancer cells and had a significant inhibitory effect on the human gastric carcinoma cell line MGC-803 in a concentration- and time-dependent manner. In vivo, cladosporol also showed antitumor activity in nude mice bearing MGC-803 gastric cancer xenografts. These findings suggest that cladosporol has potentially useful growth inhibitory effects on human gastric carcinoma cell lines.
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  • Feng Li, Suresh Awale, Yasuhiro Tezuka, Shigetoshi Kadota
    Type: Notes
    Subject area: Medicinal Chemistry
    2009 Volume 32 Issue 12 Pages 2075-2078
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Thirteen cycloartane-type tritepenes (1—13) and four prenylated flavanones (14—17) isolated from propolis collected in Myanmar, were evaluated for their cytotoxic activity against a panel of six different cancer cell lines; three murine cancer cell lines (colon 26-L5 carcinoma, B16-BL6 melanoma, and Lewis lung carcinoma) and three human cancer cell lines (lung A549 adenocarcinoma, cervix HeLa adenocarcinoma and HT-1080 fibrosarcoma). Among them, a cycloartane-type triterpene, 3α,27-dihydroxycycloart-24E-en-26-oic acid (3), showed the most potent cytotoxicity against B16-BL6 cells with an IC50 value of 5.91 μM, comparable to those of positive controls, doxorubicin (IC50, 5.66 μM) and 5-fluorouracil (IC50, 4.88 μM). In addition, (2S)-5,7-dihydroxy-4′-methoxy-8,3′-diprenylflavanone (14) exhibited strong cytotoxicity against all the tested cancer cell lines with the IC50 values ranging from 14.0 to 26.4 μM. Based on the observed results, the structure–activity relationships are discussed.
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Pharmacognosy
Regular Articles
  • Satomi Koya-Miyata, Norie Arai, Akiko Mizote, Yoshifumi Taniguchi, Shi ...
    Type: Regular Articles
    Subject area: Pharmacognosy
    2009 Volume 32 Issue 12 Pages 2022-2028
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    We examined the hypolipidemic effect of propolis in a mouse obesity model induced by a high fat-diet. C57BL/6N mice were fed a high-fat diet ad libitum and given propolis extract intragastrically at 0 mg/kg (control), 5 mg/kg or 50 mg/kg twice daily for 10 d. Compared with mice in the control group, mice in the propolis extract-administrated groups displayed a reduction in all of the following parameters: body weight gain, weight of visceral adipose tissue, liver and serum triglycerides, cholesterol, and non-esterified fatty acids. Real-time polymerase chain reaction analysis of the liver showed down-regulation of mRNA expression associated with fatty acid biosynthesis, including fatty acid synthase, acetyl-CoA carboxylase α, and sterol regulatory element binding protein in the propolis-administrated mice. Subsequently, obese C57BL/6N mice that had been administered a high-fat diet were given propolis extract at 0 mg/kg (control), 2.5 mg/kg or 25 mg/kg for 4 weeks. The propolis extract treated mice showed a decrease in weight gain, a reduction of serum non-esterified fatty acids, and lipid accumulation in the liver. These results suggest that propolis extract prevented and mitigated high-fat diet-induced hyperlipidemia by down-regulating the expression of genes associated with lipid metabolism.
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  • Kwan Hee Park, Min Park, Sun Eun Choi, Mi Sook Jeong, Joo Hee Kwon, My ...
    Type: Regular Articles
    Subject area: Pharmacognosy
    2009 Volume 32 Issue 12 Pages 2029-2033
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Activity guided fractionation of Aconitum koreanum root extract (RAK), a traditional medicine in Korea, afforded four caffeoyl derivatives, caffeic acid (1), 4,5-dicaffeoylquinic acid (2), 3,5-dicaffeoylquinic acid (3) and 3,5-dicaffeoylquinic acid methyl ester (4). In order to evaluate the anti-oxidative and anti-inflammatory effects of these compounds, their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and abilities to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 were examined. And the protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated HaCaT cells were also quantified by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). Compounds (1—4) showed potent DPPH radical scavenging and NO inhibitory activities as compared with positive controls (L-ascorbic acid and N(G)-monomethyl-L-arginine (L-NMMA), respectively). Also, these compounds dose-dependently inhibited the expressions of iNOS and COX-2 as well as their mRNA levels.
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  • Toshiaki Makino, Ryosuke Shimizu, Misaki Kanemaru, Yukio Suzuki, Masam ...
    Type: Regular Articles
    Subject area: Pharmacognosy
    2009 Volume 32 Issue 12 Pages 2034-2040
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Quercetin, a flavonol contained in various vegetables and herbal medicines, has various biological activities including anti-cancer, anti-allergic and anti-oxidative activities. However, low oral bioavailability of quercetin due to insolubility in water has limited its use as a food additive or dietary supplement. Since the water solubility is enhanced by glycosyl conjugation, in the present study, we evaluated the bioavailability of several quercetin glycosides with different sugar moieties in rats. Quercetin, quercetin-3-O-rutinoside (rutin), and quercetin-3-O-glucoside (isoquercitrin, IQC) in suspension, and quercetin-3-O-maltoside (Q3M), quercetin-3-O-gentiobioside (Q3G), α-monoglucosyl rutin (αMR), α-oligoglucosyl rutin (αOR), and enzymatically modified isoquercitrin (α-oligoglucosyl isoquercitrin, EMIQ) dissolved in water, were orally administered to rats under anesthesia. Bioavailability (F value) was calculated from the concentrations of total quercetin in plasma from 0 to 12 h after the administration. F value of quercetin was 2.0%, and those of IQC, Q3M and EMIQ were 12%, 30%, and 35%, respectively. Although Q3G, αMR and αOR have high water solubility, their F values were low (3.0%, 4.1%, 1.8%, respectively). In the in vitro study, the homogenate of rat intestinal epithelium rapidly hydrolyzed IQC, Q3M and EMIQ to quercetin, and αMR and αOR to rutin. However, it could not hydrolyze Q3G or rutin to quercetin. Elongation of α-linkage of glucose moiety in IQC enhances the bioavailability of quercetin, and intestinal epithelial enzymes such as lactase-phrolizin hydrolase or mucosal maltase-glucoamylase would play important roles in the hydrolysis and absorption of these flavonol glycosides.
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Biopharmacy
Regular Articles
  • Daisuke Kadowaki, Makoto Anraku, Yuka Tasaki, Kazuaki Taguchi, Kazuki ...
    Type: Regular Articles
    Subject area: Biopharmacy
    2009 Volume 32 Issue 12 Pages 2041-2045
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Angiotensin II type 1 receptor blockers, which inhibit the rennin-angiotensin system, are used in the treatment of hypertension. In addition to their ability to lower blood pressure, these compounds have also been reported to protect organs, such as kidney and heart. Although the mechanisms of these protective effects are not fully understood, it is generally thought that their antioxidant effects likely play a role. The aim of the present study was to characterize the relationship between the antioxidant activity of olmesartan and its pharmacological actions such as renoprotective or blood pressure lowering effects, using 5/6 nephrectomy rats. In 5/6 nephrectomy rats, the potential antioxidant power, the ratio of oxidized to unoxidized albumin, as a marker of protein oxidation in blood, both systolic and diastolic blood pressure, plasma creatinine concentration, and amounts of protein excreted into the urine were significantly higher than the corresponding values for sham operated rats. However, olmesartan significantly suppressed these parameters within 8 weeks after oral administration in 5/6 nephrectomy rats. The oxidized albumin ratio was significantly decreased 4 weeks after the administration of olmesartan and these lower levels were maintained at 8 weeks. Furthermore, olmesartan improved radical scavenging activity of isolated albumin from rat plasma. Interestingly, a good correlation was found between the oxidized albumin ratios and renal function, whereas no correlation was found in the case of blood pressure. Based on those findings, we conclude that the antioxidant properties of olmesartan may be related to its renoprotective action rather than an antihypertensive effect.
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Notes
  • Teruaki Akao, Keisuke Sato, Masato Hanada
    Type: Notes
    Subject area: Biopharmacy
    2009 Volume 32 Issue 12 Pages 2079-2082
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Baicalin (BG) and its aglycone, baicalein (B), are strong antioxidants and have various pharmacological actions and show unique metabolic fates in the rat. The aim of the present study was to evaluate the contribution of multidrug resistance-associated protein 2 (Mrp2, Abcc2) to the disposition of BG after oral administration of B using the Eisai hyperbilirubinemic rat (EHBR, Mrp2-deficient), in comparison with the Sprague-Dawley rat (SD, the wild-type form of EHBR). When B at a dose of 12.1 mg/kg was administered orally to EHBRs, the area under the concentration curve from time 0 to 24 h (AUC0—24 h) and Cmax values of plasma BG, 27.6±3.5 μM·h and 11.4±3.9 μM, respectively, were significantly higher at 5-fold and 8-fold, respectively, than those (AUC0—24 h value of 5.39±1.37 μM·h and Cmax value of 1.51±0.38 μM) in SD rats. In addition, when B at a dose of 1.2 mg/kg was injected into the portal vein of EHBRs, a marked reduction in the biliary excretion of BG (6.59±5.64 nmol) and a marked increase of BG in the systemic circulation (AUC0—120 min of 75.4±34.5 μM·min) were observed, in comparison with those (biliary excretion of 29.7±9.3 nmol and AUC0—120 min value of 2.42±1.44 μM·min) in SD rats. Thus, it was clarified that after oral administration of B, the markedly higher concentration of plasma BG in EHBRs than in SD rats was caused mainly by a drastic reduction in the biliary excretion of BG and marked enhancement of its sinusoidal efflux from the liver.
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Miscellaneous
Regular Articles
  • Yoshitaka Hasegawa, Shuichi Kishimoto, Hirokazu Takahashi, Nobuo Inots ...
    Type: Regular Articles
    Subject area: Miscellaneous
    2009 Volume 32 Issue 12 Pages 2046-2052
    Published: December 01, 2009
    Released: December 01, 2009
    JOURNALS FREE ACCESS
    Hepatic metabolism is altered in some clinical conditions owing to the changes in the expression of metabolic enzymes and transporters. Therefore, we think that investigating the altered expression of metabolic enzymes and transporters is of particular significance to studies on drug disposition in some clinical conditions. We also believe that a simultaneous in vivo investigation of all factors affecting nuclear receptors and regulated genes is important to understand the relationship between nuclear receptors and their target genes. In this study, we induced cholestasis in rats by bile duct ligation (BDL), and investigated the changes in the mRNA expression of metabolic enzymes, transporters, and nuclear receptors and the protein levels of nuclear receptors in the nucleus by reverse transcriptase-polymerase chain reaction and Western blotting. In the liver of the rats subjected to BDL, the mRNA expression levels of cytochrome P450, conjugation enzymes, and transporters were concomitantly altered. The altered mRNA and protein levels of constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα) in the nucleus were consistent with the changes in the plasma concentrations of total and conjugated bilirubin and fatty acid, respectively. The mRNA expression of CAR and PPARα was linearly associated with the expression of the corresponding target genes. These results suggested that the increase in the levels of bilirubin and fatty acid on the BDL groups altered the mRNA and protein levels of CAR and PPARα, respectively in the nucleus, and this in turn altered the mRNA expression of metabolic enzymes and transporters as a hepatoprotective mechanism.
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