Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
35 巻 , 6 号
選択された号の論文の33件中1~33を表示しています
Current Topics
  • Yuzo Yoshida
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 811-
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
  • Osamu Gotoh
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 812-817
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Cytochrome P450 (CYP) constitutes a large gene superfamily descended from a single common ancestor. CYP genes are widely distributed in all domains of life from bacteria, archaea, and viruses to higher plants and animals. Because of their monophyletic nature, all CYP genes may be hierarchically classified at several distinct levels based on similarity of the protein amino acid sequences. A five-level classification (class, group, clan, family, and subfamily) is reasonably stable and useful for conceptual categorization of CYP genes. With a few exceptions, genes in a clan are specific to a kingdom or phylum, whereas cross-kingdom genes may belong to the same group, indicating an ancient origin of CYP diversification. CYP proteins are often functionally categorized into catalysts of “endogenous,” “secondary,” and “xenobiotic” compounds according to their substrate specificities. It was once postulated that xenobiotic-metabolizing enzymes were derived from an endogenous substrate-catalyzing enzyme. Although functional flow from endogenous to xenobiotic substrates occurred, recent evidence from a wide range of genomic analyses has indicated that the opposite is the more dominant stream. Expression of most vertebrate CYP genes is regulated by internal and external stimuli through transcription factors in the nuclear receptor family and bHLH-PAS family. Some aspects of cooperative evolution between transcriptional regulators and their target genes are briefly reviewed.
  • Hiroshi Sugimoto, Yoshitsugu Shiro
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 818-823
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Mammalian cytochrome P450 (CYP) comprise a large group of enzymes that play many important roles in the biosynthesis of steroid hormones and vitamins. In addition, they participate in the metabolism of drugs and xenobiotics. All known mammalian CYP enzymes are membrane-associated proteins, which complicated their X-ray crystallographic analysis. In recent years, however, significant progress has been made in the X-ray crystallographic analysis of mammalian CYP enzymes involved in the steroid hormone and vitamin D3 metabolism. The knowledge from three-dimensional structures of mammalian CYP enzymes will benefit drug discovery and development.
  • Masaharu Mizutani
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 824-832
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Cytochrome P450 monooxygenases (P450s) catalyze a wide variety of monooxygenation reactions in primary and secondary metabolism in plants. The share of P450 genes in each plant genome is estimated to be up to 1%. This implies that the diversification of P450 has made a significant contribution to the ability to acquire the emergence of new metabolic pathways during land plant evolution. The P450 families conserved universally in land plants contribute to their chemical defense mechanisms. Several P450s are involved in the biosynthesis and catabolism of plant hormones. Species-specific P450 families are essential for the biosynthetic pathways of phytochemicals such as terpenoids and alkaloids. Genome wide analysis of the gene clusters including P450 genes will provide a clue to defining the metabolic roles of orphan P450s. Metabolic engineering with plant P450s is an important technology for large-scale production of valuable phytochemicals such as medicines.
  • Hirofumi Ichinose
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 833-837
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    A series of genome projects have uncovered an astonishing molecular diversity of cytochrome P450s in the fungal kingdom. Fungal P450s discovered from such projects are often categorized into novel families and subfamilies. It thus appears that the divergence of fungal P450s is greater than of animal, plant, or bacterial P450s. The tremendous variation implies that fungi have vigorously diversified P450 functions to meet novel metabolic needs. To better understand the metabolic diversity of fungi, one must undertake the challenging task of exploiting the catalytic functions of numerous P450s. A compilation of P450 functions will also enable us to utilize their catalytic potentials in biotechnology. Experimental screening remains essential however, to elucidate the catalytic potentials of individual P450s. This review outlines the molecular and genomic aspects of fungal P450s, and introduces new functions revealed by functionomic studies using a recently developed, rapid, functional screening system.
  • Masatoshi Iga, Hiroshi Kataoka
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 838-843
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    In insects molting and metamorphosis are primarily under the control of two insect hormones, ecdysone and juvenile hormone (JH). Physiological and biochemical studies of insect hormone metabolic pathways suggested the involvement of P450 (CYP) enzymes in the pathways, but molecular details of the enzymes were unclear. In recent years, the genome information and studies using molecular biology and genetics have allowed us to understand enzymes in the ecdysteroid and JH metabolic pathways. Genome sequencing has been accomplished in several insect species, and has shown the presence of 36–180 CYP enzymes. To date, six and one CYP enzymes have been revealed in the biosynthesis and inactivation pathways of 20-hydroxyecdysone (20E), respectively. In the 20E biosynthetic pathway, correlation among the enzymes, substrates and metabolites is elucidated in the late steps, but the enzyme(s) and intermediates in the early steps have not been fully understood and are referred to as the ‘Black Box’. The gene expression of some CYP enzymes in the 20E biosynthesis is modulated by neuropeptides and JH. Furthermore, involvement of a CYP enzyme is found in both JH biosynthesis and inactivation pathways. Thus, recent studies have shown the importance of CYP enzymes in insect hormone metabolisms.
  • Toshiyuki Sakaki
    原稿種別: Current Topics
    2012 年 35 巻 6 号 p. 844-849
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Recent progress on the application of cytochrome P450 (P450) to bioconversion processes, biosensors, and bioremediation were reviewed. Because regio- and enantioselective hydroxylation makes chemical synthesis difficult, a bioconversion process using P450 would be quite attractive. One of the most successful industrial applications of P450 may be the bioconversion process for pravastatin formation using a Streptomyces carbophilus CYP105A3. Unfortunately, practical application of P450s in the bioconversion process is limited because of their low stability, low activity and co-factor dependency. However, directed evolution is expected to generate useful P450 biocatalysts for a wide range of substrates. Shunt pathways of CYP152A1, CYP152A2, and CYP152B1 are notably promising for practical application, because these P450s require neither reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) nor electron donor proteins, and efficiently catalyze using hydrogen peroxide. A P450 biosensor using biochip technology is expected to become a tool for rapidly determining drugs and endogenous substances in plasma at a low cost. Bioremediation of dioxins and polychlorinated biphenyls (PCBs) by the CYP1 family appears to be possible by using suicidal, genetically engineered microorganisms. The P450 superfamily has tremendous potential for practical applications in various fields.
Regular Articles
  • Yingxia Liang, Weijian Jiang, Zhiyu Zhang, Jianfeng Yu, Liang Tao, Shu ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 850-854
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Neuropathic pain is a devastating neurological disease that seriously affects patients’ quality of life. Despite a high level of incidence, the underlying mechanisms of neuropathic pain are still poorly understood. However, recent evidence supports the prominent role of spinal glial cells in neuropathic pain states. In our laboratory, we observed that najanalgesin, a novel peptide isolated from the venom of Naja naja atra, exerts significant analgesic effects on acute pain in mice and neuropathic pain in rats. The objective of the present study was to determine whether spinal glia are associated with the antinociceptive effect of najanalgesin in an L5 spinal nerve ligation (SNL) rodent model of neuropathic pain. Mechanical allodynia developed after surgery, and hypersensitivity was significantly attenuated by the intrathecal administration of najanalgesin. The inhibitory effect of najanalgesin was significantly (p<0.05) enhanced after pretreatment with fluorocitrate (a glial cell antagonist). In addition, the astrocyte activation was attenuated following najanalgesin treatment in the dorsal horn of neuropathic rats, as assessed by immunohistology and Western blotting. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) content of cerebral spinal fluid and cell culture supernatants changed significantly after najanalgesin administration. The results suggest that najanalgesin may exert its anti-allodynic effect by altering astrocyte cell function.
  • Zhiyong Liao, Zhihua Wu, Mingjiang Wu
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 855-860
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Cirsium japonicum flavones have been demonstrated to possess anti-diabetic effects in diabetic rats, but the functional mechanism remains unknown. The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in glucose and lipid homeostasis. In this study, we report the effects of Cirsium japonicum flavones (pectolinarin and 5,7-dihydroxy-6,4-dimethoxy flavone) on PPARγ activation, adipocyte differentiation, and glucose uptake in 3T3-L1 cells. Reporter gene assays and Oil Red O staining showed that Cirsium japonicum flavones induced PPARγ activation and enhanced adipocyte differentiation of 3T3-L1 cells in a dose-dependent manner. In addition, Cirsium japonicum flavones increased the expression of PPARγ target genes, such as adiponectin and glucose transporter 4 (GLUT4), and enhanced the translocation of intracellular GLUT4 to the plasma membrane. In mature 3T3-L1 adipocytes, Cirsium japonicum flavones significantly enhanced the basal and insulin-stimulated glucose uptake. The flavones-induced effects in 3T3-L1 cells were abolished by the PPARγ antagonist, GW9662, and by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. This study suggests that Cirsium japonicum flavones promote adipocyte differentiation and glucose uptake by inducing PPARγ activation and then modulating the insulin signaling pathway in some way, which could benefit diabetes patients.
  • Kentaro Ninomiya, Naho Maruyama, Shigeharu Inoue, Hiroko Ishibashi, To ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 861-865
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    The therapeutic efficacy of tea tree oil (TTO), Melaleuca alternifolia, and its main component, terpinen-4-ol, were evaluated in a murine oral candidiasis model. Prednisolone -pretreated mice were orally infected with a fluconazole-susceptible (TIMM 2640) or a resistant (TIMM 3163) strain of Candida albicans to induce oral candidiasis. TTO or terpinen-4-ol was administrated with a cotton swab 3 h and 24 h after candida infection. These treatments clearly showed a decrease in the symptom score of tongues and in the viable candida cell number in the oral cavity at 2 d after azole-susceptible C. albicans infection, although the degree of the efficacy was less than that of fluconazole. Even against oral candidiasis caused by azole-resistant C. albicans, TTO and terpinen-4-ol were similarly effective, while fluconazole appeared ineffective. These results suggest that TTO and terpinen-4-ol may have the potential of therapeutic ability for mucosal candidiasis which may also be applicable to C. albicans oral candidiasis induced by the azole-resistant strain.
  • Ken Kawakubo, Asami Mori, Kenji Sakamoto, Tsutomu Nakahara, Kunio Ishi ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 866-872
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    We examined the effects of GP-1447 (3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenyl acetic acid) on existing cataracts and sorbitol content in the lens in rats with streptozotocin-induced diabetes. GP-1447 is an inhibitor of aldose reductase, which is the first enzyme in the polyol pathway. Cataracts in the central region of the lens were observed in 7 of 14 eyes (50%) by the fifth week after induction of diabetes, and development of mature cataracts was observed in most lenses by the ninth week. In diabetic rats that received GP-1447 treatment beginning in the fifth week after induction of diabetes, progression of cataracts was observed for 1 week after initiation of treatment. Thereafter, the severity of cataracts did not change substantially. Sorbitol levels in the lens peaked during the first week of diabetes, and this increase was maintained during the 9-week observation period. Elevated sorbitol levels in the lenses of diabetic rats gradually declined after GP-1447 treatment was started on the fifth week after induction of diabetes. Cataracts and sorbitol elevation were not observed in the lenses of controls or diabetic rats treated with GP-1447 immediately after induction of diabetes. These results suggest that the polyol pathway plays an important role in both the appearance and progression of cataracts in diabetic rats. Inhibition of aldose reductase could significantly prevent progression of existing cataracts.
  • Mei Jing Piao, Nam Ho Lee, Sungwook Chae, Jin Won Hyun
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 873-880
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    In previous reports, the antioxidant effects of eckol were shown to protect cells against hydrogen peroxide- and gamma ray-induced oxidative stress. In this study, the role of eckol in protecting human skin keratinocytes (HaCaT) against UVB-induced oxidative cell damage was investigated. Also, triphlorethol-A, one of the chemical components in Ecklonia cava, and quercetin a well known antioxidant, were compared with eckol in terms of antioxidant activity based on chemical structure. Eckol decreased UVB-induced intracellular reactive oxygen species (ROS), decreased injury to cellular components resulting from UVB-induced oxidative stress, and restored cell viability. In addition, eckol reduced UVB-induced apoptosis by inhibiting the disruption of mitochondrial membranes. These results suggest that eckol protects human keratinocytes against UVB-induced oxidative stress by scavenging ROS, thereby lessening injury to cellular components.
  • Li-Hua Peng, Xi Chen, Lei Chen, Ni Li, Wen-Quan Liang, Jian-Qing Gao
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 881-888
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Topical delivery of therapeutic agents at the time of injury to accelerate skin repair and prevent the formation of scars during the wound healing process has received increasing attention and represents a novel regenerative and prophylactic strategy for wound treatment. The aim of this study was to invesigate, for the first time, the influence of topical astragaloside IV-releasing hydrogel on the wound repair and regeneration. Using the sodium alginate-gelatin as a hydrogel vehicle, the astragaloside IV was incorporated into the topical carrier and kept releasing with a sustained manner at the wound site. With the rat skin excision model, regulation of the astragaloside IV hydrogel on the wound repair and regeneration were investigated. It was found that the astragaloside IV hydrogel was effective in the skin wound repair, leading to a significant improvement on the wound closure, collagen synthesis and skin tensile strength recovery. Meanwhile, for the first time, that functions of astragaloside IV hydrogel in activating the skin appendages regeneration and increasing the transforming growth factor-β1 (TGF-β1) level in serum were shown. Results of this study provided evidence for the alginate-gelatin hydrogel as efficient carrier for the topical delivery of bioactive molecules to the injured site. The astragaloside IV releasing hydrogel was shown a promising therapeutic formulation for wound healing, as well as its regenerative feature and underlying mechanism contribute to the skin regeneration were disclaimed.
  • Daisuke Inoue, Tomoyuki Furubayashi, Ken-ichi Ogawara, Toshikiro Kimur ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 889-894
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Mucus on the nasal mucosa is translocated to the pharynx by ciliary beating, which is an important nonspecific defense mechanism called mucociliary clearance (MC). MC is one of the important factors determining the rate and extent of drug absorption after nasal application. The purpose of this study is to evaluate MC using rat nasal septum under physiological condition in an in vitro system. The nasal septum was excised from rats anesthetized with urethane and the movement of fluorescent microspheres (FMS) applied on the nasal septum was observed with a fluorescence microscope. FMS were transported at a constant velocity in the same direction for a few minutes, but addition of 4% mucin solution on the nasal septum maintained MC for at least 90 min after excision. With our evaluation system established by modifying the method of Saldiva, MC was determined to be around 1 mm/min. Furthermore, the ciliostatic effect of benzalkonium chloride was observed, and it was confirmed that β-adrenergic antagonists and a cholinergic antagonist decreased MC, and that β-adrenergic agonists and a cholinergic agonist tended to increase MC, indicating that our system is valid and useful for evaluating MC function and the effect of drugs and pharmaceutical additives for nasal application on MC.
  • Ismail Ahmed Ismail, Hye Suk Kang, Heon-Jin Lee, Byoung-Mog Kwon, Su-H ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 895-902
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    2′-Benzoyloxycinnamaldehyde (BCA) is a promising antitumor agent which induces cancer cells apoptosis via reactive oxygen species (ROS) generation. BCA shows more effective antiproliferation in MDA-MB-435 than in MCF-7 breast cancer cells. DJ-1 has been known to protect cells against oxidative stress as an antioxidant because of its cysteine residues sensitive to oxidative stress. In the present study, we evaluated the mechanism of DJ-1 for cell protection from oxidative stress after BCA treatment in MCF-7 cell. BCA upregulates the expression of DJ-1 in MCF-7 cells. However, DJ-1 expression decreased continuously for 24 h after BCA treatment in MDA-MB-435 cells. DJ-1 knockdown sensitized MCF-7 cells to BCA, on the contrary, DJ-1 overexpression induced MDA-MB-435 cells less sensitive to BCA. Confocal microscopic observation showed that only in MCF-7 cells BCA increased the overlapped signal between mitochondria and DJ-1 protein. Mitochondrial membrane potential (MMP) was decreased in MDA-MB-435 cells by BCA, and DJ-1 overexpression inhibited BCA-induced MMP decrease in these cells. On the contrary, DJ-1 knockdown in MCF-7 induced MMP perturbation by BCA. These findings suggest that DJ-1 upregulation protects MCF-7 cells from BCA via inhibiting mitochondrial damage.
  • Hirotaka Miyamoto, Sumie Baba, Sayuri Nakajima, Toyoharu Mine, Naoki Y ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 903-908
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    We have developed a simple administration method, which is gastric serosal surface instillation of naked plasmid DNA (pDNA) in experimental animals. The purpose of this study was to improve gastric gene transfer efficiency by pre-treatment with a macropinocytosis enhancer, such as fetuin or epidermal growth factor (EGF), in mice. A series of concentrations of fetuin were instilled onto gastric serosal surface prior to instillation of naked pDNA in mice; however, fetuin did not improve transgene expression in the stomach 6 h after administration of pDNA. EGF also did not affect transgene expression in the stomach when pDNA was instilled immediately after EGF instillation. On the other hand, when pDNA was instilled onto gastric serosal surface 24 h after EGF treatment, transgene expression in the stomach was significantly improved by 2.6-fold. In addition, transgene-positive cells were increased 5.3-fold by EGF pre-treatment. High transgene expression in the stomach lasted for 48 h in the EGF pre-treatment group in comparison with that in the no pre-treatment group. These findings are valuable to develop an effective method of in vivo gene transfer to the stomach.
  • Takanori Tatsuno, Megumi Jinno, Yukiko Arima, Tetsuro Kawabata, Tatsuy ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 909-916
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Peanut skin (Arachis hypogaea L., Fabaceae) is an abundant source for polyphenols, such as proanthocyanidin oligomers. To determine whether proanthocyanidin has beneficial effects on skin, we tested for inhibitory activity of proanthocyanidins isolated from peanut skin on inflammatory cytokine production and melanin synthesis in cultured cell lines. Administration of peanut skin extract (PSE, 200 µg/mL) decreased melanogenesis in cultured human melanoma HMV-II co-stimulated with phorbol-12-myristate-13-acetate. It also decreased production of inflammatory cytokines (PSE at 100 µg/mL), tumor necrosis factor-α and interleukin-6, in cultured human monocytic THP-1 cells in response to lipopolysaccharide. We isolated ten known proanthocyanidins and one new proanthocyanidin trimer from the PSE. The structure of the new compound (5) was determined by 1D- and 2D-NMR and mass spectrometry analyses, and was determined as epicatechin-(2β→O→7,4β→6)-epicatechin-(4β→6)-epicatechin. The other known proanthocyanidins were identified as proanthocyanidin monomers (1), dimers (69), trimers (35) and tetramers (2, 10, 11). They showed suppressive activities against melanogenesis and cytokine production at concentrations ranging from 0.1–10 µg/mL. Among the tested compounds, suppressive activities of proanthocyanidin dimers or trimers in two assay systems were stronger than those obtained with monomer or tetramers. These data indicate that proanthocyanidin oligomers from peanut skin have the potential to reduce dermatological conditions such as inflammation and melanogenesis.
  • Paola Neri, Shunji Tokoro, Tsuyoshi Sugiyama, Kouji Umeda, Takeshi Shi ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 917-923
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Previously, we have shown that chickens immunized with Shiga toxin (Stx) produce Stx-neutralizing egg yolk immunoglobulin Y (IgY) antibody. The anti-Stx-1 IgY and anti-Stx-2 IgY exert their neutralizing activity through their antibody activity against the B subunit of the toxin but not the A subunit. In the present study, chickens were immunized with recombinant Stx-1 B subunit (rStx-1B) and recombinant Stx-2 B subunit (rStx-2B). Induced anti-rStx-1B and anti-rStx-2B IgY neutralized the toxicity of Stx-1 and Stx-2 against HeLa 229 cells. The neutralizing activity of anti-rStx-1B IgY on Stx-1 was almost 10 times stronger than that of anti-Stx-1 IgY, and that of anti-rStx-2B IgY was 2.6 times stronger than that of anti-Stx-2 IgY. Anti-rStx-1B and anti-rStx-2B IgY reacted with multimeric and monomeric forms of the B subunits in contrast to anti-Stx-1 and anti-Stx-2 IgY that reacted with only the multimeric form. These results indicated that recombinant B subunits were promising antigens for induction of neutralizing antibodies in chickens.
  • Dinesh Thapa, Youra Kang, Pil-Hoon Park, Seok Kyun Noh, Yong Rok Lee, ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 924-932
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Cannabinoid compounds have been shown to exert anti-tumor effects by affecting angiogenesis, invasion, and metastasis. In the present study, we examined the action mechanism by which LYR-8, a novel hexahydrocannabinol analog, exerts anti-angiogenic and anti-tumor activity in human cancer xenografts. In the xenografted tumor tissues, LYR-8 significantly reduced the expression of hypoxia-inducible factor-1 alpha (HIF-1α), a transcription factor responsible for induction of angiogenesis-promoting factors, and its target genes, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). In HT-29 human colon cancer cells treated with a hypoxia-inducing agent (CoCl2), LYR-8 dose-dependently suppressed the induction of HIF-1α and subsequently its targets, VEGF and COX-2. In addition, highly elevated prostaglandin E2 (PGE2) concentrations in CoCl2-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl2 did not alter the basal expression of VEGF and COX-2, or PGE2 production. Furthermore, LYR-8 effectively suppressed Akt signaling, which corresponded to the suppression of CoCl2-induced HIF-1α accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1α activation, and subsequently suppressing factors regulating tumor microenvironment, such as VEGF and COX-2. These results indicate a novel function of cannabinoid-like compound LYR-8 as an anti-tumor agent with a HIF-1α inhibitory activity.
  • Shinji Okayasu, Kiyoyuki Kitaichi, Akina Hori, Tetsuya Suwa, Yukio Hor ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 933-937
    発行日: 2012/06/01
    公開日: 2012/06/01
    ジャーナル フリー
    Metformin is a drug to improve glycemic control by reducing insulin resistance and is currently considered to be one of the first-choice drugs for type 2 diabetes mellitus (T2DM). However, during metformin use, adverse drug reactions (ADRs) including gastrointestinal adverse events were frequently observed. Thus, in the present study, we investigated the incidence of ADRs induced by metformin and further analyzed risk factors for ADRs in Japanese patients with type 2 diabetes mellitus who initially administered metformin (500–750 mg). One hundred and one hospitalized patients receiving metformin during September 1, 2009 and August 31, 2010 were studied. The incidence of ADRs and changes in laboratory data including hemoglobin A1c (HbA1c) were monitored retrospectively. The anti-glycemic effect of metformin was successfully observed as indicated by decreased HbA1c. Among ADRs, diarrhea was most frequently occurred during metformin use (26.7% of patients) although the symptom of diarrhea was mild in most cases and disappeared within 3 d after the initial use. A logistic regression analysis showed the existence of six risk factors, including initial dose (750 mg), female, age (≦65), body mass index (≧25), aspartate aminotransferase (≧30 IU/L) and alkaline phosphatase (≧270 IU/L). The incidence of diarrhea increased linearly as the number of risk factors increased. In conclusion, in order to avoid ADRs, especially diarrhea, subsequently improving the quality of life during metformin use, the optimization of the dose of metformin by considering risk factors would be beneficial for patients with T2DM.
  • Yue Lu, Seok-Jong Suh, Xian Li, Jing Lu Liang, Meijuan Chi, Kyoung Hwa ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 938-945
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Citreorosein (CIT), an anthraquinone component of Polygoni cuspidati (P. cuspidati) radix, suppressed gene expression of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in mouse bone marrow-derived mast cells (BMMCs) stimulated with phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187. To investigate the molecular mechanisms underlying CIT inhibition of the pro-inflammatory cytokine production, its effects on the activation of both nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) were assessed. CIT attenuated phosphorylation of the MAPKs including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAP kinase and c-Jun NH2-terminal kinase (JNK). Furthermore, CIT strongly inhibited DNA binding activity of NF-κB through the inhibition of phosphorylation and degradation of inhibitor of kappaB (IκB) as well as activator protein-1 (AP)-1 through the reduction of phosphorylation of c-Jun. These results demonstrate that CIT inhibits proinflammatory cytokines production through the inhibition of both MAPKs and AKT-mediated IκB kinase (IKK) phosphorylation and subsequent inhibition of transcription factor NF-κB activation, thereby attenuating the production of proinflammatory cytokines.
  • Koji Miyawaki, Yoshihiro Miwa, Masafumi Seki, Seishi Asari, Kazunori T ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 946-949
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
  • Jeong Sook Noh, Chan Hum Park, Takashi Tanaka, Takako Yokozawa
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 950-956
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    The present study was conducted to examine whether 7-O-galloyl-D-sedoheptulose (GS) has an ameliorative effect on diabetic alterations such as oxidative stress, inflammation, and apoptosis in the liver of type 2 diabetic db/db mice. GS was administered at 20 or 100 mg/kg body weight per day for 6 weeks to db/db mice, and its effect was compared with vehicle-treated db/db and m/m mice. In the serum and hepatic tissue, biochemical factors and protein expressions associated with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, inflammation, and apoptosis were examined. As a result, GS administration to type 2 diabetic mice lowered serum and hepatic oxidative stress through the reduction of reactive oxygen species and lipid peroxidation. These results were derived, at least in part, from attenuating the expression of NADPH oxidase subunit proteins, Nox-4 and p22phox. In the diabetic condition, augmented nuclear factor (NF)-E2-related factor 2 and heme oxygenase-1 were reduced with a decrease in oxidative stress on GS treatment. Furthermore, in the GS-treated group, NF-kappa B-related pro-inflammatory factors and pro-apoptotic protein expressions were alleviated in the hepatic tissue. Taking these into consideration, our findings support the therapeutic evidence for GS ameliorating the development of diabetic complications via regulating oxidative stress, inflammation, and apoptosis.
  • Nobutomo Ikarashi, Risako Kon, Tomohiko Iizasa, Noriko Suzuki, Reiko H ...
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 957-962
    発行日: 2012年
    公開日: 2012/06/02
    ジャーナル フリー
    Aquaporin (AQP) 3, which is predominantly expressed in the colon, is considered to play an important role in regulating the fecal water content in the colon. In this study, the role of AQP3 in the colon was examined using HgCl2 and CuSO4, which are known to inhibit AQP3 function. The fecal water content was measured up to 1 h after the rectal administration of HgCl2 or CuSO4 to rats. The results showed that the fecal water content in the HgCl2 administration group increased significantly to approximately 4 times that in the control group, and severe diarrhea was observed. However, no changes were observed in the mRNA expression level of the osmoregulatory genes (sodium myo-inositol transporter and taurine transporter) and the level and distribution of AQP3 protein expression, as determined 1 h after the administration of HgCl2. Comparable results were observed in the CuSO4 administration group. The results of this study indicated that the inhibition of AQP3 function in the colon caused diarrhea. Therefore, it has been revealed that the fecal water content in the colon is controlled by the transport of water from the luminal side to the vascular side, which is mediated by AQP3. Our findings suggest that a drug that modulates the function or expression of AQP3 in the colon may represent a new target for the development of laxatives.
  • Morina Adfa, Tomohiro Itoh, Yosuke Hattori, Mamoru Koketsu
    原稿種別: Regular Article
    2012 年 35 巻 6 号 p. 963-966
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Coumarin and its derivatives are well known for their anti-inflammatory and anti-oxidative effects. In this study, we synthesized 32 coumarin derivatives from commercially available 6-hydroxycoumarin (6HC) and 7-hydroxycoumarin (7HC) and examined their effects on lipopolysaccharide/interferon γ (LPS/IFNγ)-stimulated nitric oxide (NO) production in murine macrophage RAW264 cells. Among these derivatives, 6HC-8 (6-(3-phenylpropoxy)coumarin), 6HC-14 (6-(2-octynyloxy)coumarin), 7HC-14 (7-(2-octynyloxy)coumarin), and 7HC-16 (7-(3,5-dimethoxybenzyloxy)coumarin) markedly suppressed NO production at low concentration (25 µM). These synthesized coumarin derivatives also markedly inhibited inducible NO synthase (iNOS) protein and mRNA expression, as assessed by western blotting and quantitative real time-polymerase chain reaction (RT-PCR).
Notes
  • Kaori Kadoyama, Toshiyuki Sakaeda, Akiko Tamon, Yasushi Okuno
    原稿種別: Note
    2012 年 35 巻 6 号 p. 967-970
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    The recent emergence of multidrug-resistant pathogens and/or pharmacokinetics-pharmacodynamics considerations may result in off-label use of a certain class of antibacterials, including tigecycline. This study was performed to clarify the safety profile of tigecycline in the user-derived manner and to compare it with the prescribing information provided by the manufacturer. Numerous spontaneous adverse event reports (AERs) submitted to the U.S. Food and Drug Administration (FDA) were analyzed after a revision of arbitrary drug names and the deletion of duplicated submissions. Standardized official pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Based on 22017956 co-occurrences, i.e., drug-adverse event pairs, found in 1644220 AERs from 2004 to 2009, 248 adverse events were suggested as tigecycline-associated ones. Adverse events with a relatively high frequency included nausea, vomiting, pancreatitis, hepatic failure, hypoglycemia, and increase in levels of alanine aminotransferase, bilirubin, alkaline phosphatase, aspartate aminotransferase, and gamma-glutamyltransferase. It is noted that cholestasis, jaundice, an increase in International Normalized Ratio, and Stevens–Johnson syndrome were also, although they were infrequent. The adverse events suggested were in agreement with information provided by the manufacturer, suggesting that off-label use hardly results in unexpected adverse events, presumably due to usage with extreme caution.
  • Hiroki Itoh, Yosuke Suzuki, Kanako Fujisaki, Yuhki Sato, Masaharu Take ...
    原稿種別: Note
    2012 年 35 巻 6 号 p. 971-974
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Therapeutic drug monitoring of valproic acid (VPA) is essential to prevent toxicity, but the correlation between plasma ammonia level and serum VPA concentration remains unclear. We examined the correlation of plasma ammonia level with VPA dose and serum trough concentrations of total and free VPA in Japanese patients with epilepsy. Thirty-eight data sets from 19 Japanese patients with epilepsy were analyzed. The relations of VPA dose and serum total and free VPA concentrations with plasma ammonia level, and the breakpoints of VPA parameters predicting hyperammonemia (plasma ammonia higher than 60 µmol/L) were analyzed. A significant positive correlation was observed between plasma ammonia level and VPA dose (rs=0.56, p=0.00062), serum trough total VPA concentration (rs=0.55, p=0.00086) and serum trough free VPA concentration (rs=0.58, p=0.00041). The breakpoints predicting hyperammonemia were VPA dose of 30.4 mg/kg, serum trough total VPA concentration of 90.9 µg/mL, and serum trough free VPA concentration of 8.65 µg/mL, with impurity reductions at 1.35, 1.35 and 2.02, respectively. These findings suggest that serum trough concentration of free VPA is the most reliable predictor for hyperammonemia, and that the risk of developing hyperammonemia may increase in patients with serum trough free VPA concentrations higher than 8.65 µg/mL.
  • Yuko Iwase, Yoshie Maitani
    原稿種別: Note
    2012 年 35 巻 6 号 p. 975-979
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Everolimus has demonstrated antitumor efficacy for various cancers as a result of its inhibition of the mammalian target of rapamycin (mTOR) signaling cascade, which activates cell growth and cell proliferation. However, the low water solubility and low bioavailability of everolimus have prevented its clinical development as an anticancer drug. Therefore, to address the unsuitable characteristic of everolimus, we attempted to prepare liposomal everolimus as a viable drug delivery system, and then evaluated the anticancer efficacy of this system against a medullary thyroid carcinoma cell line (TT cells), a breast cancer cell line (MCF-7 cells) and a small lung carcinoma cell line (NCI-H446 cells). The particle size and entrapment efficacy of liposomal everolimus was ca. 80 nm and more than 90%, respectively. Liposomal everolimus showed higher cytotoxicity against NCI-H446 cells compared with TT cells. Against NCI-H446 tumors, significant suppression of the tumor volume was observed in liposomal everolimus-treated mice by intravenous injection, compared with free everolimus-treated mice by intraperitoneal injection, at a dose of 5 mg/kg without body weight loss. This study showed that liposomal everolimus could be a powerful formulation with anticancer efficacy for some cancers.
  • Kaori Kiso, Satoko Ueno, Mana Fukuda, Ikuyo Ichi, Keiko Kobayashi, Tak ...
    原稿種別: Note
    2012 年 35 巻 6 号 p. 980-983
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Carbon tetrachloride (CCl4)-induced acute hepatitis is assumed to involve two phases. The initial phase, initiated within 2 h after CCl4 administration, involves the generation of reactive oxygen species. The second phase is assumed to start about 8 h subsequent to CCl4 administration and involves the oxidant-induced activation of Kupffer cells, which release various pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We investigated the role of Kupffer cells during CCl4 intoxication using Nucling-knockout mice (the KO group), in which the number of Kupffer cells is largely reduced. Plasma alanine transaminase and aspartate transaminase levels demonstrated that the liver necrosis during the second phase was significantly alleviated in the KO group compared with that in the wild-type mice (the WT group). Plasma TNF-α concentrations in the WT group significantly increased 24 h after CCl4 intoxication, whereas those in the KO group did not significantly increase. Plasma IL-6 levels also significantly increased in the WT group 24 h after CCl4 administration, but those in the KO group did not increase at any time point. These results indicated that excess reactions of Kupffer cells, once primed by oxidants, were involved in the exacerbation of oxidative stress and liver damage during the second phase of CCl4 intoxication.
  • Masahiro Ohgidani, Hideaki Ichihara, Koichi Goto, Yoko Matsumoto, Ryui ...
    原稿種別: Note
    2012 年 35 巻 6 号 p. 984-987
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Barely-Shochu is a traditional Japanese liquor distilled from fermented barley with Saccharomyces cerevisiae. Barely-Shochu distillation remnants (SDR) are by-products in the manufacturing process of barley-Shochu. We have already reported on valuable powder from Shochu distillation remnants (PSDR) including antioxidative compounds such as polyphenols. In this study, we investigated the therapeutic effects of barely-PSDR against orthotopic xenograft mouse models of hepatocellular carcinoma (HCC) in vivo. We constructed a mouse model of HCC by orthotopical inoculation of HepG2 cells into the liver of SCID mice. Barely-PSDR (2250 mg/kg) was orally treated once each day for 21 d after the inoculation of HepG2 cells. The livers were removed from anaesthetized mice after the treatment with barely-PSDR and fixed in formalin. The liver sections were analyzed by hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) methods. Remarkably high reduction of tumorigenesis was obtained in the mouse models of HCC after the oral administration of barely-PSDR in vivo. Induction of apoptosis in the liver section on the mouse models treated with barely-PSDR was observed. Furthermore, prolonged survival was obtained. Thus, therapeutic effects of barely-PSDR without side effects on the orthotopic xenograft mouse models were revealed for the first time.
  • Hironori Tsuchiya, Maki Mizogami, Takahiro Ueno, Kenji Shigemi
    原稿種別: Note
    2012 年 35 巻 6 号 p. 988-992
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    The cardiotoxic effects of local anesthetics increase in cardiac ischemia which is characterized by the tissue pH lowering to 6.5 or less. Apart from the cardiac channel blockade, the membrane interaction has been referred to as another mode of their cardiotoxic action. By using biomimetic membranes, we verified the hypothesis that bupivacaine and lidocaine may increasingly interact with cardiac mitochondrial membranes under ischemia-like acidic conditions. Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicles suspended in buffers of pH 7.4, 6.9, 6.4 or 5.9. Bupivacaine and lidocaine were reacted with the membrane preparations at cardiotoxically relevant concentrations and their membrane interactivities were determined by measuring fluorescence polarization. Both drugs interacted with 100 mol% 1,2-dipalmitoylphosphatidylcholine, peripheral nerve cell-mimetic and cardiomyocyte-mimetic membranes to increase membrane fluidity, although lowering the reaction pH from 7.4 to 5.9 decreased their membrane-fluidizing effects. In cardiomyocyte mitochondria-mimetic membranes containing 20 mol% cardiolipin, however, bupivacaine and lidocaine reversely increased their membrane interactivities at pH 5.9–6.4 compared with pH 7.4. Such increases were greater in anionic phospholipid membranes which consisted of substantial amounts of cardiolipin and phosphatidylserine. Positively charged bupivacaine and lidocaine would form ion-pairs with the negatively charged head-groups of anionic phospholipids under acidic conditions, thereby increasing the induced membrane fluidization. The mitochondrial membrane interactions depending on pH lowering may be, at least in part, responsible for local anesthetic cardiotoxicity enhanced in acidosis associated with cardiac ischemia.
  • Miyako Yanagihara, Maiko Yoshimatsu, Akinori Inoue, Tomoko Kanno, Tomo ...
    原稿種別: Note
    2012 年 35 巻 6 号 p. 993-996
    発行日: 2012/06/01
    公開日: 2012/06/02
    ジャーナル フリー
    Tyrosinase is the key enzyme involved in melanogenesis. The aim of this study was to investigate the in vitro inhibitory effects of gnetin C, a resveratrol dimer isolated from melinjo (Gnetum gnemon) seeds, on tyrosinase activity and melanin biosynthesis in murine B16 cells. The inhibitory activities of gnetin C and resveratrol were shown to be almost equal against tyrosinase and melanin biosynthesis in the cells. The IC50 values of gnetin C activity against tyrosinase and melanin biosynthesis were 7.0 and 7.6 µM, respectively, whereas resveratrol demonstrated IC50 values of 7.2 and 7.3 µM, respectively. These results indicated that gnetin C inhibited melanogenesis, in a manner similar to that of resveratrol, by inhibiting tyrosinase and may therefore function as a new skin-whitening agent. However, the direct effects of gnetin C and resveratrol on murine tyrosinase activities were not equal. The IC50 value of resveratrol was 10.1 µM, while gnetin C only exhibited a 25.2% enzyme inhibition at 16 µM. The IC25 values for gnetin C and resveratrol were 15.5 and 4.0 µM, respectively. Therefore, it is suggested that the effects of gnetin C may be due to mechanisms other than the direct inhibition of tyrosinase activity.
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