Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
36 巻 , 5 号
選択された号の論文の29件中1~29を表示しています
Current Topics
  • Takuo Ogihara
    2013 年 36 巻 5 号 p. 691
    発行日: 2013/05/01
    公開日: 2013/05/01
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  • Tatsuhiro Ishida, Hiroshi Kiwada
    2013 年 36 巻 5 号 p. 692-697
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents’ pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier-based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics.
  • Ken-ichi Ogawara, Yuta Yoshizawa, Keita Un, Tomoya Araki, Toshikiro Ki ...
    2013 年 36 巻 5 号 p. 698-702
    発行日: 2013/05/01
    公開日: 2013/05/01
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    There are many potential barriers to the effective delivery of small-molecule drugs to solid tumors. Most small-molecule chemotherapeutic drugs have a large volume of distribution upon intravenous administration, which is often associated with a narrow therapeutic index due to their high level of toxicity in healthy tissues. Nanoparticle-based therapeutics for tumor targeting have emerged as one of the promising approaches to overcome the lack of tissue specificity of conventional chemotherapeutic drugs. Various different concepts have been envisioned for nanoparticle-mediated drug targeting. Among them, the passive drug targeting strategy has been the most widely investigated, and numerous preclinical studies have provided insights into the validity of the strategy. This review article briefly introduces our recent findings related to the passive drug targeting strategy including its application in anti-angiogenic therapy, along with considerations to be taken into account and implications for the rational design of a passive drug targeting strategy.
  • Kenji Hyodo, Eiichi Yamamoto, Takuya Suzuki, Hiroshi Kikuchi, Makoto A ...
    2013 年 36 巻 5 号 p. 703-707
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Liposomes are drug delivery systems that can alter the pharmacokinetic properties of compounds. The adverse effects of anticancer agents are a limiting factor for cancer chemotherapy, therefore, liposomal formulations have the potential to improve the therapeutic efficacy of anticancer agents by enhancing their accumulation in tumors and reducing non-selective distribution to normal tissues, which is known as the enhanced permeability and retention effect. To develop a liposomal anticancer agent as a drug product, its formulation must be designed to ensure its quality until it is administered to patients and to exert maximum potency in clinical use rather than in animal experiments. The chemical stability and physicochemical stability of the ingredients are key factors in the design of liposomal formulations. Drug release rates are critical factors in the therapeutic efficacy of liposomal drug products because the encapsulated drug has no pharmacological activity, and only released drug can exert antitumor/toxic activities. Liposomes should maintain the drug in a stable state in the circulation and then promptly release it after accumulation in the target tissue in order to achieve a sufficient drug concentration. To understand the profile of the formulation and to guarantee the quality of drug product, a reliable analytical method that can determine the released and encapsulated drugs in biological fluids is required. Simple online solid phase extractions of the released and encapsulated drugs using a column-switching HPLC system meet the requirements and this system enables accurate in vitro release testing and in vivo pharmacokinetic evaluation. This review introduces the process of liposomal drug product development from various viewpoints.
  • Shotaro Nagase, Ryo Doyama, Kiyohito Yagi, Masuo Kondoh
    2013 年 36 巻 5 号 p. 708-714
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Most malignant tumors are derived from epithelium, and pathologic microorganisms often invade the body through the mucosal epithelium. Thus epithelial tissues are potent targets for drug delivery. The tight junction (TJ) is the intercellular seal in epithelial cell sheets. Claudins (CLs) are a family of tetratransmembrane proteins with a molecular mass of approximately 23 kDa. CLs are key structural and sealing components of TJs. CLs are often overexpressed in malignant tumors. CL-4 is highly expressed in the epithelial cells covering mucosal immune tissues. Therefore CLs may be potent targets for drug delivery, cancer therapy, and mucosal vaccination. Herein, we overview a series of our studies using the C-terminal fragment of Clostridium perfringens enterotoxin to target and bind CLs; we also discuss the efficacy of CL-targeted drug delivery.
  • Takuya Iwamoto
    2013 年 36 巻 5 号 p. 715-718
    発行日: 2013/05/01
    公開日: 2013/05/01
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    In recent years, drug delivery systems (DDS) have been developed, along with anticancer agents for those systems based on the concept of achieving a better clinical response and tolerability. Several clinical trials have shown that these drugs have better clinical effects in the treatment of many cancers, leading to their expanded indications. Liposomal doxorubicin is one DDS agent used to treat AIDS-related Kaposi’s sarcoma and ovarian cancer in Japan. In addition to those two indications, the Food and Drug Administration (FDA) approved this drug for the treatment of multiple myeloma in 2007. Another DDS agent approved in Japan is nanoparticle albumin-bound paclitaxel, which has been used in the treatment of breast cancer. Most recently, this drug has been approved for the treatment of non-small cell lung cancer in the U.S.A. Although these DDS agents appear to be less toxic than conventional drugs, DDS-specific side effects such as various skin reactions, hypersensitivity reaction, and peripheral neuropathy sometimes occur. Therefore, medical staff must understand DDS anticancer agents fully, including characteristic side effects, to achieve the desired clinical outcomes.
  • Kyohei Watanabe, Nobuyuki Goto, Toshiaki Nakamura, Mikio Masada
    2013 年 36 巻 5 号 p. 719-722
    発行日: 2013/05/01
    公開日: 2013/05/01
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    In Japan, pharmacists who are in consultation with doctors independently prepare medications in an attempt to meet the needs of patients in the hospital. In particular, the need for hospital preparations to treat cancer is high and diverse. However, unlike gov]ernment-approved medications, independently and individually prepared hospital preparations raise concerns about their effectiveness, safety, economic efficiency, quality control, etc. One way to address these concerns is to commercialize these preparations and to understand the difference between necessity and demand from various points of view. We have conducted nation-wide utilization surveys and evaluated the literature on hospital preparations. On the basis of the findings of this survey, we have concluded that pharmaceutical companies and the government need to implement the commercialization of hospital preparations in clinical practice. In this report, we discuss the significance of commercialization of hospital preparations, concerns regarding pharmaceutical preparations, and our recent efforts on cancer treatment. We hope to continuously contribute to society and to medical care by improving individualized care and by commercializing medications needed in clinical practice.
Regular Articles
  • Chan Hum Park, Takashi Tanaka, Takako Yokozawa
    2013 年 36 巻 5 号 p. 723-732
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/15
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    Compelling evidence indicates that polyphenolic antioxidants show protective effects against diabetic complications. We investigated the effects of a polyphenolic compound, 7-O-galloyl-d-sedoheptulose (GS), from Corni Fructus on a type 2 diabetic db/db mouse model. After 6 weeks of GS treatment, the effects of GS on serum and pancreatic biochemical factors were investigated. To define the underlying mechanism of these effects, we examined several key inflammatory markers, and inflammation-related oxidative stress markers. The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, and interleukin-6 in serum were down-regulated, while adiponectin was augmented by GS treatment. In addition, GS suppressed reactive oxygen species and lipid peroxidation in the pancreas, but increased the pancreatic insulin and pancreatic C-peptide contents. Moreover, GS modulated protein expressions of pro-inflammatory nuclear factor-kappa Bp 65, cyclooxygenase-2, inducible nitric oxide synthase, c-Jun N-terminal kinase (JNK), phospho-JNK, activator protein-1, transforming growth factor-β1, and fibronectin. Based on these results, we conclude that a plausible mechanism of GS’s anti-diabetic action may well be its anti-inflammatory property and anti-inflammatory-related anti-oxidative action. Thus, further investigation of GS as an effective anti-diabetic treatment for type 2 diabetes is warranted.
  • Daijuan Zhang, Jiangyue Liu, Lin Wang, Jianying Wang, Wentao Li, Baoxi ...
    2013 年 36 巻 5 号 p. 733-740
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/15
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    3,4-Dihydroxyacetophenone (3,4-DHAP) is one herbal extract from bald Mao-dong-qing leaves. We reported that 3,4-DHAP had anti-inflammatory function by decreasing tumor necrosis factor-α (TNF-α) secretion in macrophages. The aim of the study was to examine the effects of 3,4-DHAP on plasma and liver lipids, plasma alanine aminotranferase (ALT) and TNF-α level, vascular cell adhesion molecule-1 (VCAM-1) expression, plaque vulnerability and vascular inflammation in hypercholesterolemia-induced atherosclerotic rabbits. Male New Zealand white rabbits were randomized into negative control, positive control, 3,4-DHAP and simvastatin groups. From weeks 2 to 12, the rabbits were treated with 3,4-DHAP or simvastatin. At weeks 12, all the animals were sacrificed. Plasma lipids and ALT were measured using the enzymatic endpoint method. Plasma TNF-α was measured using enzyme-linked immuno sorbent assay (ELISA). Liver lipids concentrations were estimated using commercial kits. The expression of VCAM-1 was measured using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Histological analysis was used to evaluate the pathologic changes of rabbit aortas. The results showed that 3,4-DHAP markedly lowered plasma and liver lipids, lowered plasma ALT and TNF-α levels compared with the positive control group. VCAM-1 mRNA and protein were markedly inhibited by 3,4-DHAP. Decreased aortic plaque instability was evident in 3,4-DHAP-treated rabbits, as demonstrated by a thickened elastic layer, increased vascular smooth muscle cells (VSMCs) accumulation in the plaques, less neointima hyperplasia and macrophages recruitment. 3,4-DHAP may attenuate the progression of atherosclerotic lesions and stabilize plaques by lowering plasma lipids, the number of macrophages and the expression of VCAM-1, while increasing the number of VSMCs in the atherosclerotic plaques.
  • Tamaki Watanabe, Naoko H. Tomioka, Masaru Doshi, Shigekazu Watanabe, M ...
    2013 年 36 巻 5 号 p. 741-747
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Preventing the onset of microalbuminuria in diabetic nephropathy is a problem that needs urgent rectification. The use of a mouse model for diabetes is vital in this regard. For example, db/db mice exhibit defects in the leptin receptor Ob-Rb sub-type, while the ob/ob strain exhibits defects in the leptin ligand. These mouse strains demonstrate type 2 diabetes, either with or without microalbuminuria, respectively. The purpose of the present study was to use DNA microarray technology to screen for the gene responsible for the onset of diabetic microalbuminuria. Using Affymetrix Mouse Gene ST 1.0 arrays, microarray analysis was performed using total RNA from the kidneys of ob control, ob/ob, db/m, and db/db mice. Microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that transcription of the macrophage migration inhibitory factor (MIF) gene was significantly enhanced in the kidneys of db/db mice. Western blotting showed that levels of MIF protein was enhanced in the kidneys of both diabetic db/db and ob/ob mice. On the other hand, elevation of urinary MIF excretion detected by enzyme-linked immunosorbent assay (ELISA) was only in db/db mice and preceded the onset of microalbuminuria. Immunofluorescence studies revealed that MIF was expressed in mouse kidney glomeruli. While MIF expression was enhanced in the diabetic kidneys of both mouse strains, the elevated secretion from db/db mouse kidneys may be responsible for initiating the onset of microalbuminuria in diabetic nephropathy.
  • Teruaki Akao, Keisuke Sato, Ju-Xiu He, Chao-Mei Ma, Masao Hattori
    2013 年 36 巻 5 号 p. 748-753
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Baicalin (BG) and its aglycone, baicalein (B) are strong antioxidants that exert various pharmacological actions and show unique metabolic fates in the rat. The aim of the present study was to identify major metabolite(s) besides BG in rat plasma after oral administration of BG or B. The main metabolite was detected by HPLC equipped with an electrochemical detector at a potential of +500 mV and identified as baicalein 6-O-β-d-glucopyranuronoside (B6G) by HPLC/MS/MS. When BG at a dose of 20 mg/kg was administered orally to Wistar rats, the level of B6G in plasma was higher than that of BG. Cmax and the area under the concentration–curve from 0 to 24 h (AUC0–24 h) values of the plasma B6G were 1.66±0.34 µm and 19.8±3.9 µm·h, respectively, whereas those of BG were 0.853±0.065 µm and 10.0±3.1 µm·h, respectively. When B was administered, similar results were also obtained. B6G-producing activities from B were found in microsomes of both rat jejunum and liver, in spite of the low activity. Rat everted jejunal sacs formed B6G after application of B, but only in a small amount that was excreted into the mucosal side, and not the serosal side, indicating little contribution to the appearance of B6G in plasma. On the other hand, when B was injected into the rat portal vein, B6G was detected at a higher level than BG in the systemic circulation, demonstrating the hepatic contribution to the appearance of plasma B6G.
  • Xiaobin Yu, Yao Tong, Weihuan Huang, Wei Ge
    2013 年 36 巻 5 号 p. 754-763
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/07
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    Our previous study demonstrated that Erxian Decoction (EXD), a traditional Chinese herbal formula, inhibited angiogenesis in zebrafish embryos. To further investigate the anti-angiogenic activity and mechanism of EXD, we evaluated its inhibitory effect on angiogenesis in mammalian endothelial cells in vitro. Cell based assays included proliferation, apoptosis, migration, tube formation and cell cycle analysis. Real-time quantitative polymerase chain reaction (qPCR) and Western blotting were carried out to evaluate the molecular targets and signaling pathways of EXD in human umbilical vein endothelial cells (HUVECs). EXD inhibited proliferation, migration and tube formation in HUVECs. EXD also caused HUVEC apoptosis and cell increase in G0/G1 phase in cell cycle analysis. Furthermore, it decreased the mRNA expressions of vascular endothelial growth factor A (VEGF-A), VEGFR-1 and VEGFR-2 in HUVECs. It also inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt activation, suggesting the involvement of these signaling pathways in the anti-angiogenic action of EXD in HUVECs. The anti-angiogenic activity of EXD provides new insights to its clinical application and may lead to potential drug development for treating various cancers, especially in menopausal period in the future.
  • Yang-si Li, Ying-fen Hong, Jiang He, Jian-xun Lin, Yi-long Shan, Dong- ...
    2013 年 36 巻 5 号 p. 764-771
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/28
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    Alzheimer’s disease (AD), one of the most common forms of dementia, is primarily ascribed to the cholinergic deficits and neuronal dysfunction. Magnolol (Mag), a bioactivator extracted from Magnolia officinalis, has protective effects on cholinergic neurons, but the specific mechanism remains unknown. To further evaluate the therapeutic effects of Mag on the learning and memory impairment in a scopolamine (Scop)-induced mouse model, the passive avoidance and the Morris water maze tests, the measurement of the ratio of brain/hippocampus to body weight, activities of acetyl cholinesterase (AChE), superoxide dismutase (SOD), total nitric oxide synthase (total NOS) and the content of methane dicarboxylic aldehyde (MDA) in hippocampus homogenate as well as the immunefluorescence staining of the AChE positive nerve fibers were performed. Therapeutically treated with Mag, the impaired abilities of learning and memory of the Scop-induced mice were almost restored to the native levels. The restored AChE, total NOS and SOD activities and the MDA level were observed, with a relatively normal density of AChE positive nerve fibers in hippocampus CA3 molecular layer. The improving efficacy of Mag on learning and memory impairment induced by Scop is dose-dependent, indicating that Mag has potential neuroprotective effects against neuronal impairment and memory dysfunction induced by Scop in mice. The underlying mechanisms may be associated with the anti-oxidative effects of Mag and its protective effects on hippocampus cholinergic neurons.
  • Do Hyun Lee, Dong Ha Kim, In Young Oh, So Young Kim, Yun Young Lim, Hy ...
    2013 年 36 巻 5 号 p. 772-779
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Saururus chinensis has been used in folk medicine in Korea for the treatment of edema, jaundice, gonorrhea, and several inflammatory diseases. Saururi chinensis extracts (SCE) have demonstrated anti-inflammatory and anti-oxidant activities, as well as anti-asthmatic, antihypertensive, anti-angiogenic, and therapeutic activities for atopic dermatitis. However, the inhibitory activity of SCE on the melanogenesis signaling pathway is not completely understood. This study examined the effects of SCE on the melanogenesis signaling pathway activated by α-melanocyte-stimulating hormone (α-MSH). We found that SCE inhibited melanin production in a dose-dependent manner without causing cytotoxicity in B16F10 cells. Interestingly, SCE decreased α-MSH-induced tyrosinase activity in B16F10 cells but did not inhibit tyrosinase activity under cell-free conditions. The results of this study indicate that SCE may reduce pigmentation by way of an indirect, nonenzymatic mechanism. We also found that SCE decreased α-MSH-induced microphthalmia-associated transcription factor (MITF) and tyrosinase expression and induced the activation of extracellular signal-regulated kinase (ERK). These results suggest that the depigmenting effect of SCE may result from downregulation of MITF and tyrosinase expression due to increased ERK activity. Thus, our results provide evidence that SCE might be useful as a potential skin-whitening agent.
  • Hironori Nakamura, Haruko Yokoyama, Koichi Yoshimoto, Akihiro Nakajima ...
    2013 年 36 巻 5 号 p. 780-787
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/03/04
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    5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19±6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.
  • Xiaoqian Dai, Ye Ding, Zhaofeng Zhang, Xiaxia Cai, Lei Bao, Yong Li
    2013 年 36 巻 5 号 p. 788-795
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/23
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    Skeletal muscle is a major site for glucose metabolism and its injury by cytokines can induce insulin resistance leading to type 2 diabetes. It has been suggested that quercetin may act as an anti-diabetic agent, however, the effects of quercetin on insulin resistance in skeletal muscle remain unknown. We aimed to investigate the role of quercetin and its glycoside, quercitrin in tumor necrosis factor-alpha (TNF-α) induced C2C12 skeletal muscle cell impairment. Quercetin, but not quercitrin moderately attenuated the effects of TNF-α and enhanced the basal and insulin stimulated uptake of glucose in a dose-dependent manner via the activation of the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways. Furthermore, the underlying mechanism also involved the suppression of nuclear factor-κB (NF-κB) signaling and the nitric oxide (NO)/inducible nitric oxide synthase (iNOS) system, downstream of AMPK transduction. In summary, quercetin exhibited its effect of improving glucose uptake and insulin sensitivity in skeletal muscle cells via the two independent signaling pathways of Akt and AMPK, and can be developed as a potential anti-diabetic agent.
  • Nam-Kyung Im, Je-Yong Choi, Hyuncheol Oh, Youn-Chul Kim, Gil-Saeng Jeo ...
    2013 年 36 巻 5 号 p. 796-801
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/19
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    6,4′-Dihydroxy-7-methoxyflavanone (DMF) is a flavonoid isolated from Heartwood Dalbergia odorifera. It has been known that DMF has antioxidant, anti-inflammatory and neuroprotective effects. DMF, however, the efficacy of bone related diseases has not been reported. In this study, we determined DMF’s efficacy on osteoclasts differentiation and function using in vitro bone marrow macrophage osteoclast differentiation culture system. DMF inhibited receptor activators of nuclear factor kappa-B ligand (RANKL) induced osteoclastogenesis dose dependently. In addition, DMF decreased osteoclast function through disruption of actin ring formation and consequently suppression of the pit-forming activity of mature osteoclasts. Mechanistically, DMF inhibited RANKL-induced expression of nuclear factor of activatied T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) and c-Fos via inhibition of mitogen activated protein kinases (MAPKs) pathway. Collectively, the inhibition of osteoclasts differentiation and function by DMF suggests that DMF can be a potential therapeutic molecule for osteoclastogenic bone diseases such osteoporosis, rheumatoid arthritis and periodontal diseases.
  • Yong-Sik Kim, Biswajit Podder, Ho-Yeon Song
    2013 年 36 巻 5 号 p. 802-811
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Alpha-lipoic acid (LA), a metabolic antioxidant, is a natural compound and its biological function has been well studied in various human diseases. The present study was designed to investigate the cytoprotective effect and the molecular mechanisms of LA in paraquat (PQ)-induced oxidative stress injury using BEAS-2B human bronchial epithelial cells. LA co-treatment prevented PQ-induced BEAS-2B cell death. LA also prevented PQ-induced increases in total reactive oxygen species (ROS), lactate dehydrogenase (LDH) and malondialdehyde (MDA). LA also increased the expression of detoxifying phase II enzyme encoding genes and antioxidant genes including HO-1, NQO1, CAT, GPX3 and GPX4, resulting in the attenuation of the decreases of antioxidants during PQ-induced oxidative stress. Nuclear factor erythroid related factor 2 (Nrf2) was induced by LA. Additionally, translocation of Nrf2 from the cytoplasm to the nucleus was promoted by LA treatment. While LA was responsible for the upregulation of Nrf2, it also activated and up-regulated the downstream proteins heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) quinone oxidoreductase 1 (NQO1). The data collectively suggest that the beneficial effect of LA involving the activation of cytoprotective antioxidant genes make LA a potential candidate in the prevention of PQ-induced oxidative stress-related bronchial cell death, pending clinically relevant studies.
  • Byung-Hwan Lee, Sun-Hye Choi, Sung-Hee Hwang, Hyeon-Joong Kim, Sang-Mo ...
    2013 年 36 巻 5 号 p. 812-818
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Ginsenosides is a low molecular weight substance found in ginseng as one of the active ingredients. Ginsenosides, like other herbal medicines, has a wide range of neuropharmacological actions including neuroprotective effects. The α9α10 nicotinic acetylcholine receptor is one of numerous nicotinic acetylcholine receptors that exists as a heteropentameric form in auditory hair cells of the cochlea. In this study, we report the effects of ginsenosides on rat α9α10 nicotinic acetylcholine receptor-mediated ion currents using the two-electrode voltage clamp technique. Treatment with acetylcholine evoked inward currents (IACh) in oocytes heterologously expressing the α9α10 nicotinic acetylcholine receptor. Ginsenosides blocked IACh in order of potency of Rg3> Rb2> CK>Re=Rg2> Rf>Rc> Rb1> Rg1 with reversible manners, and the blocking effect of Rg3 on IACh was same after pre-application than co-application of Rg3. The half maximal inhibitory concentration (IC50) of Rg3 was 39.6±4.9 µm. Rg3-induced IACh inhibition was not affected by acetylcholine concentration and was independent of membrane holding potential. Although the inhibitory effect of Rg3 on IACh was abolished in oocytes expressing α9 subunit alone, indicating that the presence of α10 subunit might be required for Rg3-induced regulations of α9α10 nicotinic acetylcholine receptor channel activity. These results indicate that α10 subunit of α9α10 nicotinic acetylcholine receptor might play an important role in Rg3-induced regulation of the α9α10 nicotinic acetylcholine receptor.
  • Mayako Uchida, Hiroaki Ikesue, Toshihiro Miyamoto, Koji Kato, Kimitaka ...
    2013 年 36 巻 5 号 p. 819-824
    発行日: 2013/05/01
    公開日: 2013/05/01
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    For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT3 antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 min before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60–90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1–2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT.
  • Toshio Maeda, Ichiro Noge, Yoshiyuki Kagawa
    2013 年 36 巻 5 号 p. 825-832
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/18
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    We have isolated insulin resistant mice (ddY-H mice) which are spontaneously induced at 12-weeks of age even if fed with the standard chow pellets. Since accumulated evidences have suggested that an appearance of insulin resistance is associated with obesity and a state of inflammation in adipose tissue, the present study investigated an appearance of macrophages in adipose tissue of ddY-H mice. Although ddY-H mice were fed the standard chow pellets ad libitam, increases in body weight, adipose tissue mass, and fat cell size were observed. In adipose tissues of ddY-H mice, gene expression of monocyte chemoattractant protein-1 (MCP-1) elevated slightly at 5-weeks of age and was maintained at higher levels at 9- and 12-weeks of age, and MCP-1 content in adipose tissue increased 2-fold at 12-weeks of age. Also, increased gene expressions of CD68 and F4/80, markers of macrophage, in adipose tissue were observed at 9-weeks of age. In addition, F4/80 positive cells were histologically found in adipose tissue at 15-weeks of age but not at 7-weeks of age, suggesting an increased infiltration of macrophage into adipose tissue. In adipose tissue of ddY-H mice, gene expressions of CD11c and toll-like receptor 4 (TLR4), markers of proinflammatory macrophages (M1), markedly increased although those of CD163 and mannose receptor (MR), markers of anti-inflammatory macrophages (M2), did not change. These results suggest that proinflammatory (M1) macrophages infiltrate into enlarged adipose tissues of ddY-H mice, which is preceding spontaneous appearance of insulin resistance.
  • Harue Nomura, Yasunori Isshiki, Keisuke Sakuda, Katsuya Sakuma, Seiich ...
    2013 年 36 巻 5 号 p. 833-837
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Oakmoss and its components are known as antibacterial agents, specifically against Legionella pneumophila. In the present study, we investigated the effects of oakmoss and its components (phenol, didepside and isochromen derivatives) on L. pneumophila biofilm formation, with particular reference to the bactericidal activity (minimum bactericidal concentration; MBC) of these components against the bacterial cells in the biofilm. Of the 20 compounds tested, two didepside derivatives and four phenol derivatives reduced biofilm formation by more than 50% of that observed for the control at their respective minimum inhibitory concentrations (1/2×MIC). The inhibitory activities of these compounds were either equivalent to or greater than that of the clarithromycin reference. Isochromen derivatives had no effect on biofilm formation. Analysis of bactericidal activity of didepside and isochromen derivatives revealed that three of four didepside derivatives and one of four isochromen derivatives exhibited high bactericidal activity (MBC: 32.0–74.7 µg/mL) against the L. pneumophila in the biofilm after 24 h or 48 h of co-incubation; the antibacterial activities of these compounds were almost equivalent to clarithromycin and chlorhexidine gluconate (MBC: 42.7–64.0 µg/mL) that were used as references. Thus, based on their anti-biofilm forming and bactericidal activities, didepside derivatives are considered to be good candidates for disinfectants against L. pneumophila.
  • Kentaro Ninomiya, Kazumi Hayama, Sanae A. Ishijima, Naho Maruyama, Hir ...
    2013 年 36 巻 5 号 p. 838-844
    発行日: 2013/05/01
    公開日: 2013/05/01
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    The onset of oral candidiasis is accompanied by inflammatory symptoms such as pain in the tongue, edema or tissue damage and lowers the quality of life (QOL) of the patient. In a murine oral candidiasis model, the effects were studied of terpinen-4-ol (T-4-ol), one of the main constituents of tea tree oil, Melaleuca alternifolia, on inflammatory reactions. When immunosuppressed mice were orally infected with Candida albicans, their tongues showed inflammatory symptoms within 24 h after the infection, which was monitored by an increase of myeloperoxidase activity and macrophage inflammatory protein-2 in their tongue homogenates. Oral treatment with 50 µL of 40 mg/mL terpinen-4-ol 3h after the Candida infection clearly suppressed the increase of these inflammatory parameters. In vitro analysis of the effects of terpinen-4-ol on cytokine secretion of macrophages indicated that 800 µg/mL of this substance significantly inhibited the cytokine production of the macrophages cultured in the presence of heat-killed C. albicans cells. Based on these findings, the role of the anti-inflammatory action of T-4-ol in its therapeutic activity against oral candidiasis was discussed.
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  • Hiroko Maruki-Uchida, Ikuko Kurita, Kenkichi Sugiyama, Masahiko Sai, K ...
    2013 年 36 巻 5 号 p. 845-849
    発行日: 2013/05/01
    公開日: 2013/05/01
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    The use of naturally occurring botanicals with substantial antioxidant activity to prevent photoageing is receiving increasing attention. We have previously identified piceatannol and scirpusin B, which is a dimer of piceatannol, as strong antioxidants that are present in passion fruit (Passiflora edulis) seeds. In the present study, the effects of passion fruit seed extract, piceatannol, and scirpusin B on human keratinocytes were investigated. The passion fruit seed extract and piceatannol upregulated the glutathione (GSH) levels in keratinocytes in a dose-dependent manner, indicating that piceatannol is an active component of the passion fruit seed extract in keratinocytes. The pretreatment with piceatannol also supressed the UVB-induced generation of reactive oxygen species (ROS) in the keratinocytes. In addition, the transfer of the medium from the UVB-irradiated keratinocytes to non-irradiated fibroblasts enhanced matrix-metalloproteinase (MMP)-1 activity, and this MMP-1 induction was reduced when the keratinocytes were pretreated with piceatannol. These results suggest that piceatannol attenuates the UVB-induced activity of MMP-1 along with a reduction of ROS generation in keratinocytes. Thus, piceatannol and passion fruit seed extract containing high amounts of piceatannol are potential anti-photoageing cosmetic ingredients.
  • Yang Cao, Masanori Fujii, Keiichi Ishihara, Satoshi Akiba, Hiroyuki Ya ...
    2013 年 36 巻 5 号 p. 850-855
    発行日: 2013/05/01
    公開日: 2013/05/01
    [早期公開] 公開日: 2013/02/25
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    Airway remodeling, pathological changes in the lung structure, is a characteristic feature of chronic asthma. The changes include bronchial epithelial hyperplasia and hypertrophy, excess production of mucus, and fibroblast proliferation in the lung. On the other hand, it has been known that both nitric oxide and superoxide anion are increased in exhaled air of asthmatic patients. These molecules react with each other forming a powerful oxidant, peroxynitrite. In this study, effect of a peroxynitrite scavenger, a metalloporphyrin compound, [tetrakis(4-carboxylatophenyl)porphyrinato]manganese(III) (MnTBAP) on multiple antigen challenge-induced airway remodeling was evaluated in mice. When sensitized BALB/c mice were intratracheally challenged with an antigen, ovalbumin, for 3 times, bronchial epithelial thickening and mucus accumulation in the epithelium were histologically observed. Daily treatment with MnTBAP (3, 10 mg/kg/time/twice a day, intraperitoneally (i.p.)) dose-dependently suppressed both the epithelial thickening and mucus accumulation in the epithelium. On the other hand, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining revealed that the multiple antigen challenges increased the number of apoptotic cells in the bronchial epithelium. The increase in apoptotic cells was also effectively suppressed by the treatment with MnTBAP. Taken together, it was suggested that peroxynitrite could be involved in the formation of epithelial hyperplasia associated with the mucus accumulation through induction of apoptosis of the epithelial cells. Thus, peroxynitrite can be a target molecule for development of new pharmacotherapy for asthma.
  • Yoshiyuki Hattori, Tsukasa Nakamura, Hiroaki Ohno, Nobutaka Fujii, Yos ...
    2013 年 36 巻 5 号 p. 856-860
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Previously, we prepared cationic nanoparticles (NP and NP-N) composed of cholesteryl diamine (OH-Chol, (3S)-N-(2-(2-hydroxyethylamino)ethyl)cholesteryl-3-carboxamide) and cholesteryl triamine (OH-N-Chol, (3S)-N-(2-(2-(2-hydroxyethylamino)ethylamino)ethyl)cholesteryl-3-carboxamide), respectively, with Tween 80 for small interfering RNA (siRNA) delivery into tumor cells. In this study, we prepared NP-0.25N composed of OH-Chol and OH-N-Chol at a molar ratio of 3/1 with Tween 80, and evaluated the transfection efficiency of plasmid DNA (pDNA) into tumor cells. NP-N exhibited lower transfection activity than NP; however, NP-0.25N showed higher transfection activity than both NP and NP-N in various tumor cells. NP-0.25N increased the amount of internalized pDNA by increased cellular association, and improved the escape from endosomes after clathrin-mediated endocytosis. The results of the experiments suggested that cholesteryl triamine may have potential as a helper lipid to increase the transfection for pDNA delivery by cationic cholesterol-based nanoparticles.
  • Shinichiro Nakagawa, Yusuke Matsuoka, Hideaki Ichihara, Hitoji Yoshida ...
    2013 年 36 巻 5 号 p. 861-865
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Trastuzumab (TTZ) is molecular targeted drug used for metastatic breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Therapeutic effects of lymphocytes activated with TTZ (TTZ-LAK) using xenograft mouse models of human breast cancer (MDA-MB-453) cells were examined in vivo. Remarkable reduction of tumor volume in a xenograft mouse models intravenously treated with TTZ-LAK cells after the subcutaneously inoculated of MDA-MB-453 cells was verified in vivo. The migration of TTZ-LAK cells in tumor of mouse models subcutaneously inoculated MDA-MB-453 cells was observed on the basis of histological analysis using immunostaining with CD-3. Induction of apoptosis in tumor of xenograft mice treated with TTZ-LAK cells was observed in micrographs using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. It was noteworthy that the therapeutic effects of TTZ-LAK cells along with apoptosis were obtained for xenograft mouse models of human breast tumor in vivo.
  • Takayuki Ohtomo, Chisato Nakao, Megumi Sumiya, Osamu Kaminuma, Akemi A ...
    2013 年 36 巻 5 号 p. 866-871
    発行日: 2013/05/01
    公開日: 2013/05/01
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    Acyl-CoA thioesterases (ACOTs) are a group of enzymes that catalyze the hydrolysis of fatty acyl-CoAs to free fatty acids and CoA, with the potential to regulate the intracellular levels of these molecules. In this study, we show that a cytosolic isoform, ACOT7, is expressed at a significant level in the mesenteric lymph nodes (MLNs) of mice. While crude preparations of the mesenteric visceral fat contained significant levels of palmitoyl-CoA thioesterase activity, enzyme activity was concentrated 6.9-fold in MLNs compared with the residual adipose portion after excision of MLNs. When MLN homogenates were centrifuged, 82% of the enzyme activity was recovered in the cytosolic fraction, concomitant with almost exclusive recovery of ACOT7. Immunoprecipitation using anti-ACOT7 antibody estimated that 87% of enzyme activity in the homogenates was accounted for by ACOT7. On MLN sections, the germinal centers of secondary lymphoid follicles were immunostained with the antibody. In MLNs of mice fasted for 16 h, ACOT7 levels were induced 1.8-fold, which reflected a 1.5-fold increase in enzyme activity. These findings suggest that ACOT7 may be involved in dietary intake-associated responses in fatty acid metabolism in MLNs.
  • Nobuyasu Yamaguchi, Takahiro Nishiguchi, Fuangfa Utrarachkij, Orasa Su ...
    2013 年 36 巻 5 号 p. 872-876
    発行日: 2013/05/01
    公開日: 2013/05/01
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    In Southeast Asian countries, industrialization and urbanization is occurring rapidly, and water pollution in rivers and canals poses serious problems in some areas, especially in cities. Excess inflow of domestic, agricultural, and industrial wastewater to freshwater environments disturbs the aquatic microbial ecosystem, which can further pollute water by inhibiting biodegradation of pollutants. Therefore, monitoring of microbes in freshwater environment is important to identify changes in indigenous microbial populations and to estimate the influence of wastewater inflows on them. Polymerase chain reaction (PCR)–denaturing gradient gel electrophoresis (DGGE) analysis is suitable for monitoring changes in microbial communities caused by human activities, but this method can be difficult in eutrophic freshwater samples that contain PCR inhibitors. In this study, we optimized DNA extraction procedures and PCR conditions for DGGE analysis of bacterial populations in freshwater samples (canal, river, and tap water) collected in Bangkok, Thailand. A simple freeze–thaw procedure was effective for extracting DNA from bacterial cells in the samples, and LA Taq with added bovine serum albumin provided the best PCR amplification. The PCR–DGGE approach revealed that the most common bacteria in freshwater samples belonged to Gammaproteobacteria, while a Gram-positive bacterium was present at Bangkok Noi Canal. Temporally and spatially continuous analyses of bacterial populations in Bangkok canals and rivers by PCR–DGGE approach should be useful to recognize disturbances of microbial ecosystems caused by excess inflows of wastewater.
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