Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
27 巻 , 6 号
選択された号の論文の43件中1~43を表示しています
Review
  • Tomohide Kitano, Hisashi Iizasa, In-Won Hwang, Yoko Hirose, Tomonari M ...
    2004 年 27 巻 6 号 p. 753-759
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Syncytiotrophoblasts play an essential role in restriction of drug delivery through the blood-placenta barrier (BPB). Conditionally immortalized syncytiotrophoblast cell lines, TR-TBTs, were established at gestational day 18 from pregnant transgenic rats (Tg-rats) harboring the temperature-sensitive SV 40 (ts SV40) large T-antigen. TR-TBTs exhibit temperature-sensitive cell growth due to the expression of SV 40 large T-antigen, and thus the cell growth can be regulated by changing the culture temperature. TR-TBTs exhibit typical properties of syncytiotrophoblast cells, such as syncytium-like morphology, the expression of cytokeratins and hormones, and polarized expression of glucose transporter 1 (GLUT1) and GLUT3. TR-TBTs express in vivo influx and efflux transporters, such as taurine transporter (TauT), betaine/GABA transporter (BGT-1), amino acid transporter 2 (ATA2), organic anion transporting polypeptide 2 (oatp2), organic cation/carnitine transporter (OCTN2), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP/ABCG2). Moreover, TR-TBTs exhibit taurine, GABA, and DHEA-S uptake activity via TauT, BGT-1, and oatp2, respectively. Therefore, TR-TBTs can be used for the analysis of these functions and would be a good in vitro models for investigating carrier-mediated transport functions at the BPB.
Current Topics
  • Masafumi Tsujimoto
    2004 年 27 巻 6 号 p. 760
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
  • Susanna Renata Keller
    2004 年 27 巻 6 号 p. 761-764
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The insulin-regulated aminopeptidase (IRAP) is a member of the family of zinc-dependent membrane aminopeptidases. It is the homolog of the human placental leucine aminopeptidase (P-LAP). IRAP is expressed in different cell types but has been best characterized in two major insulin target cells, muscle and fat. In these cells IRAP localizes to intracellular membrane compartments under basal conditions. In response to insulin IRAP redistributes to the cell surface. IRAP shares this behavior with the insulin-responsive glucose transporter GLUT4. It is established that insulin's dramatic effect on glucose disposal is mediated through its action on GLUT4. The role IRAP plays in insulin action is unknown. IRAP cleaves several peptide hormones in vitro. In insulin-treated cells, concomitant with the appearance of IRAP at the cell surface, aminopeptidase activity toward extracellular substrates increases. Thus, insulin, by bringing IRAP to the cell surface, could increase the processing of extracellular peptide hormones and thereby change their activities. Investigations are underway to determine the in vivo substrates for IRAP and to measure the effect of insulin on the cleavage of identified substrates. In individuals with type 2 diabetes the insulin-stimulated translocation of IRAP to the cell surface of muscle and fat cells is impaired. This defect may lead to decreased cleavage and consequently increased action of peptide hormones that are substrates for IRAP. Impaired IRAP action may thus play a role in the development of complications in type 2 diabetes. The findings of decreased expression of GLUT4 and increased heart size in mice in which IRAP was deleted support this hypothesis.
  • Anthony Lloyd Albiston, Ruani Fernando, Siying Ye, Grantley Ross Peck, ...
    2004 年 27 巻 6 号 p. 765-767
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The angiotensin AT4 receptor was originally defined as the specific, high affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT4 receptor. Central administration of Ang IV or LVV-hemorphin 7 (LVV-H7) markedly enhances learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The high affinity binding site has a broad distribution in the brain including areas such as the hippocmapus that are involved in memory processing. The high affinity Ang IV binding site (AT4 receptor) has been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). Insulin-regulated aminopeptidase is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and in insulin-responsive cells colocalizes with GLUT4 in specific intra-cellular vesicles. Both Ang IV and LVV-H7 are competitive inhibitors of IRAP catalytic activity and are not substrates of the enzyme.
  • Takashi Mitsui, Seiji Nomura, Atsuo Itakura, Shigehiko Mizutani
    2004 年 27 巻 6 号 p. 768-771
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    In addition to the neural and autoregulatory factors, blood pressure (BP) is regulated by humoral factors including vasoactive peptides. When evaluating the peptide actions, degradation by proteases should be also considered in addition to the generation of peptides and their receptors. This review describes the roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP) and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the association of the proteases with preeclampsia, hypertensive disorder peculiar to pregnancy, since one of the representative organs that are rich in theses proteases is placenta. Although the physiological roles of the placental proteases have not been fully understood, several lines of evidence suggest that the proteases are involved in the maintenance of pregnancy homeostasis including fetal and maternal BP regulation through the metabolism of bioactive peptides at the interface between mother and fetus.
  • Yasufumi Sato
    2004 年 27 巻 6 号 p. 772-776
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Microvessels are composed of endothelial cells and surrounding pericytes. Angiogenesis, a neo-vessel formation from pre-existing microvessels, is a complex phenomenon, which requires following sequential steps: detachment of pre-existing pericytes for vascular destabilization, extracellular matrix turnover, migration, proliferation, tube formation by endothelial cells (ECs), and reattachment of pericytes for vascular stabilization. Aminopeptidases regulate the N-terminal modification of proteins and peptides for maturation, activation or degradation, and thereby relate to a variety of biological processes. Recently, three aminopeptidases have been reported to be involved in angiogenesis. They include type 2 methionine aminopeptidase, aminopeptidase N, and adipocyte-derived leucine aminopeptidase/puromycin insensitive leucyl-specific aminopeptidase. This review will focus on the possible role of these aminopeptideses in angiogenesis.
  • Akira Hattori, Masafumi Tsujimoto
    2004 年 27 巻 6 号 p. 777-780
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Antigenic peptides presented to major histocompatibility complex (MHC) class I molecules are generated in the cytosol during degradation of cellular proteins by the ubiquitin-proteasome proteolytic pathway. Proteasome can generate N-extended precursors as well as final epitopes, and then the precursors are processed to mature epitopes by aminopeptidases. Both cytosolic peptidases (i.e. puromycin-sensitive aminopeptidase, bleomycin hydrolase and interferon-γ-inducible leucine aminopeptidase) and recently identified metallo-aminopeptidase located in the endoplasmic reticulum (i.e. adipocyte-derived leucine aminopeptidase/endoplasmic reticulum aminopeptidase 1 and leukocyte-derived arginine aminopeptidase) can generate final epitopes from precursor peptides. Some of these aminopeptidases are also considered to destroy certain antigenic peptides to limit the antigen presentation. Taken together, it is getting evident that aminopeptidases located in the cytosol and the lumen of endoplasmic reticulum play important roles in the generation of antigenic peptides presented to MHC class I molecules.
Analytical Biochemistry
Notes
Biochemistry/Molecular Biology
Regular Articles
  • Masashi Hyuga, Sumiko Hyuga, Nana Kawasaki, Miyako Ohta, Satsuki Itoh, ...
    2004 年 27 巻 6 号 p. 781-785
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    N-Acetylglucosaminyltransferase III (GnT-III), which catalyzes the synthesis of a bisecting GlcNAc residue of N-glycans, is thought to be involved in the function of glycoproteins such as growth factor receptors. We investigated the effects of the overexpression of GnT-III on the hepatocyte growth factor (HGF) receptor c-Met, a glycoprotein, in human hepatocarcinoma HepG2 cells. GnT-III activity was elevated about 250-fold in HepG2 cells stably transfected with the GnT-III gene, whereas no significant change in GnT-III activity was observed in mock transfectants. Cell scattering assay revealed that HGF-induced cell scattering was enhanced depending on the GnT-III activities in the GnT-III transfectants. Western blot analysis and E-PHA lectin blot analysis showed that the level of c-Met protein was the same in both transfectants; however, the bisecting GlcNAc residue on c-Met was detected only in the GnT-III transfectants. Although the peak level of c-Met phosphorylation was not different in both transfectants, the level of tyrosine phosphorylation of c-Met decreased more rapidly in the GnT-III transfectants than in the mock transfectants. Furthermore, HGF-induced extracellular-regulated kinase (ERK) phosphorylation was slightly higher in the GnT-III transfectants than in the mock transfectants. These results show that overexpression of GnT-III in HepG2 cells enhances HGF-induced cell scattering, which may result from, at least in part, enhancement of HGF-induced ERK phosphorylation.
  • Seung Ho Lee, Min Jung Son, Hye Kyung Ju, Chang Xiu Lin, Tae Chul Moon ...
    2004 年 27 巻 6 号 p. 786-788
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Deoxypodophyllotoxin (Anthricin) is a medicinal herbal product isolated from Anthriscus sylvestris HOFFM. that inhibits cyclooxygenase-2 (COX-2) and COX-1-dependent phases of prostaglandin D2 (PGD2) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner with IC50 values of 1.89 μM and 65.3 μM, respectively. This study also found that this compound inhibited COX-1 and 2-dependent conversion of the exogenous arachidonic acid to PGD2 in a dose-dependent manner with an IC50 values of 0.01 μM and 12.1 μM, respectively using a COX enzyme assay kit. However, this compound did not inhibit COX-2 protein expression up to a concentration of 30 μM in the BMMC, indicating that deoxypodophyllotoxin directly inhibits COX-2 activity. Furthermore, this compound consistently inhibited the production of leukotriene C4 (LTC4) in a dose dependent manner, with an IC50 value of 0.37 μM. These results demonstrate that deoxypodophyllotoxin has a dual cyclooxygenase-2 selective/5-lipoxygenase inhibitory activity, and therefore this compound might provide a basis for novel anti-inflammatory drugs.
  • Tomoyasu Watanabe, Hirofumi Satoo, Kazuhisa Kohara, Reiko Takami, Tosh ...
    2004 年 27 巻 6 号 p. 789-796
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Orthovanadate (vanadate) as well as insulin stimulated phosphodiesterase 3 (PDE3) in the particulate fraction of rat hepatocytes. The vanadate-induced activations of PDE3 and mitogen-activated protein kinase (MAPK) were inhibited by H-89 and PD98059, suggesting that the MAPK activation via cAMP-dependent protein kinase (PKA) and MAPK kinase is involved in the vanadate action. On the other hand, the insulin-induced activations of PDE3 and Akt were inhibited by wortmannin, suggesting involvement of the Akt activation via phosphatidylinositol 3-kinase (PI3K) in the insulin action. The vanadate-induced activations of PKA and PDE3 were inhibited in part by propranolol or genistein, suggesting that vanadate may exert its actions via dual signaling pathways of β-adrenergic receptors and receptor tyrosine kinases of growth factors. Vanadate, in contrast to insulin, did not promote the phosphorylation of insulin receptor substrate-1. The vanadate-induced increase in the phosphorylation of a main isoform of MAPKs, p44 protein, was detected by immunoblotting migration patterns of SDS-PAGE. A partially purified PDE3 activity was increased by addition of MAPK or Akt to the reaction mixture, suggesting that MAPK as well as Akt acts upstream of PDE3. The activation of PDE3 by insulin was independent of a transient increase in the MAPK activity, probably due to the dephosphorylated inactivation mediated by the induced activation of MAPK phosphatases (MKPs). Vanadate did not affect the MKP activity. These results indicate that vanadate stimulates the particulate PDE3 activity by activating mainly p44 MAPK via a PKA-dependent process, and that it differs from insulin with regard to a phosphorylation cascade of PDE3 activation.
Notes
  • Yuki Kitabatake, Shunsuke Kawamura, Masamichi Yamashita, Kaori Okuyama ...
    2004 年 27 巻 6 号 p. 896-898
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) belong to a calcitonin-family of regulatory peptides. Receptors for CGRP and ADM have been suggested to be present on both mucosal (MMC) and connective tissue (CTMC) type of mast cells, based on histamine release by these peptides. Recently, it was reported that mRNA for ADM receptors, but not for CGRP receptors, was expressed in rat peritoneal mast cells, a representative of type CTMC. However, mRNA expression for the receptors in MMC has not been studied yet. Therefore, we examined whether mRNAs encoding CGRP or ADM receptor subunit, RDC-1, calcitonin receptor-like receptor (CRLR), and receptor activity-modifying proteins (RAMPs) are present, and if so, whether their expression is modified by IgE receptor triggering, in a mucosal type mast cell line, rat basophilic leukemia (RBL-2H3) cells using RT-PCR. RBL-2H3 cells constitutively express mRNA for RDC-1, CRLR, RAMP3 but not that for RAMP1 and RAMP2, and IgE receptor triggering was shown neither to induce the gene expression of RAMP1 and RAMP2, nor to enhance that of RDC-1, CRLR or RAMP3. These results indicate that RBL-2H3 cells posses receptors for both CGRP and ADM, suggesting various functions of these peptides in physiological and pathophysiological conditions where mast cells of the mucosal type are involved.
  • Yasuhiro Morita, Eiko Matsumura, Toshihiro Okabe, Toru Fukui, Mitsunob ...
    2004 年 27 巻 6 号 p. 899-902
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    α-Thujaplicin, a minor component of Aomori Hiba (Thujopsis dolabrata SIEB. et ZUCC. var. hondai MAKINO), showed rather strong antifungal activity against seven kinds of plant-pathogenic fungi, their minimum inhibitory concentrations (MICs) being in the range of 12.0—50.0 μg/ml. α-Thujaplicin and hinokitiol (the major component of Aomori Hiba) also showed clear antibacterial activity against Legionella pneumophila SG 1 and L. pneumophila SG 3, and their MICs are in the range of 6.25—50 μg/ml. This compound showed strong insecticidal activity against Reticulitermes speratus [50%-lethal concentration (LC50): 0.02 g/m2], and it also had clear acaricidal activity against Dermatophagoides farinae (LC50: 0.66 g/m2). At 24 h after treatment, α-thujaplicin at 0.63 μg/ml inhibited the cell growth of murine P388 lymphocytic leukemia by 78%, and its cytotoxic activity at a concentration higher than 0.63 μg/ml was as high as that of vincristine, used as a positive control. On the other hand, the cytotoxic effect of α-thujaplicin at 0.63 μg/ml was weaker than that of vinblastine. In this respect, the strong cytotoxic effect of α-thujaplicin on murine P388 lymphocytic leukemia cell line should be emphasized, considering that it has recently been found to be low in toxicity to mice.
  • Yoshihiro Konno, Masakuni Degawa
    2004 年 27 巻 6 号 p. 903-905
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    We investigated the gene activations of CYP2B1 and CYP3A1 by 1,4-dihydropyridine calcium channel antagonists, including nifedipine (Nif), nisoldipine (Nis), nitrendipine (Nit), nimodipine (Nim), and nicardipine (Nic), in the rat liver and their structure–activity relationships. All calcium channel antagonists used have nitrophenyl substituents at the 4-position of the dihydropyridine ring and their nitro group was located at o- or m-position. The m-nitro derivatives Nic, Nim, and Nit showed much higher capacities for activating CYP3A1 than the o-nitro derivatives Nif and Nis. On the other hand, in the activation of CYP2B1, the length of the side chain at the 3-position of the dihydropyridine ring was correlated with the activating capacity of each chemical, and Nif and Nit, with a shorter side chain than the other calcium channel antagonists examined, had potent capacities. The present findings suggest that the ability of dihydropyridine calcium channel antagonists to activate the CYP2B1 and CYP3A1 are mainly dependent on the length of the side chain at the 3-position of the dihydropyridine ring and the position of the nitro group in the nitrophenyl substituent, respectively.
Pharmacology
Regular Articles
  • Xingchao Geng, Liangwen Song, Xiaoping Pu, Pengfei Tu
    2004 年 27 巻 6 号 p. 797-801
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been employed to create a Parkinson's disease-like model in both rodents and primates based primarily on its ability to create a striatal dopamine deficit due to the loss of dopaminergic neurons in the substantia nigra compacta. The present study was carried out to determine the possible effects of phenylethanoid glycosides (PhGs) from Cistanches salsa (C. A. MEY, G. BECK) on attenuating the serious behavioral disorder and increasing dopamine (DA) levels in the striata of MPTP-lesioned C57 mice. MPTP (30 mg/kg i.p. for 4 d) induced serious behavioral disorders and significantly reduced striatal DA levels in C57 mice. In spontaneous motor activity and rotarod tests, obvious behavioral differences were seen between control and model groups. PhGs (10, 50 mg/kg) significantly increased the spontaneous movement number and latent period of mice on the rotating rod (p<0.01). Injections of MPTP 30 mg/kg for 4 d caused a significant reduction in DA, 3,4-dihydroxyphenyl acetic acid, and homovanillic acid in striata analyzed by HPLC-electrochemistry (p<0.01). The neurotoxic effects of MPTP were attenuated by pretreatment with PhGs (10, 50 mg/kg) in a dose-dependent fashion. The apparent neuroprotective effects of PhGs on nigral dopaminergic neurons were also confirmed by the results of immunohistochemical staining. The present in vivo data clearly demonstrate that PhGs can protect dopaminergic neurons against dopamine neurotoxicity induced by MPTP, as suggested by an earlier in vitro study. The neuroprotective effects of PhGs were the first reported for a natural product.
  • Ya-Mei Yu, Weng-Cheng Chang, Chu-Sun Liu, Ching-Min Tsai
    2004 年 27 巻 6 号 p. 802-805
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Forty hyperlipidemic patients, smokers and non-smokers, were studied. Subjects received 15 g young barley leaf extract (BL) or 60 g adlay daily for four weeks. Overnight fasting blood samples were drawn immediately prior to and after four weeks of supplementation. Blood samples were analyzed for plasma lipid profiles and their susceptibility to low-density lipoprotein (LDL) oxidation. The plasma total and LDL-cholesterol (LDL-C) levels were reduced following treatment with either BL or adlay; furthermore, the lag phase of LDL oxidation increased after either supplementation. However, it seemed that BL had stronger antioxidative effect on the prevention of LDL oxidation than adlay. Our results also indicated that the antioxidative effect was less pronounced in smokers than in non-smokers. Therefore, supplementation with BL or adlay can decrease plasma lipids and inhibit LDL oxidation in hyperlipidemic smokers and/or non-smokers.
  • Yeun-Ja Mun, Sung-Won Lee, Hyun-Woo Jeong, Kwang-Gyu Lee, Joung-Hoon K ...
    2004 年 27 巻 6 号 p. 806-809
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Miconazole (MIC), a regional antifungal agent, has been used worldwide in the treatment of superficial mycosis. However, the effect of MIC on skin pigmentation is not known. In this study, we investigated the inhibitory effect of MIC on melanogenesis in B16 melanoma cells. Tyrosinase activity and melanin content were dose dependently decreased by MIC as compared with untreated cells. The level of tyrosinase protein expression was reduced with treatment MIC. A decrease in cell proliferation was observed in B16 cells treated with MIC 30 μM, indicating that the MIC-induced depigmenting effect was caused by inhibition of melanin synthesis and not by destruction of B16 cells. Furthermore, MIC markedly suppressed α-melanocyte stimulating hormone or forskolin-induced tyrosinase activity in B16 cells. Therefore the depigmenting effect of MIC might be due to the inhibition of tyrosinase activity and tyrosinase expression, which eventually slows melanin biosynthesis. These results indicate that MIC may be a useful inhibitor of melanogenesis in B16 cells and suggest that it may have beneficial effects in the treatment of hyperpigmentation disorders such as ephelis and melasma.
  • Tao Ma, Ying-Lin Cao, Bei-Bei Xu, Xiao-Mian Zhou
    2004 年 27 巻 6 号 p. 810-812
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The effect of (3,5,6-trimethylpyrazin-2-yl)methyl 2-[4-(2-methylpropyl)phenyl]propanoate (ITE) on type II collagen (CII)-induced arthritis in mice was studied. Mice were immunized twice with CII, ITE being given orally once a day for 40 d after the 1st immunization. Clinical assessment showed that ITE had no effect on the day of onset of arthritis but did lowered the incidence rate of arthritis and the arthritis score. And ITE had a marked suppressive effect on the mouse`hind paw edema induced by CII. ITE suppressed the delayed-type mouse ear skin reaction to CII but had no effect on the level of serum anti-CII antibodies. These results suggest that ITE inhibits the development of CII-induced arthritis in mice by suppressing delayed-type hypersensitivity to CII.
  • Atsushi Nishida, Hiroshi Iwata, Yukitsuka Kudo, Tsutomu Kobayashi, Yuz ...
    2004 年 27 巻 6 号 p. 813-816
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    To establish an assay system for evaluation of the uptake and reversed transport of glutamate, we examined the effects of Na+-concentration and pharmacological agents on the extracellular glutamate concentration ([Glu]o) in rat cortical synaptosomes in vitro. There was a decrease and increase of the [Glu]o at high and low Na+ concentrations, respectively, in a Ca2+-free medium. The changes in [Glu]o in both directions were temperature-sensitive, and reversed at around 30 mM of Na+. Dihydrokainate (DHK), a non-transportable inhibitor selective for glial glutamate transporter GLT-1, suppressed the decrease in [Glu]o, and the reversal of [Glu]o change was shifted to about 60 mM Na+. There was no change in the maximum [Glu]o at total Na+ substitution. Further pharmacological analysis revealed that D-aspartate and DL-threo-β-hydroxy-aspartate (THA), transportable substrates of glutamate transporters, increased the [Glu]o in standard media. In contrast, β-phenylglutamic acid, a structural analogue of glutamate, suppressed both the decrease in [Glu]o in standard medium and the increase in [Glu]o in low Na+ medium. It is, thus, concluded that both the direction and the amount of [Glu]o changes are determined by a balance of the uptake and reversed transport of glutamate, and that this assay system is suitable for evaluation of the effect of this on glutamate transporters.
  • Atsushi Nishida, Hiroshi Iwata, Yukitsuka Kudo, Tsutomu Kobayashi, Yuz ...
    2004 年 27 巻 6 号 p. 817-820
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    To elucidate the mechanisms of neuroprotective action of nicergoline, we examined its effect on glutamate transport in rat cortical synaptosomes and cloned glutamate transporters. In synaptosomes, nicergoline enhanced the glutamate uptake at 1—10 μM in standard medium and suppressed the increase of extracellular glutamate by reversed transport in low Na+ medium. Apparent increase of extracellular glutamate concentration by dihydrokinate, an inhibitor of glial glutamate transporter GLT-1, was antagonized by nicergoline. In Xenopus oocytes expressing mouse neuronal glutamate transporter (mEAAC1), the glutamate-induced inward current was enhanced by nicergoline. These results suggest that nicergoline reduces the extracellular glutamate concentration through its effect on glutamate transporters.
  • Letícia Veras Costa-Lotufo, David Freitas de Lucena, Manoel And ...
    2004 年 27 巻 6 号 p. 821-824
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    This work studied antinociceptive, antiedematogenic and central depressor effects of the hydroalcoholic extract (HAE) from Aeolanthus suaveolens and its fractions: hexane (ASHAE-H), ethyl acetate (ASHAE-A), aqueous (ASHAE-E) and precipitate (ASHAE-PPT) in experimental models in mice. The highest activity in the writhing test was presented by ASHAE-A followed by ASHAE-PPT and ASHAE-E and the lowest by ASHAE-H. In the formalin test the effect was manifested at both phases, although more intensely at the 2nd phase of the response. In this test, the most active fraction was ASHAE-PPT causing inhibitions of the order of 76 and 90% of the 2nd phase of the test at the doses of 10 and 100 mg/kg i.p., respectively. Naloxone reversed the effects of ASHAE-PPT in both phases of the test, suggesting the participation of the opioid system in the antinociceptive effect. On the other hand, the HAE effect on both phases of the formalin test was only partially reversed by naloxone, suggesting that the extract presents more than one active compound, and at least one, of a polar nature, acting through the opioid system. HAE and ASHAE-PPT presented antiinflammatory activity and were very effective in decreasing the mouse paw edema induced by carrageenan. All fractions significantly decreased locomotor activity in the open field test in mice. However, only the nonpolar fractions presented myorelaxant activity as demonstrated by the rota rod test.
  • Kazuya I. P. J. Hidari, Eisaku Tsujii, Jun Hiroi, Eriko Mano, Akihiko ...
    2004 年 27 巻 6 号 p. 825-830
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Disodium cromoglycate (DSCG) is one of the safest drugs for the prevention of bronchial asthma and allergic rhinitis attacks. The effect of DSCG on acute upper respiratory tract viral infection is still controversial. Here we investigated DSCG inhibition of influenza virus infection in vivo and in vitro. In vivo effects of DSCG on viral infection were assessed using a murine model of respiratory tract infection. Intranasal administration of DSCG protected mice from death induced by infection with influenza virus A/PR/8/34. We analyzed DSCG anti-viral effects in vitro by either (i) treating cells prior to viral adsorption, (ii) treating cells concurrently with viral adsorption, or (iii) treating cells after viral adsorption. DSCG treatment of cells during or after, but not before, viral adsorption significantly inhibited influenza viral infection, indicating DSCG acts on events late in viral infection. DSCG exerts anti-influenza effect both in vitro and in vivo at the doses compatible with treatment for asthma. DSCG marginally inhibited influenza viral neuraminidase and membrane fusion functions, suggesting that DSCG inhibition of viral neuraminidase and fusion activities may partially mediate this anti-influenza effect. Our results indicate that treatment of patients including children with DSCG may take advantages for prevention from influenza virus infection.
Notes
  • Yong Soo Kwon, Toshitaka Nabeshima, Eun-Joo Shin, Wanjoo Chun, Jin Hye ...
    2004 年 27 巻 6 号 p. 906-909
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The effect of PAP 9704, a traditional prescription in Korea consisting of Polygala tenuifolia, Acorus gramineus, and Poria cocos at a ratio of 1 : 1 : 1 (dry weight), on methamphetamine (MA)-induced hyperlocomotion was examined in mice. The increased locomotor activity induced by MA (1 mg/kg/d, i.p.×7) was significantly attenuated by co-administration with PAP 9704 (100 or 200 mg/kg/d, p.o.×7) in a dose dependent manner. Consistently, it was found that the hyperlocomotor activity occurred in parallel with the expression of striatal fos-related antigen immunoreactivity. The adenosine A2A receptor antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1.0 mg/kg, i.p.), significantly reversed the pharmacological action of PAP 9704 in a dose related manner, but the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (0.5 or 1.0 mg/kg, i.p.) and the A2B receptor antagonist alloxazine (1.5 or 3.0 mg/kg, i.p.) did not significantly affect this pharmacological action. Our results suggest that PAP 9704 prevents MA-induced hyperlocomotion, at least in part, via the stimulation of the adenosine A2A receptor.
  • Damião Pergentino de Sousa, Ellen Raphael, Ursula Brocksom, Tim ...
    2004 年 27 巻 6 号 p. 910-911
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    2-Phenylselenenyl-1,8-cineole (PSC) increased both the pentobarbital-induced sleeping time and the reaction time (up to 2 h) in the tail immersion method. PSC also caused dose-dependent inhibition of acetic acid induced writhing with maximum inhibition of 93.4% and was approximately 8.5-fold more potent than 1,8-cineole. These findings show that PSC presents sedative effect and significant antinociceptive activity.
Toxicology
Regular Articles
  • Masahiro Kozuka, Yasuhisa Tsujimoto
    2004 年 27 巻 6 号 p. 831-834
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    L-Ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] potassium salt (EPC-K1) is a conjugate of vitamin C and vitamin E that is water-soluble and stable at room temperature. EPC-K1 has been developed as a hydroxyl radical (·OH) scavenger and antioxidant. In a previous tooth whitening experiment, it was accidentally found that tooth (dentin) blocks were dissolved by EPC-K1 with H2O2. In the current study, high concentrations of EPC-K1 (2.5, 25 mM) with 3% H2O2 dissolved and caused the collapse of dentin blocks. Similar concentrations of EPC-K1 without 3% H2O2, however, dissolved the dentin blocks without collapse over a 3-week period. In these cases, a ·OH-like signal was detected using an ESR spin-trapping method. The volume of calcium in solution (including the dentin block) increased on the addition of EPC-K1 in a concentration-dependent manner. In addition, the calcium : phosphorus ratio changed from 2 : 1 in sound dentin to 1 : 2 in the collapsed dentin block. High concentrations of EPC-K1 are therefore considered to have calcium chelating and dentin dissolving activity. The dentin dissolving activity was enhanced when EPC-K1 was used with H2O2. EPC-K1 had no protective effect when used in tooth whitening with H2O2.
  • Shinji Taneda, Yoki Mori, Kazuyuki Kamata, Hideyuki Hayashi, Chie Furu ...
    2004 年 27 巻 6 号 p. 835-837
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    We recently isolated 4-nitrophenol, 2-methyl-4-nitrophenol, 3-methyl-4-nitrophenol, and 4-nitro-3-phenylphenol from diesel exhaust particles (DEP) and identified them as vasodilators. Because these compounds are alkylphenolic derivatives that might mimic hormones, we evaluated their estrogenic activity by human estrogen receptor (hER)-yeast screen assay. All of these nitrophenol derivatives except 2-methyl-4-nitrophenol exhibited estrogenic activity. Some estrogenic compounds are also anti-androgenic, so we measured the anti-androgenic activity of the same compounds by human androgen receptor (hAR)-yeast screen assay. We found anti-androgenicity in all four nitrophenols. Nitrophenols in DEP possess not only vasodilatory activity but also estrogenic and anti-androgenic activity.
Medicinal Chemistry
Regular Articles
  • Rong-Fu Chen, Chung-Long Chou, Ming-Ren Wang, Chieh-Fu Chen, Jyh-Fei L ...
    2004 年 27 巻 6 号 p. 838-845
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    A series of anthracene derivatives have been synthesized, and their potential individual cytotoxicity was evaluated using Jurkat T cells and peripheral blood mononuclear cells (PBMCs) in vitro. These compounds, except for 2l, showed less cytotoxicity in PBMCs than mitoxantrone. We also analyzed the antiproliferative activity of these derivatives using the annexin V/propidium iodide assay. These synthetic compounds induced apoptosis, thus leading to antitumor effects. Compounds 2b, 2e, 2f, 2g, 2h, 2i, 2j, and mitoxantrone produced dose-dependent cytotoxicity, while the antiproliferative activity of the anthracene pharmacophore was retained in Jurkat T cells base on the detection of DNA degradation and membrane unpacking. These clearly indicate a correlation between cytotoxicity and antitumor activity. Unlike mitoxantrone, cytotoxic properties were observed, as documented by the reactivity of these novel compounds against Jurkat T cells and PBMCs as normal cells, respectively. Various concentrations of 2b, 2e, 2f, 2g, 2h, 2i, and 2j preparations also inhibited Jurkat T cell proliferation and induced apoptosis of Jurkat T cells, potentially confirmed through the detection of DNA degradation and membrane unpacking. In the present report we also investigated the antiinflammatory activity against phorbol-12-myristate-13-acetate induced superoxide anion production, a marker for an inflammatory mediator produced by neutrophils, with IC50M) values of 2b, 2h, 2l, and 2o of 4.28±0.89, 3.31±0.88, 4.38±0.25, and 5.45±1.78, respectively. These results suggest that, in addition to the specific chromosomal aberrations and cell death, elevated apoptosis could also be a marker for exposure to anthracene derivatives.
  • Atsushi Shimazaki, Hiroshi Suhara, Masaki Ichikawa, Takeshi Matsugi, K ...
    2004 年 27 巻 6 号 p. 846-850
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    A series of ethacrynic acid (ECA) derivatives were synthesized and examined for ocular hypotensive activity. Efficacy was evaluated in a cell-shape assay, using human trabecular meshwork cells, and cytotoxicity in a (3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, using cultured bovine trabecular meshwork cells. Many of the derivatives demonstrated efficacy equal to or greater than that of ECA. SA9000 was selected as the most promising candidate for a novel ocular hypotensive drug with few side effects.
  • Wanchun Jin, Yoshichika Arakawa, Hisami Yasuzawa, Tomoko Taki, Ryo Has ...
    2004 年 27 巻 6 号 p. 851-856
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    For the purpose of screening of inhibitors that are effective for wide range of metallo-β-lactamases, the inhibitory effect of two series of compounds, 2-ω-phenylalkyl-3-mercaptopropionic acid (PhenylCnSH (n=1—4)) and N-[(7-chloro-quinolin-4-ylamino)-alkyl]-3-mercapto-propionamide (QuinolineCnSH (n=2—6)), where n denotes the alkyl chain length, on metallo-β-lactamases IMP-1 and VIM-2 was examined. These inhibitors contain a thiol group and a hydrophobic group linked by variable-length methylene chain. PhenylCnSH (n=1—4) was found to be a potent inhibitor of both IMP-1 and VIM-2. PhenylC4SH was the potent inhibitor of both IMP-1 (IC50=1.2 μM) and VIM-2 (IC50=1.1 μM) among this study. When the number of methylene units was varied, QuinolineC4SH showed the maximum inhibitory activity against IMP-1 and VIM-2 (IC50=2.5 μM and IC50=2.4 μM). The relationship between the inhibitory effect of the alkyl chain length was different for both series of inhibitors, suggesting that IMP-1 has a tighter binding site than VIM-2. QuinolineCnSH did not serve as a fluorescence reagent for metallo-β-lactamases.
Notes
Pharmacognosy
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  • Makoto Inoue, Yuka Ono, Hajime Mizukami
    2004 年 27 巻 6 号 p. 857-862
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Dai-bofu-to (DBT) is a traditional Japanese herbal medicine (Kampo medicine) used for the treatment of rheumatoid arthritis (RA). In the present study, to establish the usefulness of DBT, we examined the effect of DBT on collagen-induced arthritis (CIA). DBT (1.72 g/kg/d) significantly reduced the severity of arthritis throughout the experiment and significantly delayed the onset of arthritis. The induction of CIA decreased T cells and increased B cells in popliteal lymph nodes close to the affected joints, while the treatment of CIA with DBT counteracted the changes in T and B cells. In pX transgenic mice as a spontaneously developed arthritis model, a decrease in T cells and increase in B cells in popliteal lymph nodes were observed, as compared to BALB/c mice, the littermates of pX transgenic mice. In contrast, DBT returned the cell number of T and B cells to the level of BALB/c mice. As osteoclastogenesis is regulated by some T cell cytokines and osteotropic factors, we examined the effect of DBT on the receptor activator of NF-κB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG) and M-CSF mRNAs, which were induced by arthritis induction. Although DBT had no effect on RNAK or RANKL mRNA levels, DBT stimulated an increase in OPG mRNA levels and suppressed an increase in M-CSF mRNA level. These results suggest that DBT may possess an anti-osteoclastogenetic effect, which is brought by reducing the ratio of RANKL/OPG and by decreasing M-CSF mRNA levels. In conclusion, immunomodulatory and anti-osteoclastogenetic effects might be involved in the suppression of arthritis by DBT.
  • Eui-Ju Hong, Ki-Jeung Na, In-Gyu Choi, Kyung-Chul Choi, Eui-Bae Jeung
    2004 年 27 巻 6 号 p. 863-866
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Essential oils have potential biological effects, i.e., antibiotic, anticarcinogenic, and sedative effects during stress. In the present study, we investigated the antibacterial and antifungal effects of essential oils extracted from the coniferous species Pinus densiflora, Pinus koraiensis, and Chamaecyparis obtusa, because their biological activities have not been yet elucidated. The essential oils were quantified using gas chromatography and identified in gas chromatography-mass spectrometric analysis. Simultaneously, antibacterial and antifungal assays were performed using the essential oils distilled from the needles of coniferous trees. The major components and the percentage of each essential oil were: 19.33% β-thujene in P. densiflora; 10.49% α-pinene in P. koraiensis; 10.88% bornyl acetate in C. obtusa. The essential oils from P. densiflora and C. obtusa have antibacterial effects, whereas essential oils from P. koraiensis and C. obtusa have antifungal effects. These results indicate that the essential oils from the three coniferous trees, which have mild antimicrobial properties, can inhibit the growth of gram-positive and gram-negative bacteria and fungi.
  • Dan Yuan, Junna Mori, Ken-ich Komatsu, Toshiaki Makino, Yoshihiro Kano
    2004 年 27 巻 6 号 p. 867-870
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Polyporus Sclerotium (猪苓), botanically from the Polyporus umbellatus (PERS.) FRIES, was traditionally used for the purpose of promoting diuresis. The present study investigated the diuretic effect of ergosta-4,6,8(14),22-tetraen-3-one (ergone) which is a maker component according to the chemical assay for its quality standardization. It resulted in a reversion to ordinary value of the urinary ratio of Na/K in deoxycoricosterone acetate (DOCA)-treated and adrenalectomized rats, although it had no this effect on the Na or K contents as well as Na/K value both in normal rats and in adrenalectomized rats without DOCA. These data indicate that ergone possesses an anti-aldosteronic diuretic effect. Moreover, it was identified in the blood and bile of rats after its administration to the gastrointestinal tract. The above results demonstrate that it is an active component of Polyporus Sclerotium.
Notes
  • Maira Huerta-Reyes, Maria del Carmen Basualdo, Lucio Lozada, Manuel Ji ...
    2004 年 27 巻 6 号 p. 916-920
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The organic plant extracts of 21 species of Clusiaceae from Mexico were screened for anti HIV-1 reverse transcriptase activity in a non-radioactive immuno colorimetric assay. The extracts of 5 species (23.8%) exhibited significant inhibition (≥70%) of HIV-1 RT activity; of these, only 4 extracts showed reduced toxicity to human lymphocytic MT2 cells and were further tested as inhibitors of HIV-1 IIIb/LAV replication in a cellular system. The best extracts were Calophyllum brasiliense (hexane) and Clusia quadrangula (CH2Cl2–MeOH) which inhibited HIV-1 RT (IC50=29.6 μg/ml and 42 μg/ml), and showed an EC50=92.5 μg/ml and 91 μg/ml, respectively, on MT2 cells. However, only Calophyllum brasiliense hexane extract showed significant inhibition on viral replication (ED50=37.1 μg/ml), while Clusia quadrangula was less active (ED50=124 μg/ml). These results support the idea that plant extracts represent a valuable source of potential anti HIV compounds.
  • Marii Takahashi, Hiroyuki Fuchino, Motoyoshi Satake, Yutaka Agatsuma, ...
    2004 年 27 巻 6 号 p. 921-925
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Seventy-five Myanmar timber extracts belonging to 27 families were examined for their leishmanicidal activities. Some timber extracts had significant leishmanicidal activity, especially extracts of Millettia pendula, which exhibited the most potent activity (MLC 3.1 μg/ml, MIC 1.6 μg/ml). Other timber extracts showing potent activity included those from Cedrela serrata, Cedrela toona, Cordia fragrantissima, Calophyllum kunstleri, Dalbergia cultrate, Grevillea robusta, Haplophragma adenophyllum, Michelia champaca, and Tectona grandis. From a literature search for reports on the chemical constituents of these plants, most constituents were found to be quinone derivatives or other compounds with unsaturated carbonyl groups.
  • Hui Zi Jin, Jeong Hyung Lee, Dongho Lee, Hyun Sun Lee, Young Soo Hong, ...
    2004 年 27 巻 6 号 p. 926-928
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Nine quinolone alkaloids (1—9) from the fruits of Evodia rutaecarpa were investigated for their inhibitory activity on nuclear factor of activated T cells (NFAT)-dependent transcription in comparison with nuclear factor (NF)-κB-dependent transcription using a reporter gene assay. These alkaloids showed inhibitory effects against NFAT activity, with IC50 values between 0.91 μM and 15.91 μM. Of the N-methylated quinolones, the longer aliphatic side chain at the quinolone ring showed stronger inhibition of NFAT activity. These N-methylated compounds showed comparable inhibitory effects against NF-κB activity. However, quinolone alkaloids without the N-methyl group showed a more selective inhibition of NFAT activity.
Biopharmacy
Regular Articles
  • Tomoko Akase, Satoshi Onodera, Ryo Matsushita, Tomohide Akase, Shin-ic ...
    2004 年 27 巻 6 号 p. 871-878
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    In order to more closely examine the effect of Toki-shakuyaku-san and an iron preparation in vivo in an animal experiment, we prepared anemic rats, divided them into 4 groups, i.e., an untreated group, a Toki-shakuyaku-san group, an iron-preparation group and a Toki-shakuyaku-san+iron-preparation group, and assessed the results of laboratory parameters, hematology, and general symptoms of anemia. The results showed trends toward improvement in indices of anemia, i.e., erythrocyte (RBC) count, hemoglobin (Hb), hematocrit (Ht) and serum iron (Fe), and improvement of anemic symptoms in the 3 treated groups. Examination of erythrocyte morphology showed that erythrocyte destruction had occurred only slightly in the 3 treated groups. The organ weight measurements showed an increase in the weight of the heart and spleen in the untreated group, but tended to be closer to normal in the 3 treated groups. The number and wet weight of the feces in the untreated group were markedly lower than normal, but increased in the Toki-shakuyaku-san group. In the iron-preparation group, the hemorrhage of stomach and pigmentation of the tail which seem to be a side effect of iron were observed, but was not seen in the Toki-shakuyaku-san group. The results animal experiment more closely examined the results of clinical study, and we concluded that by using Toki-shakuyaku-san and the iron preparation in combination, it is possible to lessen the adverse reactions such as gastrointestinal symptoms, and that more ameliorative effect on the anemic state can be expected.
  • Yasutami Shigeta, Hiromichi Imanaka, Sei Yonezawa, Naoto Oku, Naomichi ...
    2004 年 27 巻 6 号 p. 879-882
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Since the liposomal formulation of linoleic acid (LA) exhibited an enhanced skin-whitening effect, the influence of liposomalization on the cutaneous absorption of LA was examined using a three-dimensional (3D) reconstructed skin model. Liposome entrapped [14C]-LA was applied on the skin model, and the permeation of LA through the skin was monitored. The permeation rate of LA in the liposomal formulation was found to be lower than that in the conventional formulation without liposomes, suggesting the increased retention time of LA in the skin by the liposomal formulation. Next, to investigate the dependence of the LA permeation on melanocyte conditions and intactness of the reconstructed skin model, the effect of UV irradiation on LA permeation was examined. Low-dose UVB irradiation (0.03 J/cm2 for 3 times), which activated melanocytes in the skin, did not influence the extent of LA permeation, while high-dose irradiation (0.30 J/cm2 for 3 times) enhanced the permeation of LA in both the conventional and liposomal formulation. The present results suggest the importance of skin intactness for LA permeation and that the 3D reconstructed skin model would be useful for evaluating the characteristics of skin-oriented cosmetics and drugs.
Notes
  • Tomoaki Yoshimura, Emi Hamaguchi, Eiseki Usami, Keiji Nakashima, Mayum ...
    2004 年 27 巻 6 号 p. 929-931
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Stevens–Johnson syndrome (SJS) was diagnosed in a 39-year-old woman, treated with ampicillin (4000—8000 mg daily), phenytoin (250 mg daily), and furosemide (20—40 mg daily) for 25, 21, and 20 d, respectively, before the appearance of the eruption. The lymphocyte stimulation test with the MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay on ampicillin, phenytoin, and furosemide showed a low value of stimulation index, which indicated negative reactivity. An in vitro IFN-γ release test was conducted on the patient with SJS and on two healthy controls. IFN-γ release increased by 52% following the in vitro challenge of the patient's peripheral blood mononuclear cells (PBMCs) with 15 μg/ml of ampicillin, but not with phenytoin or furosemide. Neither of the controls experienced increased IFN-γ release. In the present case, increased in vitro IFN-γ release was observed on ampicillin-stimulated PBMCs, which may indicate the role of ampicillin as the drug responsible for the induction of SJS, and may imply the role of IFN-γ in the pathogenesis of SJS.
  • Yoshiaki Moriki, Toyofumi Suzuki, Toshiro Fukami, Manabu Hanano, Kazuo ...
    2004 年 27 巻 6 号 p. 932-935
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The involvement of P-glycoprotein (P-gp) in pentazocine (PTZ) transport at the blood–brain barrier (BBB) in rats was evaluated by means of an in vivo study using the brain uptake index (BUI) method. The amount of radioactivity in the brain was estimated at different intervals (up to 240 s) after carotid injection in rats. The apparent elimination rate constant (ktest) due to efflux of PTZ from the brain was calculated as 0.22 min−1. The observed BUI values of [3H]-PTZ (0.35 μM) were not significantly different between 5 and 15 s after the carotid injection. The concentration-dependent uptake of PTZ by the brain was increased gradually by increasing the concentration (0.01—1 mM) of PTZ in the injection solution. The apparent uptake of PTZ by the brain increased in the presence of P-gp inhibitors such as cyclosporin A, quinidine, verapamil and vinblastine after the carotid injection. These results suggest that the increment of PTZ uptake by the brain could be explained by the saturable efflux transport system involving a P-gp-mediated efflux mechanism of PTZ transport at the BBB.
  • Yusuke Eto, Jian-Qing Gao, Fumiko Sekiguchi, Shinnosuke Kurachi, Kazuf ...
    2004 年 27 巻 6 号 p. 936-938
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Although adenovirus vectors (Ad) which possesses high transduction efficiency are widely used for gene therapy in animal models, clinical use is very limited. One of the main reason is that nearly 80% of human beings possess anti-Ad antibodies. In this study, we tried to modify Ad with methoxypolyethylene glycol (MPEG) activated by succinimidyl propionate, and, the neutralizing antibody evasion ability of PEGylated Ad was evaluated. The results demonstrated that PEG-Ad showed stronger protection ability against anti-Ad neutralizing antibody compared to that with unmodified-Ad. Considering there are many people carrying neutralizing antibody against Ad and readministration of Ad was necessary for treating chronic diseases, this strategy, which was also applicable to other vectors, can be used for developing improved vectors.
Miscellaneous
Regular Articles
  • Masahiro Kaneko, Tsunehide Mizunuma, Hiroaki Takimoto, Yoshio Kumazawa
    2004 年 27 巻 6 号 p. 883-889
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    The microbes present in the intestine have a strong influence on the development and maturation of lymphoid organs. The cross-talk mechanisms between intestinal intraepithelial lymphocytes (i-IEL) and noninvasive microbes are still poorly understood. The influence of microbes and lipopolysaccharides on the development of i-IEL, especially the TCRαβ+ CD8αα subset, was investigated using the different TLR4-mutant mouse strains C3H/HeJ, BALB/lpsd, and C57BL/10ScCr. Intestinal epithelial cells (i-EC) from TLR4-mutant strains did not express interleukin (IL)-15 mRNA, while IL-15 mRNA expression in i-EC from the corresponding wild-type, C3H/He, BALB/c, and C57BL/10ScSn mice was detected. The development of TCRαβ+ CD8αα cells in i-IEL significantly decreased in TLR4-mutant mice compared with the corresponding wild-type mice, while other T cell subsets in i-IEL showed similar percentages in the TLR4-mutant and wild-type mice. Adult thymectomized (ATx-) and lethally irradiated C3H/HeJ mice reconstituted with T cell-depleted bone marrow cells from C3H/He mice showed a significantly lower percentage of TCRαβ CD8αα i-IEL than ATx-C3H/He mice after transfer of C3H/HeJ BM cells. The percentage of TCRαβ CD8αα i-IEL and IL-15 mRNA expression in i-EC from BALB/lpsd mice did not increase during Salmonella typhimurium infection but was significantly enhanced during Listeria monocytogenes infection. Our findings suggest that LPS induces IL-15 production by i-EC, resulting in the development of TCRαβ CD8αα i-IEL.
  • Yukihiro Ueno, Makoto Fukumatsu, Ayako Ogasawara, Toshihiko Watanabe, ...
    2004 年 27 巻 6 号 p. 890-892
    発行日: 2004年
    公開日: 2004/06/01
    ジャーナル フリー
    Candida albicans generally grows in hyphae form in RPMI1640 medium. However, addition of 1,4-diamino-2-butanone (DAB), a competitive inhibitor of ornithine decarboxylase, decreased the amount of polyamines in C. albicans, and induced the proliferation of the C. albicans yeast form. The expression of CYR1 mRNA was significantly inhibited by the addition of DAB compared with that of the control. The amount of intracellular cAMP was also decreased by the addition of DAB. A specific adenylate cyclase inhibitor, cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine (MDL-12,330A) promoted the growth of the yeast form. These results indicated that polyamines exist upstream of the adenylate cyclase-cAMP signal pathway and regulate the transformation of C. albicans.
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