Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
36 巻 , 6 号
選択された号の論文の27件中1~27を表示しています
Current Topics
  • Yasuyuki Sadzuka
    2013 年 36 巻 6 号 p. 877
    発行日: 2013/06/01
    公開日: 2013/06/01
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  • Kouichi Shiraishi, Masayuki Yokoyama
    2013 年 36 巻 6 号 p. 878-882
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Polymeric micelles are assemblies of synthetic polymers and have been studied and developed as drug carriers for targeting. Polymeric micelles are composed of the inner core and the outer shell, and typically form from AB-type block copolymers in which two polymer blocks are connected in a tandem form. Polyethyleneglycol (PEG) has been most commonly used as one polymer block composing the outer shell. This review describes the reasons that PEG is used for the outer shell of the polymeric micelle carrier systems. On the other hand, accelerated blood clearance (ABC) phenomenon is a well-known immunological response of PEG-coated liposomes. Since the ABC phenomenon greatly influences targeting functions of carrier systems, elaborative studies on polymeric micelles’ ABC phenomenon have been done, and revealed different behaviors of the polymeric micelle systems from those of PEG-coated liposomes. These studies indicate that polymeric micelle systems are highly feasible tools for contrast agent targeting as well as theranostics.
  • Hiroshi Ishihara
    2013 年 36 巻 6 号 p. 883-888
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Polyethyleneglycol (PEG) compounds have a large hydrogen bonding capability and possess various functions that depend on the length of the chain and conformational diversity. Modification of a drug with PEG is a well-known technology for improving the physicochemical properties and biological responses of a drug. There are many reports about the modification of small molecules with PEG, however, there are no modified small molecule products currently on the market. Several protein products for medical use are commercially available. In this review, the effects of modification with PEG on biopharmaceuticals are described through the comparison of two interferon-α products modified with PEG, one with 12 kDa linear PEG and the other 40 kDa branched PEG. There is one original drug delivery system product, Doxil®/Caelyx®, on the market in which liposomes modified with PEG and encapsulating doxorubicin are stabilized sterically and invisible to the reticuloendothelial system. The benefits of modification with PEG are described here with examples of modified products on the market and used in clinical trials.
  • Tatsuhiro Ishida, Hiroshi Kiwada
    2013 年 36 巻 6 号 p. 889-891
    発行日: 2013/06/01
    公開日: 2013/06/01
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    In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.
  • Hiroto Hatakeyama, Hidetaka Akita, Hideyoshi Harashima
    2013 年 36 巻 6 号 p. 892-899
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the “PEG dilemma” must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.
  • Ikumi Sugiyama, Yasuyuki Sadzuka
    2013 年 36 巻 6 号 p. 900-906
    発行日: 2013/06/01
    公開日: 2013/06/01
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    When liposomes, as a superior drug carrier, are injected intravenously, active liposomes as medicines require polyethyleneglycol (PEG) as a modification tool around the liposomal membrane. PEG modification of a liposome forms a fixed aqueous layer, and the trapping by cells of the reticuloendothelial system (RES) is avoided. Hence, PEG-modified liposomes have long circulation in the bloodstream, and passive targeting to tumors has been achieved by PEG modification. We have been studying the passive targeting by liposomes with the expectation of more usefulness. It was proved a correlation between the PEG molecular weight of PEG-modified liposomes and blood circulation time and antitumor effect, too. Liposomes modified by PEG2000 were useful for uptake into tumor cells. We thought that the re-uptake in the liposomal membrane also increased accumulation. Moreover, it was proved that mixing two different PEGs to modify the liposome surface gives a bigger fixed aqueous layer thickness (FALT) around the liposome, giving the liposome strong antitumor activity. Then, we designed a novel PEG-lipid, 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-PEG (different double arms PEG; DDA-PEG), which had two different PEGs (2000 and 500) in one molecule. One of the innovative characteristics of DDA-PEG-modified liposome (DDAL) is that it heightens the contact ability with tumor cells. DDAL may be an effective DDS carrier for solving various PEG dilemmas. It was observed that passive targeting by PEG-modified liposomes had different characteristics by changing PEG length, anchor type or those combination. Thus, it should be applied to liposomes suitable for various diseases.
Regular Articles
  • Shinji Kobuchi, Yukako Ito, Kae Okada, Kazuki Imoto, Shota Kuwano, Kan ...
    2013 年 36 巻 6 号 p. 907-916
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/04/11
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    We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r2=0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.
  • Peng-Cheng Fan, Hui-Ping Ma, Lin-lin Jing, Lin Li, Zheng-Ping Jia
    2013 年 36 巻 6 号 p. 917-924
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/03/12
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    Acute mountain sickness is caused by sub-acute hypoxia in healthy individuals going rapidly to altitude. Both tissue hypoxia in vitro and whole-body hypoxia in vivo have been found to promote the release of reactive oxygen species. Nitronyl nitroxide can trap free radicals such as ·NO or ·OH, and may therefore be efficient protective agents. This study assessed the ability of nitronyl nitroxide to against acute mountain sickness as a free radical scavenger in acute high-altitude hypoxia mice model. Normobaric hypoxia and hypobaric hypoxia model were used to estimate the protect effects of nitronyl nitroxide against acute mountain sickness. Low pressure oxygen compartment system was used to stimulate high-altitude hypobaric hypoxia environment. Mice in nitronyl nitroxide groups survived longer than acetazolamide group in normobaric hypoxia test. Hydrogen peroxide (H2O2) and malondialdehyde (MDA) increased in both cerebrum and myocardium in vehicle group. The results indicated more radicals were generated during high-altitude hypobaric hypoxia environment. In therapeutic groups H2O2 and MDA were significantly reduced while the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were similar to normal group. These results demonstrated that nitronyl nitroxide was an efficient tissue radical scavenger and a potential protective agent for acute mountain sickness.
  • Soo-Hyun Park, Yun-Beom Sim, Yu-Jung Kang, Sung-Su Kim, Chea-Ha Kim, S ...
    2013 年 36 巻 6 号 p. 925-930
    発行日: 2013/06/01
    公開日: 2013/06/01
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    In the present study, the antinociceptive profiles of coumarin were examined in ICR mice. Coumarin administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of coumarin maintained at least for 60 min. But, the cumulative response time of nociceptive behaviors induced by a subcutaneous (s.c.) formalin injection, intrathecal (i.t.) substance P (0.7 µg) or glutamate (20 µg) injection was not affected by coumarin. In addition, intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration with coumarin (10–40 µg) attenuated acetic acid-induced writhing response in a dose dependent manner. Intraperitoneal (i.p.) pretreatment with naloxone (an opioid receptor antagonist) attenuated antinociceptive effect induced by coumarin in the writhing test. Furthermore, i.c.v. or i.t. pretreatment with naloxone (5 µg) reversed the decreased acetic acid-induced writhing response. However, methysergide (a 5-HT serotonergic receptor antagonist) or yohimbine (an α2-adrenergic receptor antagonist) did not affect antinociception induced by coumarin in the writhing test. Our results suggest that coumarin exerts a selective antinociceptive property in the acetic acid-induced visceral-derived pain model. Furthermore, the antinociceptive effect of coumarin may be mediated by activation of central opioid receptors, but not serotonergic and adrenergic receptors.
  • Teng Shen, Huinan Xu, Weiyu Weng, Jianfang Zhang
    2013 年 36 巻 6 号 p. 931-937
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/03/19
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    A novel reservoir-type transdermal system of 2,3,5,6-tetramethylpyrazine (TMP) was developed containing eucalyptus oil as a penetration enhancer. The single and multiple-dose pharmacokinetic profiles of TMP administrated by TMP transdermal patch were characterized in healthy volunteers using an in vivo, randomized, open-label, two-way crossover design. 2,3,5,6-Tetramethylpyrazine phosphate (TMPP) oral tablets were chosen as reference. Following single/multiple oral administration of 200/100 mg TMPP tablets, a TMP Cmax of 1284/613.5 ng/mL was observed within 0.75 h. Single/multiple applications of the TMP patch yielded mean Cmax of 309/325 ng/mL at a median Tmax of 5/4 h, with steady state achieved at second application. The mean Cmin of the patch was 131±30.38 ng/mL, contrasting to nearly zero for the tablet. Multiple applications of patch produced an accumulative effect over single application. At steady state 250 mg/20 cm2 TMP patch given daily provided comparable exposure to 100 mg TMPP tablets three times daily (3753.91 versus 3563.67 ng·h/mL). TMP tablets and patch yielded similar steady-state plasma concentrations: Cav (148.48±51.27, 156.41±40.31 ng/mL). The results demonstrated that TMP patch can achieve a therapeutic effect that is comparable to oral administration, exhibited prolonged and sustained plasma levels, fewer drug fluctuations, lower adverse effects, more convenience, and improved patient compliance. In-vitro permeation through human skin demonstrated zero-order kinetics with the flux of 364 µg/cm2/h. The predicted Cav (163.9 ng/mL) was in agreement with the observed Cav (156.4 ng/mL).
  • Xiao-bao Jin, Han-fang Mei, Qiao-hong Pu, Juan Shen, Xue-mei Lu, Fu-ji ...
    2013 年 36 巻 6 号 p. 938-943
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/03/18
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    This study was designed to explore the effects of Musca domestica antimicrobial peptides cecropin on the adhesion and migration of human hepatocellular carcinoma BEL-7402 cells. The adhesive and migratory capacities were determined by adhesion assay and transwell assay, respectively. The changes in microvilli of tumor cells were determined by scanning electron microscopy (SEM). Western blotting and quantitative polymerase chain reaction (qPCR) were carried out to determine the expression levels of proteins related to adhesion and migration, such as matrix metalloproteinase-2 (MMP2), tissue inhibitors of metalloproteinase-2 (TIMP2), and epithelial cadherin (E-cadherin). We found that Musca domestica cecropin inhibited the adhesion and migration of BEL-7402 cells, which also displayed curling microvilli, increased ball structures on cell surface, gradually broken connections between tumor cells, and even disappeared microvilli on some cells. The expression of MMP2 was significantly reduced after cecropin treatment, while the levels of TIMP2 and E-cadherin were significantly increased. These results suggest that Musca domestica cecropin inhibits the adhesion and migration of human hepatocellular carcinoma BEL-7402 cells by destroying the microvilli of tumor cells and changing the expression of MMP2, TIMP2 and E-cadherin.
  • HyeSook Youn, Ji-Cheon Jeong, Young Seok Jeong, Eun-Joo Kim, Soo-Jong ...
    2013 年 36 巻 6 号 p. 944-951
    発行日: 2013/06/01
    公開日: 2013/06/01
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    The herbal flavonoid quercetin inhibits the growth of various cancer cells, but how it affects human cancer cells, particularly lung cancer cells, is unclear. We investigated the anticancer activity of quercetin and the underlying molecular mechanisms in non-small cell lung cancer (NSCLC) cells. Quercetin strongly inhibited cell proliferation, and increased sub-G1 and apoptotic cell populations regardless of p53 status. Quercetin-induced apoptosis was verified by caspase cleavage, Hoechst staining, trypan blue exclusion, and DNA fragmentation assays. Microarray analysis using H460 cells indicated that quercetin increased the expression of genes associated with death receptor signaling tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAILR), caspase-10, interleukin (IL) 1R DNA fragmentation faotor 45 (DFF45), tumor necrosis factor receptor (TNFR) 1, FAS, inhibitor of kappaBalpha (IκBα)) and cell cycle inhibition growth arrest and DNA-damage inducible 45 (GADD45), p21Cip1), but decreased the expression of genes involved in nuclear factor (NF)-kappaB activation (NF-κB, IKKα). Further validation assays confirmed that quercetin inhibited growth by suppressing NF-κB and by increasing the expression of death receptors and cell cycle inhibitors. Taken together, these findings suggest that quercetin may be useful in the prevention and therapy of NSCLC.
  • Takahiro Okuno, Nobuhiro Kashige, Tomomitsu Satho, Keiichi Irie, Yukih ...
    2013 年 36 巻 6 号 p. 952-958
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Lactic acid bacteria (LAB) are used in various fields, including in food and medical supplies. There has been a great deal of research into vaccine development using LAB as carriers due to their “generally recognized as safe” status. Cholera is an infectious disease that causes diarrhea due to cholera toxin (CT) produced by Vibrio cholerae. The pentameric cholera toxin B (CTB) subunit has no toxicity, and is used as an antigen in cholera vaccines and as a delivery molecule in vaccines to various diseases. In this study, we generated recombinant LAB expressing and secreting CTB. Here, we first report that CTB expressed and secreted from LAB bound to GM1 ganglioside. The secreted CTB was purified, and its immunogenicity was determined by intranasal administration into mice. The results of the present study suggested that it may be useful as the basis of a new oral cholera vaccine combining LAB and CTB.
  • Ji Eun Kim, Na Young Kim, Hye Sun Lee, Hae Keum Kil
    2013 年 36 巻 6 号 p. 959-965
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Low-dose bupivacaine can limit the spinal block level with minimal hemodynamic effects and yield a rapid recovery, but sometimes it may not provide adequate anesthesia for surgery. Dexmedetomidine, a selective α2-adrenoreceptor agonist, was shown to be a potent antinociceptive agent when given intrathecally in animals and humans. The purpose of this study was to evaluate the adjuvant effects of intrathecal dexmedetomidine in elderly patients undergoing transurethral prostate surgery with low-dose bupivacaine spinal anesthesia. Fifty-four patients undergoing transurethral prostate surgery were randomized into two groups receiving either dexmedetomidine 3 µg (n=27) or normal saline (n=27) intrathecally with 6 mg of 0.5% hyperbaric bupivacaine. The characteristics of the spinal block and postoperative analgesic effects were evaluated. The peak block level was similar for the two groups. However, the dexmedetomidine group demonstrated a faster onset time to the peak block and longer duration of spinal block than the saline group (p<0.01). The motor block scales at the time of peak sensory block and regression of 2-sensory dermatomes were higher in the dexmedetomidine group than in the saline group (p<0.001). There was less analgesic request and the time to the first analgesic request was longer in the dexmedetomidine group than in the saline group (each 487, 345 min, p<0.05). Dexmedetomidine 3 µg when added to intrathecal bupivacaine 6 mg produced fast onset and a prolonged duration of sensory block and postoperative analgesia in elderly patients for transurethral surgery. However, recovery of motor block could be delayed in dexmedetomidine-added patients.
  • Daisuke Inoue, Tomoyuki Furubayashi, Ken-ichi Ogawara, Toshikiro Kimur ...
    2013 年 36 巻 6 号 p. 966-973
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Mucociliary clearance (MC) is an important factor in determining nasal drug absorption and the ciliary beat of ciliated epithelial cells of the nasal mucosa is the driving force of MC. However, the relationship between MC and ciliary beat frequency (CBF) is still ambiguous. The purpose of this study was to establish an evaluation method of CBF as an index of mucociliary function and examine the relationship between MC and CBF. A sequence of images of ciliary beating of an excised rat nasal septum was captured using a high-speed digital video camera. CBF (beats per second, Hz) was determined from periodic changes in the contrast value of a specific location in a sequence of images. CBF under control conditions was 8.49±0.38 Hz, which is similar to values reported for cultured human nasal epithelial cells and rat tracheal cells. β-Adrenergic and cholinergic antagonists decreased CBF, while β-adrenergic agonists and acetylcholine increased CBF. These results were similar with those observed for MC in our previous study. It was found that CBFs were significantly and linearly correlated with MC, indicating that MC is directly regulated by CBF and that this evaluation system allows the quantitative determination of nasal mucociliary function.
  • Takako Yoshino Furukawa, Hiroe Nakayama, Aya Kikuchi, Katsunori Imazum ...
    2013 年 36 巻 6 号 p. 974-979
    発行日: 2013/06/01
    公開日: 2013/06/01
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    The antiemetic properties of a novel neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied in dog models of cisplatin- and apomorphine-induced emesis. Intravenously administered FK886 (0.32–1 mg/kg) significantly inhibited cisplatin-induced acute emesis during the 5-h observation period. Nearly complete inhibition was observed at 1 mg/kg. At an equivalent dose range, orally administered FK886 also significantly inhibited emesis, indicating good oral absorption. Similarly, FK886 inhibited apomorphine-induced emetic responses effectively following both intravenous and oral administration. The effects were long lasting, with 1.6 mg/kg of FK886 completely blocking apomorphine-induced retching and vomiting after a 12-h pretreatment period. Furthermore, FK886 showed rapid onset of antiemetic activity after oral administration. At doses of 0.32 mg/kg or more, a pretreatment time of 0.5 h was sufficient for complete inhibition of apomorphine-induced emetic responses. This fast onset after oral administration was supported by pharmacokinetic data, which demonstrated plasma levels of FK886 after oral administration reached levels similar to those 30 min after intravenous administration. These results suggest that FK886 has excellent antiemetic properties in dogs, and that its rapid-onset and long-lasting properties might make it a promising antiemetic agent.
  • Ning Zhang, Wei Chen, Xinbo Zhou, Xiaolin Zhou, Xinni Xie, Aimin Meng, ...
    2013 年 36 巻 6 号 p. 980-987
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/04/06
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    Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPARγ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.
  • Xiaobing Liu, Jianmin Gu, Yuqi Fan, Huihua Shi, Mier Jiang
    2013 年 36 巻 6 号 p. 988-994
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/03/30
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    Baicalin is a bioactive ingredient from the herb and has possessed various pharmacological actions. The present study was performed to evaluate the cardioprotective potential of baicalin against myocardial infarction and explore the potential mechanism. Baicalin was intraperitoneally injected into the rats by the doses of 50, 100 and 200 mg/kg, respectively, once a day for 7 d and, 30 min after the last administration, the left coronary artery was ligated. Infarct size was measured to analyze the myocardial damage. Myocardial specific enzymes, including creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) were determined with the colorimetric method. Evidence for myocardial apoptosis was detected by caspase-3 activity measurement and Western blot analysis. We also examined the protein levels of three major subgroups of mitogen-activated protein kinases (MAPKs), namely, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 by immuoblotting. Our results indicated that baicalin significantly reduced the infarct size and myocardial enzymes (CK, CK-MB, LDH and cTnT). Administration of baicalin also suppressed the activity and protein expression of caspase-3. Moreover, the protein level of phosphorylated ERK (p-ERK) was found to be evidently augmented while the phosphorylated JNK (p-JNK) and phosphorylated p38 (p-p38) were strikingly diminished in infarcted rats with baicalin treatment. These findings suggest that the baicalin’s cardioprotection associates with mediation of MAPK cascades in acute myocardial infarction of rats.
  • Yukinobu Kodama, Satoe Harauchi, Saki Kawanabe, Nobuhiro Ichikawa, Hir ...
    2013 年 36 巻 6 号 p. 995-1001
    発行日: 2013/06/01
    公開日: 2013/06/01
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    We developed binary and ternary complexes based on polymers and liposomes for safe and effective delivery of small interfering RNA (siRNA). Anti-luciferase siRNA was used as a model of nucleic acid medicine. The binary complexes of siRNA were prepared with cationic polymers and cationic liposomes such as polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly-l-arginine (PLA), trimethyl[2,3-(dioleoxy)-propyl]ammonium chloride (DOTMA), and cholesteryl 3β-N-(dimetylaminnoethyl)carbamate hydrochloride (DC-Chol). The ternary complexes were constructed by the addition of γ-polyglutamic acid (γ-PGA) to the binary complexes. The complexes were approximately 54–153 nm in particle size. The binary complexes showed a cationic surface charge although an anionic surface charge was observed in the ternary complexes. The polymer-based complexes did not show a silencing effect in the mouse colon carcinoma cell line expressing luciferase regularly (Colon26/Luc cells). The binary complexes based on liposomes and their ternary complexes coated by γ-PGA showed a significant silencing effect. The binary complexes showed significant cytotoxicity although the ternary complexes coated by γ-PGA did not show significant cytotoxicity. The ternary complexes coated by γ-PGA suppressed luciferase activity in the tumor after their direct injection into the tumors of mice bearing Colon26/Luc cells. Thus, we have newly identified safe and efficient ternary complexes of siRNA for clinical use.
  • Sun Young Yin, Hyoung Jin Kim, Hong-Jin Kim
    2013 年 36 巻 6 号 p. 1002-1007
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Total extracts of ginseng (the root of Panax ginseng C. A. Meyer) and saponin and polysaccharide fractions have been the main products used to investigate novel effects of ginseng over the last five decades. However, the differences if any between the pharmacological effects of total extract and saponin and polysaccharide fractions are largely unknown. In this study, we compared their effects on influenza A virus infection. Mice received total extract of Korean red ginseng (RG), and polysaccharide and saponin fractions of Korean RG, orally for 14 d prior to influenza A virus infection. Seventy eight percent of mice infected with 2× the 50% lethal dose (LD50) of virus survived when administered the polysaccharide fraction, compared to 67%, 56% and 17% when administered total extract, saponin fraction and phosphate-buffered saline (PBS), respectively. Moreover, body weight loss in mice given the polysaccharide fraction was significantly reduced while there was mild reduction in body weight loss in that receiving saponin fraction or total extract when mice were infected with 0.2× or 0.5×LD50 of virus. We also confirmed that the polysaccharide fraction was most effective in reducing the accumulation of tumor necrosis factor alpha (TNF-α)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (tipDCs) in the mouse lungs. Our results indicate that the polysaccharides of RG have a pronounced beneficial effect on the symptoms of influenza virus infection.
  • Wen-zhi Guo, Yanwen Wang, Eri Umeda, Isamu Shiina, Shingo Dan, Takao Y ...
    2013 年 36 巻 6 号 p. 1008-1016
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/04/09
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    To overcome the heterogeneous nature of cancer, the search for potent anti-cancer drug candidates with new modes of action is essential. For that purpose, we prepared forty-eight Ridaifens (RIDs), a novel series of tamoxifen-derivatives. Then, we screened them, searching for novel candidates for a new class of anti-cancer drug using a panel of human cancer cell lines (JFCR39) and by a binding assay to estrogen receptor α (ERα). First, the growth inhibition of the forty-eight RIDs against JFCR39 was evaluated. Forty RIDs showed higher growth-inhibitory activity than that of tamoxifen. The structure–activity relationship (SAR) study revealed that the aminoalkoxyphenyl groups at the C-1 position and the common central ethylenic bond were important in retaining a high level of growth-inhibitory activity. Subsequently, the ERα binding activity of all the RIDs was measured by a competitive binding assay. The SAR study for ERα binding activity indicated that both the phenyl group and the ethyl group at the C-2 position in the ethylenic bond were essential. Based on the screenings, we identified RID-SB1 and RID-SB8, which demonstrated potent tumor growth inhibition but had completely lost ERα binding activity. Furthermore, the COMPARE analysis using JFCR39 suggested that RID-SB1 and RID-SB8 had different molecular modes of action compared to those of the current anti-cancer drugs including tamoxifen. These results indicate that RID-SB1 and RID-SB8 are interesting candidates for novel anti-cancer agents with unique modes of action.
  • Yoshimasa Ito, Noriaki Nagai, Norio Okamoto, Yoshikazu Shimomura, Kuni ...
    2013 年 36 巻 6 号 p. 1017-1023
    発行日: 2013/06/01
    公開日: 2013/06/01
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    l-Pyroglutamic acid (PGA) is an endogenous molecule derived from l-glutamate. We demonstrate the effects of PGA on intraocular pressure (IOP) in experimentally induced ocular hypertension in rabbits. In the in vitro and in vivo transcorneal penetration studies, the PGA solution (PGA in saline) did not penetrate the rabbit cornea. On the other hand, the penetration of PGA was improved by the addition of zinc chloride and 2-hydroxypropyl-β-cyclodextrin (HPCD), and PGA penetration was enhanced with increasing HPCD concentration. Therefore, PGA solutions containing 0.5% zinc chloride and 5% or 10% HPCD (PGA/HPCD5% or 10% eye drops) were used to investigate the effects for IOP in this study. An elevation in IOP was induced by the rapid infusion of 5% glucose solution (15 mL/kg of body weight) through the marginal ear vein or maintaining under dark phase for 5 h. In the both models, the induced elevation in IOP was prevented by the instillation of PGA/HPCD eye drops, and the IOP-reducing effect enhanced with increasing HPCD concentration in the drops. Nitric oxide (NO) levels elevated in the aqueous humor following the infusion of 5% glucose solution, and this increase was also suppressed by the instillation of PGA/HPCD eye drops. In conclusion, the present study demonstrates that the instillation of PGA/HPCD eye drops has an IOP-reducing effect in rabbits with experimentally induced ocular hypertension, probably as a result of the suppression of NO production.
Notes
  • Kazuaki Matsumoto, Naoko Kanazawa, Erika Watanabe, Yuta Yokoyama, Tomo ...
    2013 年 36 巻 6 号 p. 1024-1026
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Methicillin-resistant Staphylococcus aureus (MRSA) is now endemic in many hospitals. Infection with MRSA is more frequent in the intensive care unit (ICU) than in general wards. Therefore, appropriate treatments for MRSA infections will lead to good outcomes in the ICU. Teicoplanin is an anti-MRSA agent. Recently, it was recommended at a new target trough concentration of 15–30 µg/mL. However, the initial loading procedure for teicoplanin to allow it to reach the target concentration promptly remains uncertain. Therefore, this study aimed to determine the appropriate initial loading procedure for teicoplanin in critically ill patients with severe infections. We performed a retrospective study in patients given teicoplanin in the ICU in order to determine the initial loading procedure to promptly reach the target trough concentration. We then evaluated the trough concentration on the third day after commencement of teicoplanin therapy. The mean loading dose and trough concentration were 11.5±1.0 mg/kg and 18.9±5.9 µg/mL, respectively. A correlation (r=0.45, p=0.046) was shown between teicoplanin loading dose and trough concentration. The correlation equation was trough concentration=2.563·loading dose −10.672. In the cases of 11.0 and 15.0 mg/kg for the loading dose, respectively, trough concentrations were 17.5 and 27.8 µg/mL. We suggested that an initial loading dose of 11–15 mg/kg every 12 h for 3 doses should be administered to promptly achieve the target trough concentration of 15–30 µg/mL on the third day after commencement of teicoplanin therapy in the ICU.
  • Yujin Natori, Naoki Ohkura, Miwako Nasui, Gen-ichi Atsumi, Fumiko Kiha ...
    2013 年 36 巻 6 号 p. 1027-1031
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Mammalian sialidases (NEU1, NEU2, NEU3 and NEU4) that remove sialic acids from glycoconjugates have been implicated in diverse cellular functions. Human sialidases are involved in the development of various disease states such as cancer, diabetes and arteriosclerosis. Unregulated acidic sialidase NEU1 activity is associated with the pathogenesis of lysosomal storage disorder (LSD) sialidosis, abnormal immune responses and cancer progression. Obesity is closely related to several chronic diseases such as diabetes, cardiovascular diseases, hyperlipidemia or hypertension that are associated with metabolic syndrome. We examined fluctuations in mRNA levels and sialidase activities of NEU1 in two strains of obese and diabetic mice to assess the involvement of NEU1 in obesity. The activity of NEU1 was preferentially higher in epididymal fat and lower in the livers of two strains of obese and diabetic mice. Fluctuations in NEU1 activity might be associated with the pathological status of these tissues in obesity.
  • Cathérine Gebhard, Barbara Elisabeth Stähli, Stephanie Largiadèr, Erik ...
    2013 年 36 巻 6 号 p. 1032-1035
    発行日: 2013/06/01
    公開日: 2013/06/01
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    Caffeic acid phenethyl ester (CAPE) is a component of honeybee hives with various beneficial properties. Tissue factor (TF), the key trigger of thrombosis, is expressed in human endothelial cells. This study was designed to investigate whether CAPE modulates TF expression in human aortic endothelial cells (HAECs). Western blots and real-time polymerase chain reactions were performed. CAPE (10−7–10−5m) inhibited tumor necrosis factor (TNF)-α induced endothelial TF protein expression by 2.1-fold at 10−5m (p<0.0001). Similarly, TF surface activity was reduced (p<0.02). In contrast, TF mRNA expression, TF promoter activity, and mitogen-activated protein (MAP) kinase activation remained unaltered. In conclusion, CAPE inhibits TF protein expression and activity at the posttranscriptional level thereby exhibiting anti-thrombotic potential.
  • Kazunori Yamaguchi, Noriyasu Fukuoka, Sumio Kimura, Masahiro Watanabe, ...
    2013 年 36 巻 6 号 p. 1036-1039
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/04/05
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    Mycophenolate mofetil (MMF) is used for oral administration to prevent rejection in renal transplant recipients, and is rapidly converted into mycophenolic acid (MPA), the active metabolite, by hydrolysis in vivo. The area under the concentration–time curve (AUC0–12 h) of MPA is considered to be an effective pharmacokinetics parameter for predicting acute rejection. However, frequent blood sampling is required to calculate AUC0–12 h, which imposes a burden on patients and providers. Therefore, we examined a limited sampling strategy (LSS) for estimation of MPA-AUC0–12 h using only a trough level (C0) and two points including C0 in Japanese living-related renal transplant recipients with concomitant extended-release tacrolimus (ER-TAC). The present study suggests that better estimation of MPA-AUC0–12 h can be obtained by using two points including C0 as compared with only C0 regardless of transplant progress. Furthermore, blood collection points showing the highest estimation of MPA-AUC0–12 h by adding to C0 were C4 at pre-transplantation (Tx) and 1 month post-Tx, and C6 at 3 months post-Tx. We conjecture that changes in renal function and serum albumin (Alb) accompanying transplant progress are aggravating factors in terms of estimation, because there was also a significant difference in the reciprocal of serum creatinine (1/Scr) and Alb between pre-Tx and post-Tx in this study. In conclusion, the present study provides useful information for effective and efficient monitoring of MPA levels in Japanese living-related renal transplant recipients.
  • Seoyoung Park, Jungsug Gwak, Seung Jin Han, Sangtaek Oh
    2013 年 36 巻 6 号 p. 1040-1044
    発行日: 2013/06/01
    公開日: 2013/06/01
    [早期公開] 公開日: 2013/03/29
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    Aberrant accumulation of intracellular β-catenin and subsequent activation of β-catenin response transcription (CRT) in intestinal epithelial cells is a frequent early event during the development of colon cancer. Here we show that cardamonin, a chalcone isolated from Aplinia katsumadai Hayata, inhibited CRT in SW480 colon cancer cells that carry inactivating mutation in the adenomatous polyposis coli (APC) gene. Cardamonin also down-regulated intracellular β-catenin levels in SW480 cells without affecting its mRNA levels. Interestingly, pharmacological inhibition of the proteasome prevented the cardamonin-induced down-regulation of β-catenin. In addition, cardamonin suppressed the expression of cyclin D1 and c-myc, which are known β-catenin/T cell factor (TCF)-dependent genes. Moreover, cardamonin inhibited the growth of various colon cancer cells and induced G2/M cell cycle arrest in SW480 colon cancer cells. These findings indicate that cardamonin is a potential chemotherapeutic agent against colon cancer.
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