Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
36 巻 , 12 号
選択された号の論文の22件中1~22を表示しています
Review
  • Toshio Matsuda
    2013 年 36 巻 12 号 p. 1871-1882
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuropsychiatric disorders such as anxiety-spectrum disorders, depression, and schizophrenia. The neuromodulatory effects of 5-HT are mediated through 14 receptor subtypes, and those receptors, including the 5-HT1A receptor, are considered to be potential targets for the treatment of psychiatric disorders. We developed the novel 5-HT1A receptor agonist MKC-242 (called osemozotan) and characterized its neurochemical and pharmacological profiles. 5-HT1A receptor agonists modulate the release of amine neurotransmitters through the activation of presynaptic or postsynaptic 5-HT1A receptors in the brain. The agonist has antianxiety and antidepressant effects and improves abnormal behaviors such as aggressive behavior and deficits of prepulse inhibition in isolation-reared mice. We also demonstrated that spinal 5-HT1A receptor activation is involved in isolation rearing-induced hypoalgesia. Concerning the mechanism for induction of isolation-induced abnormal behaviors, we have recently found that the raphe-prefrontal 5-HT system plays a key role in encounter stimulation-induced hyperactivity in isolation-reared mice. Furthermore, we showed that osemozotan attenuates psychostimulant-induced behavioral sensitization and that prefrontal dopamine release is enhanced by functional interaction between the 5-HT1A receptor and other receptors. This review summarizes the neuropharmacology of the 5-HT1A receptor, focusing on our studies using osemozotan, and suggests that the 5-HT1A receptor may be a target molecule for the treatment of psychiatric disorders, pain, and drug dependence.
Regular Articles
  • Guangyu Zhou, Yanqiu Wang, Ping He, Detian Li
    2013 年 36 巻 12 号 p. 1883-1890
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/09/26
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    The present study was conducted to investigate the effects of probucol on the progression of diabetic nephropathy and the underlying mechanism in type 2 diabetic db/db mice. Eight weeks db/db mice were treated with regular diet or probucol-containing diet (1%) for 12 weeks. Non-diabetic db/m mice were used as controls. We examined body weight, blood glucose, and urinary albumin. At 20 weeks, experimental mice were sacrificed and their blood and kidneys were extracted for the analysis of blood chemistry, kidney histology, oxidative stress marker, and podocyte marker. As a result, 24 h urinary albumin excretions were reduced after probucol treatment. There were improvements of extracellular matrix accumulation and fibronectin and collagen IV deposition in glomeruli in the probucol-treated db/db mice. The reduction of nephrin and the loss of podocytes were effectively prevented by probucol in db/db mice. Furthermore, probucol significantly decreased the production of thiobarbituric acid-reactive substances (TBARS), an index of reactive oxygen species (ROS) generation and down-regulated the expression of Nox2. Taken together, our findings support that probucol may have the potential to protect against type 2 diabetic nephropathy via amelioration of podocyte injury and reduction of oxidative stress.
  • Daisuke Kobayashi, Shigeru Hosaka, Emiko Inoue, Kimie Ohshima, Nobuaki ...
    2013 年 36 巻 12 号 p. 1891-1901
    発行日: 2013/12/01
    公開日: 2013/12/01
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    In prescription dispensing in Japan, to avoid adverse drug reactions (ADR) pharmacists provide patients with information concerning the initial symptoms (IS) of any ADR that might be caused by the drugs they have been prescribed. However, the usefulness of such information for preventing ADR has not been quantitatively evaluated. We previously performed a trial calculation of the usefulness of rash as a predictor of drug-induced liver disorders by applying Bayes’ theorem and showed that the predictive utility of IS can be quantitatively evaluated using likelihood ratios. However, for other drug-ADR-IS combinations it was difficult to obtain the information required for the calculations from Japanese data alone. In this study, using the Adverse Event Reporting System (AERS) database of the U.S. Food and Drug Administration (FDA), we evaluated 132 drug-ADR-IS combinations that were considered to be potentially clinical significant. Regarding bezafibrate-associated rhabdomyolysis and cibenzoline-associated hypoglycemia, these ADR were not detected in cases involving monotherapy. For 58 combinations, no events that were considered to be IS of the target ADR developed. Fever, nausea, and decreased appetite were the IS of many ADR, making them very useful predictors. In contrast, pruritus and rash were not very useful. Fever might be a predictor of thiamazole-induced agranulocytosis or levofloxacin- or terbinafine-induced liver disorder, tremors might be useful for predicting paroxetine-induced serotonin syndrome, and decreased appetite might be a useful indicator of terbinafine-induced liver dysfunction.
  • Saori Nakagawa, Yuko Kojima, Koichi Sekino, Susumu Yamato
    2013 年 36 巻 12 号 p. 1902-1906
    発行日: 2013/12/01
    公開日: 2013/12/01
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    When carbohydrate metabolism is impaired, fatty acid metabolism is activated. Excess acetyl-coenzyme A (CoA) is generated from fatty acids by β-oxidation and is used for the formation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and subsequently for acetoacetate. High levels of secreted ketone bodies (acetoacetate and 3β-hydroxybutyrate) lower the pH of blood and urine, resulting in ketoacidosis. HMG-CoA lyase in hepatic cells is a rate-limiting enzyme catalyzing the cleavage of HMG-CoA to acetoacetate, and thus inhibition of this enzyme results in reduced acetoacetate production, in other words, impaired ketoacidosis. Inhibition of HMG-CoA lyase activity possibly prevents ketoacidosis and should be the therapeutic target. Polyphenols are common and abundant dietary constituents with beneficial effects on human health. We examined the inhibitory effects of dietary polyphenols on HMG-CoA lyase activity in cellular extracts of human hepatoma HepG2 cells. Of the nine representative dietary polyphenols tested, (−)-epigallocatechin (EGC), (−)-epigallocatechin gallate (EGCG), and gallic acid (GA) effectively inhibited HMG-CoA lyase activity. Lineweaver–Burk analysis revealed that EGC and EGCG are likely to be mixed-type noncompetitive inhibitors. Pyrogallol with the gallyl structure also inhibited HMG-CoA lyase activity, suggesting that the gallyl moiety of polyphenols is important for the inhibition of HMG-CoA lyase activity.
  • Emine Şalva, Suna Özbaş Turan, Jülide Akbuğa
    2013 年 36 巻 12 号 p. 1907-1914
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/10/03
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    Targeted posttranscriptional gene silencing by RNA interference (RNAi) has garnered considerable interest as an attractive new class of drugs for several diseases, such as cancer. Chitosan and protamine are commonly used as a vehicle to deliver and protect small interfering RNA (siRNA), but the strong interaction still remains to be modulated for efficient siRNA uptake and silencing. Therefore, in this study, ternary nanoplexes containing chitosan and protamine were designed to substantially enhance the siRNA efficiency. Binary and ternary nanoplexes were prepared at different the ratios of moles of the amine groups of cationic polymers to those of the phosphate ones of siRNA (N/P) ratios and characterized in terms of size, zeta potential, morphology and serum stability. The silencing efficiencies and cytotoxicities of prepared nanoplexes were evaluated by enzyme-linked immunosorbent assay (ELISA) (for human vascular endothelial growth factor; hVEGF) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. The mean diameter of ternary nanoplexes ranged from 151 to 282 nm, depending on the weight ratio between polymers and siRNA. The gene silencing effect after transfection with ternary nanoplexes (chitosan/siRNA/protamine 83%) was significantly higher than that with binary nanoplexes (chitosan/siRNA 71% and protamine/siRNA 74%). Ternary nanoplexes showed the highest cellular uptake ability when compared with binary nanoplexes. Ternary nanoplexes did not induce substantial cytotoxicity. Serum stability and the lack of cytotoxicity of the nanoplexes provided advantages over other gene silencing studies. These results suggest ternary nanoplexes have the potential to be an effective siRNA carrier to study the gene silencing effect.
  • Rita de Cássia Ribeiro Gonçalves, Rodrigo Rezende Kitagawa, Maria Stel ...
    2013 年 36 巻 12 号 p. 1915-1920
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/09/12
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    The naturally occurring pigment, melanin is found in organisms of all phylogenetic kingdoms, including fungi, and exhibits a wide range of biological activities. Our objective was to investigate the effects of melanin extracted from the fungus Aspergillus nidulans on the production of the pro-inflammatory mediators nitric oxide (NO) and tumour necrosis factor-α (TNF-α) in peritoneal macrophages and on the viability of McCoy mouse fibroblasts. The results showed that A. nidulans melanin did not stimulate NO production in macrophages, but it inhibited the NO production in lipopolysaccharide (LPS)-stimulated macrophages by approximately 82%. Similarly, A. nidulans melanin inhibited LPS-stimulated TNF-α production by 52% and showed a slight stimulatory effect on TNF-α production in macrophages. In addition, the toxicity of A. nidulans melanin to McCoy cells was much lesser (IC50=373.5±2.4 µg/mL) than that of known agents such as cisplatin (IC50=41.2 µg/mL). The viability of peritoneal macrophages was greater than 90% at the highest melanin concentration tested (100 µg/mL). Thus, the combination of low cytotoxicity and marked inhibition of TNF-α and NO production suggests that A. nidulans melanin has potential as an anti-inflammatory agent and may be used in the future for development of new drugs with therapeutic utility.
  • Naoki Kaneko, Kentaro Yamanaka, Aya Kita, Kenji Tabata, Takafumi Akaba ...
    2013 年 36 巻 12 号 p. 1921-1927
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/09/19
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    Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes, and effective treatment options are limited to cytotoxic agents, including microtubule-targeting agents, due to the lack of molecular targets. Here, we examined the combined effect of sepantronium bromide (YM155) and microtubule-targeting agents in TNBC models. The combination of YM155 with docetaxel showed synergistic antiproliferative and caspase 3/7-inducing effects in MRK-nu-1 and MDA-MB-453 human TNBC cell lines in vitro. YM155 also synergistically enhanced the efficacies of other microtubule-targeting agents, including paclitaxel and vinorelbine, which induced accumulation of survivin at the G2/M phase, whereas it did not affect the efficacy of doxorubicin. Combination treatment with YM155 and microtubule-targeting agents decreased the accumulation of survivin at the G2/M phase and induced greater apoptosis than either single agent alone. Further, combination treatment with YM155 and docetaxel also had a synergistic antitumor effect, achieving complete regression without exacerbation of body weight loss in all mice, in a MRK-nu-1 human TNBC xenograft model. These results suggest that survivin inhibition synergistically sensitize human TNBC cells to microtubule-targeting agents.
  • Ji-Hi Pyo, You-Kyung Jeong, Sujung Yeo, Je-Hyun Lee, Mi-Young Jeong, S ...
    2013 年 36 巻 12 号 p. 1928-1935
    発行日: 2013/12/01
    公開日: 2013/12/01
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    The anti-inflammatory and neuroprotective effects of trans-cinnamaldehyde (TCA) were investigated on the inflammatory cells and the dopaminergic degeneration in mice. TCA inhibited the up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the lipopolysaccharide (LPS)-induced inflammatory BV2 microglial cells. To investigate the TCA efficacy on the 6-hydroxydopamine (6-OHDA)-induced dopaminergic degeneration in mice, an intracerebroventricular injection of 6-OHDA was given to the mice, and TCA (30 mg/kg) was intraperitoneally administered. At 7 d after the 6-OHDA injection, 6-OHDA led to a severe loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the striatum and substantia nigra (SN). On the other hand, TCA dramatically maintained the number of TH-positive dopaminergic neurons in the striatum and SN regions of the 6-OHDA-treated mice, which indicates that TCA is able to inhibit the 6-OHDA-induced reduction of TH expression in the dopaminergic neurons in the striatum and SN regions. TCA also inhibited the induction of iNOS and COX-2 in the 6-OHDA model, similarly as shown in the LPS-induced inflammatory BV2 microglial cells. These results indicate that TCA has a neuroprotective effect on dopaminergic neurons and that this effect may be associated with the inhibition of inflammatory responses. These findings suggest that TCA may be a therapeutic candidate for the prevention of inflammation-mediated neurodegenerative diseases.
  • Shimako Tanaka, Shinya Uchida, Sachiko Miyakawa, Naoki Inui, Kazuhiko ...
    2013 年 36 巻 12 号 p. 1936-1941
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 µg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (Cmax) and the area under the plasma concentration–time curve from 0 to 8 h (AUC0–8) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The Cmax and AUC0–8 returned to the control levels on days 3 and 7. In contrast, AUC0–8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC0–8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h.
  • Junya Nagai, Takuji Komeda, Yuki Katagiri, Ryoko Yumoto, Mikihisa Taka ...
    2013 年 36 巻 12 号 p. 1942-1949
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Protamine, a mixture of polypeptides that is rich in arginine, has been used clinically as an antidote to heparin overdoses and a complexing agent in a long-acting insulin preparation. When protamine is administered intravenously, its abundant accumulation in the kidneys has been reported. However, the renal uptake mechanism for protamine is not clear. In this study, we examined the transport mechanism for protamine in opossum kidney (OK) cells, a suitable in vitro model for renal proximal tubular epithelial cells. Flow cytometric analysis revealed that the association of fluorescein isothiocyanate (FITC)-labeled protamine from salmon (FITC-protamine) by OK cells was inhibited by unlabeled protamine in a concentration-dependent manner. The association of FITC-protamine was temperature- and energy-dependent. Confocal microscopy analysis showed that the fluorescence was localized in the cytoplasm and nucleus of OK cells. In addition, FITC-protamine association was inhibited by cationic drugs such as polycationic gentamicin and polymixin B, but it was increased by a basic amino acid, arginine. Inhibitors for clathrin- and caveolin-dependent endocytosis showed inhibitory effects on FITC-protamine association. Pretreatment with heparinase III partially but significantly decreased the association of FITC-protamine. These results suggest that protamine may be taken up by OK cells via receptor-mediated endocytosis, which may result in its localization in the cytoplasm and nucleus of the cells.
  • Yu Hu, Qingping Wen, Wenbo Liang, Tingguo Kang, Lu Ren, Nan Zhang, Dan ...
    2013 年 36 巻 12 号 p. 1950-1958
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/09/20
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    Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer’s disease (AD). Previous studies have demonstrated the neuroprotective role of osthole against oxygen and glucose deprivation in cortical neurons. However, the effects of osthole on Aβ-induced neurotoxicity in neural cells have rarely been reported. The current study was designed to investigate the protective effects of osthole on a cell model of AD insulted by exogenous Aβ25-35 and the potential mechanism(s). In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence analysis, apoptosis assay, reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques were used in primary cortical neurons and SH-SY5Y cells. Our data showed that osthole reduced intracellular Aβ levels in neural cells, which was associated with decreased BACE1 protein; osthole reversed exogenous Aβ25-35-induced cell viability loss, apoptosis, and synapsin-1 reduction, which was related to the reestablishment of phosphorylation of cyclic AMP response element-binding protein (CREB). The collective evidence indicates that osthole possesses the ability to protect cortical neurons and SH-SY5Y cells against Aβ injury, and the underlying mechanism may be attributed to the enhancement of CREB phosphorylation.
  • Masaya Sakamoto, Tomoo Itoh, Ryoichi Fujiwara
    2013 年 36 巻 12 号 p. 1959-1963
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Hepatic intrinsic clearance (CLint) of drugs is often predicted based on in vitro data that are obtained from the Michaelis–Menten analysis. While most of the metabolic rate-substrate concentration kinetic curves fit to the Michaelis–Menten equation, cytochrome P450 (CYP) and uridine 5′-diphosphate (UDP)-glucuronosyltransferases exhibit sigmoidal kinetics for certain drugs. In our study, the kinetics of CYP3A4-catalyzed carbamazepine 10,11-epoxidation in human liver microsomes was sigmoidal and fitted to the Hill equation, revealing the S50 value of 358 µM, n of 2.0, and the Vmax value of 463 pmol/min/mg. While the intrinsic clearance calculated from Michaelis–Menten parameters (CLint) overestimated the observed in vivo intrinsic clearance (CLint, in vivo), the maximum intrinsic clearance calculated based on the Hill equation (CLmax) exhibited better predictions of CLint, in vivo. Such better prediction using the CLmax was also observed for other four drugs, all of which also exhibited sigmoidal metabolic rate-concentration curves, according to the literature data. However, even if we assume such Hill equation, intrinsic clearances predicted at their therapeutic concentrations from in vitro data were still much lower than their CLint, in vivo, suggesting the existence of unknown factors causing discrepancy between in vitro intrinsic clearance in human liver microsomes and in vivo data. Thus, even if we assume sigmoidal kinetics, that would not be enough for accurate prediction of CLint, in vivo, and it would be preferable to use CLmax to quantitatively extrapolate the in vitro data to in vivo clearance.
  • Tetsuya Saita, Masashi Shin, Hiroshi Fujito
    2013 年 36 巻 12 号 p. 1964-1968
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Imatinib is an oral tyrosine kinase inhibitor used for first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring targeting trough plasma levels of about 1000 ng/mL may help to optimize imantinib’s therapeutic effect. This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for a pharmacokinetic evaluation of imatinib. Anti-imatinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin and succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. Enzyme labeling of imatinib with horseradish peroxidase was similarly performed using succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. A simple ELISA for imatinib was developed using the principle of direct competition between imatinib and the enzyme marker for anti-imatinib antibody which had been adsorbed by the plastic surface of a microtiter plate. Serum imatinib concentrations lower than 40 pg/mL were reproducibly measurable using the ELISA. This ELISA was specific to imatinib and showed very slight cross-reactivity (1.2%) with a major metabolite, N-desmethyl imatinib. Using this assay, drug levels were easily measured in the blood of mice after their oral administration of imatinib at a single dose of 50 mg/kg. The specificity and sensitivity of the ELISA for imatinib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of imatinib.
  • Tomohiro Arakawa, Takeshi Deguchi, Fumitoshi Sakazaki, Hirofumi Ogino, ...
    2013 年 36 巻 12 号 p. 1969-1974
    発行日: 2013/12/01
    公開日: 2013/12/01
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    To clarify the relationship between selenium supplementation and type I allergic reaction, we investigated the effect of seleno-L-methionine (SeMet) supplementation on the active cutaneous anaphylaxis (ACA) reaction and cytokine production in splenocytes. Female BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), and SeMet was administered orally for 2 weeks followed by a challenge with OVA to induce an ACA reaction. SeMet supplementation suppressed the ACA reaction in a dose-dependent manner. Plasma OVA-specific immunoglobulin E (IgE) level was strongly inhibited in SeMet-supplemented mice compared with control mice. The mRNA expression levels of the T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13 in the spleen of SeMet-supplemented mice were lower than those in control mice. The mRNA expression level of a Th1 cytokine, interferon (IFN)-γ, in the spleen of SeMet-supplemented mice was higher than that in control mice. Splenocytes restimulated with OVA in vitro from SeMet-supplemented mice produced lower amounts of IL-4 and IL-13 than those of control mice and higher amounts of IFN-γ than those from the control mice. These results suggest that oral SeMet supplementation suppresses OVA-induced ACA reaction by lowered Th2 cytokine production and augmenting Th1 cytokine production.
  • Ting Gao, Xinye Ma, Xunzhi Zhu
    2013 年 36 巻 12 号 p. 1975-1979
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/10/08
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    Fabaceae is a huge family that contains a large number of medicinal plants, many of which are commonly used in Chinese traditional medicine. However, traditional taxonomy has not been able to meet the complicated demands of species discrimination within Fabaceae. Thus, we employed a famous DNA barcode, the psbA-trnH region, to discriminate commonly used medicinal species of the family Fabaceae. Here, the psbA-trnH regions derived from 152 samples were amplified. These samples represented 104 Fabaceae medicinal species from 60 genera, including 25 authentic Fabaceae species listed in the Chinese pharmacopoeia and common adulterant species. The results indicate that the psbA-trnH region performed well in terms of its universality and high variability in length and composition. Species discriminative power analysis of the psbA-trnH region showed that 91.3% of species could be identified successfully by the BLAST1 method in conjunction with the nearest distance method. And, the species resolution rate of the TaxonGap method exceeded 93%. The results provide support for the use of the psbA-trnH plastid region as a sensitive marker to the authentication of Fabaceae medicinal plants.
  • Jinbin Wei, Quanfang Huang, Renbin Huang, Yongxing Chen, Shujuan Lv, L ...
    2013 年 36 巻 12 号 p. 1980-1989
    発行日: 2013/12/01
    公開日: 2013/12/01
    [早期公開] 公開日: 2013/09/26
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    This study examined the effect of Asiatic acid from Potentilla chinensis (AAPC) on chronic ethanol-induced hepatic injury. Rats underwent intragastric administration of ethanol (5.0–9.0 g/kg) once a day for 12 weeks. A subset of rats were also intragastrically treated with AAPC (2, 4 or 8 mg/kg) once a day. In the end, AAPC treatment significantly protected against ethanol-induced liver injury, as evidenced by the decrease in serum alanine and aspartate aminotransferases levels and the attenuation of histopathological changes in rats. Additionally, AAPC significantly decreased blood alcohol and acetaldehyde concentrations by enhancing alcohol dehydrogenase and aldehyde dehydrogenase activities. Mechanistically, studies showed that AAPC remarkably alleviated the formations of malondialdehyde and myeloperoxidase, restored impaired antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase, and inhibited cytochrome P450 (CYP)2E1 activity. Moreover, the over-expression of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), the elevated plasma endotoxin level and the up-regulated Toll-like receptor 4 (TLR4), CD14 and myeloid differentiation factor 88 (MyD88) as well as nuclear factor-κB were also suppressed by AAPC in ethanol-intoxicated rats. In conclusion, the protective effect of AAPC on ethanol-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress and inhibit Kupffer cell activation by decreasing the level of plasma endotoxin and the expression of TLR4, CD14 and MyD88.
  • Akira Minami, Hiroshi Matsushita, Yuuki Horii, Daisuke Ieno, Yukino Ma ...
    2013 年 36 巻 12 号 p. 1990-1995
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Ethanol extract of Pleurotus eryngii (DC.) QUÉL has estrogen-like activities that protect against bone loss caused by estrogen deficiency. In the present study, we investigated the effect of P. eryngii on depression-like behavior and memory impairment in ovariectomized (OVX) rats. Immobility time during a forced swimming test was significantly longer for OVX rats than for sham-operated rats. The depression-like behavior in OVX rats was improved by long-term administration of the ethanol extract of P. eryngii (500 mg/kg body weight (b.w.)/d). Spatial memory impairment in OVX rats assessed by the Morris water maze test was also improved by P. eryngii extract without any effect on motility. These results suggested that P. eryngii extract has estrogen-like improvement activity against depression-like behavior and memory impairment in OVX rats. Additionally, increase in the amount of synaptosomal zinc after ovariectomy was inhibited by P. eryngii extract. Since zinc in synaptic vesicles is important for memory function and is linked to the pathophysiology of depression, normalization of zinc signaling would be involved in the beneficial effect of P. eryngii extract on neurological disorders after ovariectomy.
  • Kanako Takahashi, Reiko Ishii-Nozawa, Koichi Takeuchi, Ken Nakazawa, Y ...
    2013 年 36 巻 12 号 p. 1996-2004
    発行日: 2013/12/01
    公開日: 2013/12/01
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    The astrocytic L-glutamate (L-Glu) transporter EAAT1 participates in the removal of L-Glu from the synaptic cleft and maintenance of non-toxic concentrations in the extracellular fluid. We have shown that niflumic acid (NFA), a non-steroidal anti-inflammatory drug (NSAIDs), alters L-Glu-induced EAAT1 currents in a voltage-dependent manner using the two-electrode voltage clamp technique in Xenopus oocytes expressing EAAT1. In this study, we characterised the effects of NFA on each type of ion-flux through EAAT1. NFA modulated currents induced by both L-Glu and L-aspartate (L-Asp) in a voltage-dependent manner. Ion-substitution experiments revealed that the activation of additional H+ conductance was involved in the modulation of currents induced by L-Asp and L-Glu, but Cl was involved only with the L-Asp currents. NFA activated additional currents of EAAT1 in a substrate-dependent manner.
Notes
  • Yayoi Kagami, Yoshitaka Kondo, Setsuko Handa, Naoki Maruyama, Akihito ...
    2013 年 36 巻 12 号 p. 2005-2008
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Senescence marker protein-30 (SMP30) was first described as a physiologic entity that decreases in the rat liver and kidney with aging. Previously, we established that SMP30 is the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in ascorbic acid (AA) biosynthesis. In the present study, we found SMP30/GNL mRNA expressed in the mouse ovary. To ascertain the reason for ovarian SMP30/GNL expression, we examined mice during gestation. SMP30/GNL mRNA expression was evident at the start of gestation, increased for the next eight days then decreased rapidly. Moreover, L-gulono-γ-lactone oxidase (Gulo) mRNA, which catalyzes the last step of AA, was found in the ovaries of these mice. The variations of these genes’ expression showed an inverse pattern to that of Cyp19a1 (aromatase) mRNA expression. Therefore, the SMP30/GNL and Gulo mRNA expression might be regulated by estrogen levels in the ovary. Since the presence of both SMP30/GNL and Gulo mRNAs could indicate that AA synthesis occurs in the ovary, we quantified AA levels in mouse ovaries during gestation. However, no correlation was found between changes of AA content and SMP30/GNL or Gulo mRNAs expression at this site. Moreover, we compared the changes of AA content during gestation between wild-type and SMP30/GNL knockout mice, which cannot synthesize AA, and found no significant differences between them. These results indicated that, although AA synthesis might occur in the ovaries, the amount of AA which is synthesized in ovaries must be quite low and insufficient to influence the AA content in ovary.
  • Shinya Iida, Hiroyuki Kamiya, Akihiro Nakaya, Yasuhiro Hayashi, Akihir ...
    2013 年 36 巻 12 号 p. 2009-2011
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Expression of the asparagine synthetase gene is dependent on extracellular glucose concentration. This gene was knocked-down in livers of male Balb/c mice by a hydrodynamic tail vein injection of small interfering RNA (siRNA) against the gene. This knockdown resulted in a significant decrease in plasma glucose concentration. These results suggested that asparagine synthetase is a novel protein that regulates plasma glucose levels.
  • Yuki Sato, Hanami Mutoh, Mika Suzuki, Yoh Takekuma, Ken Iseki, Mitsuru ...
    2013 年 36 巻 12 号 p. 2012-2017
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Coenzyme Q10 (CoQ10) is an essential component in the electron-transport systems of mitochondria and bacteria and is often used as a supplementary treatment for some diseases. We previously reported that the bioavailability of CoQ10 powder was less than 10%. In this study, we investigated various preparations to improve the intestinal absorption of CoQ10 with focus on the effect of emulsification. We prepared a suspension and some emulsions with four types of surfactants and investigated the plasma concentration profile after oral administration to rats. The absorption of CoQ10 was improved by an emulsion formulation although there was little absorption of CoQ10 when a suspension was administered. However, little CoQ10 was absorbed in the bile duct-ligated group even when the emulsion formulation was administered (about 50% of the control group). Bile and emulsion formulation are essential for absorption of CoQ10. When the preparations containing Tween20 (polysorbate (20) sorbitan monolaurate) and Tween80 (polyoxyethylene (20) sorbitan monooleate) were administered, plasma concentrations of CoQ10 were higher than those obtained with preparations containing Tween65 (polyoxyethylene (20) sorbitan tristearate) and Span20 (sorbitan monolaurate). Tween20 and Tween80 have higher hydrophile–lipophile balance (HLB) values than those Tween65 and Span20. Our study suggests that highly lipophilic compounds like CoQ10 would diffuse the unstirred water layer and would easily access the intestinal apical membrane by an emulsion containing a surfactant with a high HLB value. Attention must be given to CoQ10 supplementation for patients whose bile is not excreted to the intestine such as patients with cholestasis.
  • Manami Kurisu, Rie Nakasone, Yusaku Miyamae, Daisuke Matsuura, Hirotos ...
    2013 年 36 巻 12 号 p. 2018-2021
    発行日: 2013/12/01
    公開日: 2013/12/01
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    Hepatocyte growth factor (HGF) has mitogenic, motogenic, and morphogenic activities in epithelial cells. Induction of HGF production may be involved in organ regeneration, wound healing and embryogenesis. In this study, we examined the effects of caffeic acid derivatives including 4,5-di-O-caffeoylquinic acid (1) and acteoside (2) on HGF production in Neonatal Normal Human Dermal Fibroblasts (NHDF). Both 4,5-di-O-caffeoylquinic acid (1) and acteoside (2) significantly induced HGF production dose-dependent manner. To know the important substructure for HGF production activity, we next investigated the effect of the partial structure of these caffeic acid derivatives. From the results, caffeic acid (3) showed strong activity on the promotion of HGF production, while hydroxytyrosol (4) and quinic acid (5) didn’t show any activity. Our findings suggest that the caffeoyl moiety of caffeic acid derivatives is essential for accelerated production of HGF. The compound which has the caffeoyl moiety may be useful for the treatment of some intractable organ disease.
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