Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
最新号
選択された号の論文の22件中1~22を表示しています
Review
  • Hitoshi Sasaki
    2020 年 43 巻 8 号 p. 1147-1153
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Gene and nucleic medicines have recently gained attention as novel drugs with the advancement of molecular biology and genetics; however, they have low bioavailability and low target delivery due to their low stability and poor membrane permeability. Therefore, the development of an effective drug delivery system (DDS) is necessary for the practical use of gene and nucleic acid medicines; however, despite considerable research, both safety and efficiency remain poor. Furthermore, the healthcare needs are not met by traditional DDS. Therefore, we developed an effective multi-functional DDS, which is constructed using materials that are safe for human consumption. This DDS involves several ternary complexes as novel gene delivery carriers constructed by coating the cationic complex of the gene and nucleic acid medicines as well as the biodegradable cationic polymer with a biocompatible anionic polymer. Early implementation of the ternary complex in clinical studies is expected due to their efficacy and safety. Furthermore, these complexes may be prepared using large-scale manufacturing. In addition, personalized DDS may be prepared according to the patient’s disease stage, which is useful for advanced therapy.

    Graphical Abstract Fullsize Image
    Editor’s picks

    The clinical application of gene/nucleic acid medicines is highly dependent on the development of effective and reliable drug delivery systems. Dr. Sasaki successfully developed several ternary complexes as novel gene delivery carriers, which were constructed by gene/nucleic acid medicine, the cationic polymer, and the anionic polymer. This ternary complex consists of biodegradable materials found in foods and medical products that are already in clinical use and can deliver gene/nucleic acid medicines to specific organs (liver, spleen, lung, and cancer cells etc.) without toxicity. The ternary complexes are expected to apply to clinical practice.

Communication to the Editor
Regular Articles
  • Shaolei Luo, Yangyang Hou, Yaping Zhang, Tengfei Ma, Wenping Shao, Chu ...
    2020 年 43 巻 8 号 p. 1159-1171
    発行日: 2020/08/01
    公開日: 2020/08/01
    [早期公開] 公開日: 2020/05/23
    ジャーナル フリー HTML

    Regulating synaptic formation and transmission is critical for the physiology and pathology of psychiatric disorders. The adenosine A2A receptor subtype has attracted widespread attention as a key regulator of neuropsychiatric activity, neuroprotection and injury. In this study, we systematically investigated the regulatory effects of a novel A2A receptor agonist, PSB-0777, on the expression of synaptic proteins and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPA receptors) at the cellular level in a time- and dose-dependent manner. After 30 min of high-dose PSB-0777 stimulation, the expression of Synapsin-1 (Syn-1), postsynaptic density protein 95 (PSD95), and AMPA receptors and the number of synapses were rapidly and significantly increased in rat primary cortical neurons compared with the control. Sustained elevation was found in the low and medium-dose groups after 24 h and 3 d of treatment. In contrast, after stimulation with PSB-0777 for 3 consecutive days, the expression of Syn-1 was decreased, and PSD95, AMPA receptors and the number of synapses were no longer increased in the high-dose group. Our study focuses on the detailed and systematic regulation of synaptic proteins and AMPA receptors by an A2A receptor agonist, PSB-0777, which may result in both beneficial and detrimental effects on neurotransmission and neuroprotection and may contribute to the pathophysiology of psychiatric disorders related to A2A receptors. These experimental data may contribute to understanding of the mechanisms for neuroprotective and therapeutic effect of A2A receptor agonists.

    Graphical Abstract Fullsize Image
  • Ying Mei, Yihe Kuai, Hui Hu, Fei Liu, Bo Liu, Xiaoou Sun, Wen Tan
    2020 年 43 巻 8 号 p. 1172-1178
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    The sodium salt of isosteviol (STVNa) is a beyerane diterpene synthesized through acid hydrolysis of stevioside. STVNa improves multiple types of tissue injuries. However, it is not known how isosteviol sodium affects high-fat and high cholesterol diet (HFD)-induced kidney. Therefore, in this study we examined the potential molecular mechanism underlying STVNa mediated protective effect against high fat/high cholesterol-induced kidney dysfunction in HFD-induced kidney injury. Sprague-Dawley (SD) rats were allocated into six groups: the normal group, HFD group and HFD treated with three doses of STVNa, fenofibrate treatment group. The results indicated that HFD induced kidney injury evident by a 60% increase in serum creatinine (CRE) leves. In addition, there was a significant accumulation of triglycerides (approx. 60%), fatty acids (approx. 50%) and total cholesterol (approx. 2.5 fold) in the kidneys. STVNa inhibited HFD-induced kidney injury evident by reducing the increased levels of serum CRE. Specifically, STVNa attenuated HFD-induced kidney injury by inhibiting inflammation, oxidative stress, and apoptosis. These findings indicate that STVNa has a therapeutic potential for HFD-induced kidney dysfunction. The mechanisms of this pharmacological effect are through the inhibition of inflammation, oxidative stress and apoptosis.

    Graphical Abstract Fullsize Image
    Editor’s picks

    The sodium salt of isosteviol (STVNa) is a beyerane diterpene synthesized through acid hydrolysis of stevioside. STVNa improves multiple types of tissue injuries. However, it is not known how Isosteviol sodium affects high-fat and high cholesterol diet (HFD)-induced kidney. The current study suggested that STVNa inhibited HFD-induced kidney injury evident by reducing the increased levels of serum CRE. Specifically, STVNa attenuated HFD-induced kidney injury by inhibiting inflammation, oxidative stress, and apoptosis. These findings indicate that STVNa may have a therapeutic potential for metabolic syndrome associated kidney dysfunction by inhibiting inflammation, oxidative stress and apoptosis.

  • Yuki Yamaguchi, Naozumi Nishizono, Kazuaki Oda
    2020 年 43 巻 8 号 p. 1179-1187
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML
    電子付録

    Aromatase inhibitors are effective for the treatment of diseases such as breast cancer, which has led to an increase in their demand. However, only a limited number of aromatase inhibitor drugs are currently being marketed. In addition, considering the important aspect of drug resistance, the development of newer drug types is required. We have been developing inhibitors with backbone structures that differ from existing aromatase inhibitors. In this regard, we previously reported that diethylaminocoumarin dimers and thiazolyl coumarin derivatives possess strong aromatase inhibiting capabilities. In this study, we further examined the structure–activity relationships of coumarin derivatives synthesized from thiazolyl coumarin derivatives and their aromatase inhibiting capabilities. Consequently, amide coumarin N-benzhydryl-7-(diethylamino)-2-oxo-2H-chromene-3-carboxamide (IC50 values 4.5 µM) is inhibitor of aromatase. This inhibitor was found to be comparable aromatase inhibitory activity to the 1st generation aromatase inhibitor aminoglutethimide (3.2 µM). Substitution of the amide group on the amide coumarin derivative affects the aromatase inhibiting activity. Our findings suggest that the structure of each substituent changes the orientation of the compound in the active site of aromatase, thus creating a difference in their activities.

    Graphical Abstract Fullsize Image
  • Wenqing Liao, Sakiko Akahira, Rintaro Iwata Hara, Takeshi Wada, Kosuke ...
    2020 年 43 巻 8 号 p. 1188-1195
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML
    電子付録

    The immunostimulatory activity of unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) could be improved via delivery to immune cells expressing Toll-like receptor 9 (TLR9). Previously, we showed that the polypod-like structured nucleic acid (polypodna), a nanostructured DNA comprised of three or more ODNs, was an efficient system for the delivery of CpG ODNs to immune cells. Because some TLR9-positive immune cells express mannose receptors (MR), the uptake of polypodna by immune cells can be further increased by its modification with mannose. In this study, we selected the phosphodiester CpG ODN, ODN1668, which has a sequence identical to CpG1668, and a hexapodna, a polypodna with six pods, to design a hexapodna that harbored ODN1668 or the mannosylated CpG ODN (Man-ODN1668) synthesized via modification of the 5′-terminal of ODN1668 with a synthesized mannose motif. By mixing ODN1668 or Man-ODN1668 with the hexapodna, ODN1668/hexapodna and Man-ODN1668/hexapodna were successfully formed with high yields. However, Man-ODN1668/hexapodna was found to induce a greater tumor necrosis factor-α release from TLR9- and MR-positive mouse peritoneal macrophages and macrophage-like J774.1 cells than Man-ODN1668 or ODN1668/hexapodna. These results indicate that the combination of mannose modification and incorporation into nanostructured DNA is a useful approach for enhancing the immunostimulatory activity of CpG ODN.

    Graphical Abstract Fullsize Image
    Editor’s picks

    Increasing the immunostimulatory activity of unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) is an important issue for its clinical application as immunoadjuvant. In this study, the authors combined two approaches, i.e., nanostructured DNA formation and mannose modification, for efficient delivery of CpG ODN to mannose receptor-positive immune cells. Mannosylated CpG ODN (Man-CpG ODN) loaded onto polypod-like structured nucleic acid (polypodna) induced a greater tumor necrosis factor-α release than Man-CpG ODN or CpG ODN/polypodna from the cells. Thus, this study provides a new and promising approach to increasing the therapeutic potency of CpG ODN.

  • Jizu Ling, Qin Yu, Yuning Li, Xinhui Yuan, Xiaoya Wang, Weiying Liu, T ...
    2020 年 43 巻 8 号 p. 1196-1201
    発行日: 2020/08/01
    公開日: 2020/08/01
    [早期公開] 公開日: 2020/05/30
    ジャーナル フリー HTML
    電子付録

    Oxidative stress plays an essential role in obstructive sleep apnea-hypopnea syndrome-induced cognitive dysfunction in children. This study investigated the effects of edaravone, a potent free radical scavenger, on intermittent hypoxia (IH)-induced oxidative damage and cognition impairment in a young rat model of IH. IH rats were treated with edaravone for 4 weeks. Behavioral testing was performed using the Morris water maze, and hippocampal tissues were harvested for further analyses. Edaravone attenuated IH-induced cognitive impairment, reduced morphological and structural abnormalities, and increased the number of mitochondria in the IH rats. Furthermore, edaravone significantly increased the inhibition of hydroxyl free radicals; reduced expressions of superoxide anion, malondialdehyde, and 8-hydroxy-2′-deoxyguanosine; and upregulated the expression of manganese superoxide dismutase, catalase, cAMP, protein kinase A, phosphorylated-cAMP response element-binding (p-CREB), B-cell lymphoma 2, and brain-derived neurotrophic factor in the hippocampal tissue of IH rats. Our findings suggest that edaravone attenuated IH-induced cognitive impairment and hippocampal damage by upregulating p-CREB in young rats.

    Graphical Abstract Fullsize Image
  • Tatsuya Isayama, Hikaru Etoh, Naoki Kishimoto, Toshimasa Takasaki, Ayu ...
    2020 年 43 巻 8 号 p. 1202-1209
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML
    電子付録

    The effective antigen (Ag) uptake by microfold cells (M-cells) is important for the induction of an efficient mucosal immune responses. Here, we show that 10-hydroxydecanoic acid (10-HDAA) from royal jelly (RJ) potentially supports M-cell differentiation and induces effective antigen-specific mucosal immune responses in cynomolgus macaques. 10-HDAA increases the expression level of receptor activator of nuclear factor-kappaB (NF-κB) (RANK) in Caco-2 cells, which suggests that 10-HDAA potentially prompts the differentiation of Caco-2 cells into M-cells and increased transcytosis efficiency. This idea is supported by the following observations. Intranasal administration of 10-HDAA increased the number of M-cells in the epithelium overlying nasopharynx-associated lymphoid tissue (NALT) in macaques. Oral administration of 10-HDAA increased the number of M-cells in the follicle-associated epithelium (FAE) covering Peyer’s patches (PPs) and significantly increased the antigen-specific immunoglobulin A (IgA) level in macaques. These findings suggest that the exogenous honeybee-derived medium-chain fatty acid 10-HDAA may effectively enhance antigen-specific immune responses.

    Graphical Abstract Fullsize Image
  • Xiaofan Pan, Yanmei Song, Meijun He, Xiaoling Yan, Caiyun Huang, Jie L ...
    2020 年 43 巻 8 号 p. 1210-1219
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Intracerebral hemorrhage (ICH) is a disease with high disability and mortality rates. Currently, the efficacy of therapies available for ICH is limited. Microglia-mediated neuroinflammation substantially exacerbates brain damage following ICH. Here, we investigated whether mitochondrial uncouplers conferred protection by suppressing neuroinflammation following ICH. To mimic ICH-induced neuroinflammation in vitro, we treated microglia with red blood cell (RBC) lysate. RBC lysate enhanced the expression of pro-inflammatory cytokines in microglia. A clinically used uncoupler, niclosamide (Nic), reduced the RBC lysate-induced expression of pro-inflammatory cytokines in microglia. Moreover, Nic ameliorated brain edema, decreased neuroinflammation, and improved neurological deficits in a well-established mouse model of ICH. Like niclosamide, the structurally unrelated uncoupler carbonyl cyanide p-triflouromethoxyphenylhydrazone (FCCP) reduced brain edema, decreased neuroinflammation, and improved neurological deficits following ICH. It has been reported that mitochondrial uncouplers activate AMP-activated protein kinase (AMPK). Mechanistically, Nic enhanced AMPK activation following ICH, and AMPK knockdown abolished the beneficial effects of Nic following ICH. In conclusion, mitochondrial uncouplers conferred protection by activating AMPK to inhibit microglial neuroinflammation following ICH.

    Graphical Abstract Fullsize Image
  • Yuya Mizukami, Ai Moriya, Yuki Takahashi, Kazunori Shimizu, Satoshi Ko ...
    2020 年 43 巻 8 号 p. 1220-1225
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    The multicellular spheroid three-dimensional cell culture system can be used as a formulation for cell-based therapy. However, the viability and functions of the cells in the core region of the spheroid tend to decrease because of limited oxygen supply. In this study, we incorporated gelatin microspheres (GMS) into HepG2 human hepatocyte spheroids to allow oxygen to reach the spheroid core. GMS with an approximate diameter of 37 µm were fabricated by water-in-oil emulsification followed by freeze drying. GMS-containing HepG2 spheroids (GMS/HepG2 spheroids) were prepared by incubation of the cells with GMS at various mixing ratios in agarose gel-based microwells. Increasing the GMS ratio increased the diameter of the spheroids, and few spheroids formed with excess GMS. HepG2 cells in the GMS/HepG2 spheroids were more oxygenated than those in the GMS-free spheroids. GMS incorporation increased the viability of HepG2 cells in the spheroids and increased the CYP1A1 activity of the cells to metabolize 7-ethoxyresorufin, although mRNA expression of the CYP1A1 gene was hardly affected by GMS incorporation. These results indicate that incorporating GMS into HepG2 spheroids improves the hypoxic microenvironment in the spheroids and increases cell viability and CYP1A1 metabolic activity.

    Graphical Abstract Fullsize Image
  • Fukie Yaoita, Kouta Namura, Kaede Shibata, Sayaka Sugawara, Masahiro T ...
    2020 年 43 巻 8 号 p. 1226-1234
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Attention deficit/hyperactivity disorder (AD/HD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. In patients with AD/HD, a decrease in the total and rapid eye movement (REM) sleep times has been observed. We have previously reported that mice with REM sleep deprivation-induced stress (REMSD) may show the hyperactivity- and inattention-like symptoms of AD/HD. However, in this model, impulsivity has not yet been investigated. Impulsivity and anxiety-related behaviors are evaluated by the elevated plus maze test (EPM). In this study, we investigated whether REMSD causes changes in the EPM and expression of alpha2A-adrenoceptors in the hippocampus and frontal cortex in a mouse model. Mice were deprived of REM sleep intermittently using the small-platform method (20 h/d) for 3 d. The time spent in the open arm and the expression levels of alpha2A-adrenoceptor in the hippocampus were significantly increased and decreased, respectively, by the REMSD. The time spent in the open arm was significantly limited by oxymetazoline (an alpha2A-adrenoceptor agonist), methylphenidate, and atomoxetine, which are clinically used to treat AD/HD. Moreover, the positive effects of oxymetazoline were attenuated by yohimbine and BRL44408, which are selective alpha2- and alpha2A-adrenoceptor antagonists, respectively. These results suggest that the increase in the time spent in the open arm induced by REMSD may serve as a model of impulsivity in AD/HD. Furthermore, the REMSD eliciting impulsivity-like behavior and the low-levels of anxiety may be linked to alpha2A-adrenoceptor signaling, as indicated by a decrease in alpha2A-adrenoceptor signaling, particularly in the mouse hippocampus.

    Graphical Abstract Fullsize Image
  • Mayako Uchida, Yuki Yamaguchi, Syuhei Hosomi, Hiroaki Ikesue, Yasuhiro ...
    2020 年 43 巻 8 号 p. 1235-1240
    発行日: 2020/08/01
    公開日: 2020/08/01
    [早期公開] 公開日: 2020/05/21
    ジャーナル フリー HTML

    We retrospectively obtained data of patient background and pretreatment characteristics from medical records and identified the predictive factors of febrile neutropenia (FN) in patients with non-small cell lung cancer (NSCLC) treated with docetaxel alone or in combination with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. Patients were eligible for inclusion in the study if they were 20 years or older, diagnosed with NSCLC, and received docetaxel monotherapy alone or in combination with bevacizumab at the Department of Respiratory Medicine, Kobe City Medical Center General Hospital, between July 1, 2011, and March 31, 2018. Eighty-one patients with recurrent or advanced NSCLC were included. Multivariate stepwise logistic regression analysis with backward selection revealed that lower baseline Eastern Cooperative Oncology Group performance status (ECOG-PS) scores of 1 and 2 (odds ratio (OR), 5.098; 95% confidence interval (CI), 1.045–24.879, p = 0.021) and baseline platelet count below 18.8 × 104/µL (OR, 3.861; 95% CI, 1.211–12.311, p = 0.022) were significant factors influencing the FN occurrence rate. Our results demonstrated that ECOG-PS 1–2 and lower baseline platelet count were significant risk factors of FN in patients with NSCLC receiving docetaxel-based chemotherapy. Moreover, the combination of anti-VEGF antibodies and docetaxel might be associated with increased FN frequency. Despite the limitations of this study including its retrospective design, single-center site, and small sample size, baseline ECOG-PS score and platelet count may be regarded as important indices to identify patients for prophylactic granulocyte-colony stimulating factor (G-CSF) treatment before docetaxel-based chemotherapy.

    Graphical Abstract Fullsize Image
  • Souhei Maruyama, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya
    2020 年 43 巻 8 号 p. 1241-1247
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML
    電子付録

    Retinal pigment epithelial (RPE) cells form the outer blood–retinal barrier (BRB) and regulate drug/compound exchange between the neural retina and blood in the fenestrated blood vessels of retinal choroid via membrane transporters. Recent studies have elucidated that RPE cells express hemichannels, which are opened by extracellular Ca2+ depletion and accept several drugs/compounds as a transporting substrate. The objective of this study was to elucidate the hemichannel-mediated compound transport properties of the outer BRB. In human RPE cells, namely ARPE-19 cells, time-dependent uptake of fluorescent hemichannel substrates, such as Lucifer Yellow, sulforhodamine-101 (SR-101), and propidium iodide (PI) was promoted under Ca2+-depleted conditions. The uptake of these substrates under Ca2+-depleted conditions exhibited saturable kinetics with a Michaelis–Menten constant (Km) of 87–109 µM. In addition, SR-101 and PI uptake by ARPE-19 cells was dependent of extracellular Ca2+ concentration, and that under Ca2+-depleted conditions was significantly decreased by typical substrates and/or inhibitors for hemichannels. Moreover, Ca2+-depleted conditions promoted the efflux transport of calcein from ARPE-19 cells, and the promoted calcein efflux transport was significantly inhibited by a typical hemichannel inhibitor. These results suggested that hemichannels at the outer BRB were involved in the influx and efflux transport of drugs/compounds.

    Graphical Abstract Fullsize Image
  • Ayako Kawabe, Yuichi Muraki, Ryo Inose, Yoshiki Kusama, Ryota Goto, Ai ...
    2020 年 43 巻 8 号 p. 1248-1252
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    The detailed epidemiology of invasive mycoses and superficial mycoses has not been clarified in Japan. In addition, treatment options have increased because of novel antifungals and/or guidelines for fungal infection. In the present study, we aimed to clarify the trends of antifungal use in Japan from 2006 to 2015 based on sales data to serve as an alternative indicator of fungal infection trends. We found that the total antifungal use decreased over time (r = −0.057, Pfor trend < 0.0001). Oral and parenteral use significantly decreased by 44.1% (r = −0.056, Pfor trend < 0.0001) and 27.1% (r = −0.0012, Pfor trend = 0.00061), respectively. The trend of antifungal use for superficial mycoses significantly decreased by 49.8% (r = −0.061, Pfor trend < 0.0001). However, the trend of antifungal use for invasive mycoses was significantly increased by 19.9% (r = 0.0032, Pfor trend = 0.00045). In Japan, the increase in the number of immunocompromised patients might be associated with the increase in the frequency of antifungal use for invasive mycoses. This is the first study to clarify the trends of antifungal use in Japan. Further research is needed to establish a continuous surveillance system to compare fungal infections between Japan and the world.

    Graphical Abstract Fullsize Image
    Editor’s picks

    The detailed epidemiology of invasive mycoses and superficial mycoses has not been clarified in Japan. This is the first study to clarify the trends of antifungal use in Japan. The authors found that total antifungal use decreased over time. Notably, the trend of antifungal use for invasive mycoses was significantly increased by 19.9% whereas the trend of antifungal use for superficial mycoses significantly decreased by 49.8%. In Japan, the increase in the number of immunocompromised patients might be associated with an increase in the frequency of antifungal use for invasive mycoses.

  • Yoko Kado, Masayuki Tsujimoto, Shin-ichi Fuchida, Akira Okano, Mayumi ...
    2020 年 43 巻 8 号 p. 1253-1258
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

    Graphical Abstract Fullsize Image
  • Keisuke Soga, Shinya Kimata, Jumpei Narushima, Sakiko Sato, Emi Sato, ...
    2020 年 43 巻 8 号 p. 1259-1266
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML
    電子付録

    A genetically modified (GM) soybean kernel detection system using combination of DNA preparation from individual soybean kernels and event-specific real-time PCR was developed to simultaneously identify GM soybean events authorized for food after safety assessments in Japan. Over 100 kernels in the non-identity-preserved soybean samples imported from the United States of America (two U.S.A. lots) and Brazil (one lot) were randomly selected and examined. In total, 98 and 96% of the two independent U.S.A. lots, and 100% of the Brazilian lot contained GM soybean kernels. Herbicide-tolerant events, MON89788 (trade name Genuity® Roundup Ready 2 Yield™), GTS 40-3-2 (trade name Roundup Ready™ soybean) and A2704-12 (trade name Liberty Link® soybean), were detected similarly in both U.S.A. lots. In the Brazilian lot, in addition to GTS 40-3-2, a stacked GM event, MON87701 × MON89788, having insect-resistance and herbicide-tolerance, was detected. There were no unauthorized GM soybeans comingled, and the ratio of GM soybean events detected was consistent with statistical reports on the cultivated GM soybean events in both countries.

    Graphical Abstract Fullsize Image
    Editor’s picks

    Today, majority of soybeans in Japan comes from foreign countries, where genetically modified (GM) soybeans are cultivated. The details of GM soybean actually consumed for food in Japan have been unknown. The article by Soga et al. reported a quantitative GM soybean kernel detection system and that the most of imported soybean in the non-identity-preserved soybean samples examined were herbicide-tolerant and insect-resistant GM soybean events that were authorized in Japan. These data would provide useful information on risk analysis concerning regulations on GM soybean for food use.

Notes
  • Pei-Li Zhu, Dick Fai Lam, Jun-Kui Li, Xiu-Qiong Fu, Cheng-Le Yin, Ji-Y ...
    2020 年 43 巻 8 号 p. 1267-1271
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N (GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K–Akt pathway and regulates the mTOR–ULK1 pathway in liver cancer cells.

    Graphical Abstract Fullsize Image
  • Tatsuya Fukuta, Shota Hirai, Tatsusada Yoshida, Takashi Maoka, Kentaro ...
    2020 年 43 巻 8 号 p. 1272-1274
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Our previous study reported that co-encapsulation of potent antioxidants astaxanthin (Asx) and capsaisin (Cap) into liposomes brought about synergistically higher antioxidative activity than the calculated additive activity of each single antioxidant encapsulating liposome. Based on the previous computational chemistry analysis, the synergistic effect was revealed to be resulted from intermolecular interactions between Asx, especially 3R,3′R-form of Asx stereoisomer (Asx-R), and Cap, by which changes of electronic states of the polyene moiety of Asx-R were induced. Although liposomes co-encapsulating Asx-R and Cap (Asx-R/Cap-Lipo) at an optimal ratio clearly showed synergistic antioxidative activity in vitro, it is unclear whether the effective antioxidative activity derived from intermolecular interaction between Asx-R and Cap is also exerted in vivo. Therefore, in this study, we investigated therapeutic potential of Asx-R/Cap-Lipo as an antioxidant formulation in vivo. For this purpose, we employed carbon tetrachloride (CCl4)-induced acute liver injury rat model, since CCl4 is known to cause oxidative damage in liver. CCl4 administration significantly increased the levels of aspartate transaminase (AST) and alanine aminotransferase (ALT). Intravenous combined administration of liposomes encapsulating Asx-R (Asx-R-Lipo) and liposomes encapsulating Cap (Cap-Lipo) significantly decreased CCl4-induced increase of AST and ALT levels. Importantly, the treatment with Asx-R/Cap-Lipo tended to show higher protective effect on acute liver injury than combined treatment with Asx-R-Lipo plus Cap-Lipo. These results suggest that co-encapsulated Asx-R and Cap in liposomal membranes could exert more effective antioxidative activities in vivo, and that Asx-R/Cap-Lipo would be a hopeful antioxidant formulation for treating reactive oxygen species-related diseases.

    Graphical Abstract Fullsize Image
  • Satoru Mitsuboshi, Kazuhiko Nagai, Hideo Okajima
    2020 年 43 巻 8 号 p. 1275-1278
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Although distigmine is known to sometimes cause severe adverse drug reactions (ADRs), such as cholinergic crisis, there are limited data on the risk factors for these ADRs. In this study, we defined a serum cholinesterase (sChE) cutoff level for early detection of ADRs to distigmine and sought to identify risk factors for these ADRs based on this value. This retrospective cohort study included all patients who were prescribed distigmine and underwent measurement of sChE over a period of 8 years at Kaetsu Hospital. Ninety-three patients were included. The sChE cutoff level below which there was an increase in risk of ADRs was defined as 129 U/L based on the levels in patients who had ADRs by receiver operating characteristic analysis. The percentage of ADRs tended to increase with advancing chronic kidney disease (CKD) stage. Multivariate logistic regression analyses showed that a distigmine dose >0.1 mg/kg/d (odds ratio 3.19, 95% confidence interval 1.24–8.19) and age >85 years (odds ratio 3.04, 95% confidence interval 1.18–7.82) were positively associated with an sChE level ≤129 U/L. An sChE cutoff level of 129 U/L is a useful predictor of the risk of an ADR to distigmine, and dose per body weight, age, and CKD progression may pose potential risk of an ADR to distigmine. Therefore, for patients taking distigmine who have these risk factors, the risk of a severe ADR to distigmine can be reduced by decreasing the dose of distigmine and close monitoring of the sChE level.

    Graphical Abstract Fullsize Image
  • Norifumi Shimizu, Chiaki Hara
    2020 年 43 巻 8 号 p. 1279-1282
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Clinical studies, especially those in animal models, have provided evidence that chronic stress may play a role in the etiology of psychiatric diseases, such as depression. Because chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the excessive secretion of glucocorticoids, the chronic stimulation of glucocorticoid receptors (GRs) may be involved in the pathogenesis of depression. To further investigate the relationship between GR activation and depression, we used the synthetic glucocorticoid dexamethasone (DEX) and the GR antagonist mifepristone to examine the effects of chronic GR stimulation on the circadian rhythms of locomotor activity and serotonergic neurotransmission in the basolateral amygdala (BLA) of rats. Chronic treatment with DEX reduced locomotor activity during the dark phase, without changing overall activity patterns. Measuring the basal release of serotonin in the BLA, using in vivo microdialysis, confirmed that chronic treatment with DEX induced serotonergic hypofunction in the BLA. The co-administration of DEX with mifepristone effectively suppressed the depressive-like symptoms caused by chronic treatment with DEX. Our results provided further evidence for a relationship between GR and depression and suggest that the pharmacological blockade of GR may increase the effectiveness of conventional pharmacotherapies used to treat depression.

    Graphical Abstract Fullsize Image
  • Takayuki Matsumoto, Keisuke Takayanagi, Mihoka Kojima, Kumiko Taguchi, ...
    2020 年 43 巻 8 号 p. 1283-1287
    発行日: 2020/08/01
    公開日: 2020/08/01
    ジャーナル フリー HTML

    Although vascular dysfunction is a key event in the development of diabetic complications, and abnormal toll-like receptor 4 (TLR4) may contribute to the pathophysiology of vascular diseases, the direct relationships between TLR4 and vascular function in diabetic arteries are still poorly understood. Thus, to investigate whether pharmacological blockade of TLR4 affects vascular function in the superior mesenteric artery (SMA) of streptozotocin (STZ)-induced diabetic rats, the SMA was isolated from male Wistar rat injected once with STZ (65 mg/kg, 27–34 weeks) which was treated with TAK-242 (10−6 M), a TLR4 inhibitor, for approximately 1 d using organ culture techniques. After incubation, functional and biochemical studies were performed. In the functional study, treatment with TAK-242 increased acetylcholine (ACh)-induced relaxation of the diabetic SMA in the intact condition. Sodium nitroprusside (SNP)-induced relaxation was also increased in the TAK-242-treated group compared with the vehicle-treated group. Under cyclooxygenase (COX) blockade by indomethacin (10−5 M), ACh-induced relaxation was similar in the vehicle- and TAK-242-treated groups. In addition, ACh-induced relaxation in the combined presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NNA) (10−4 M), and indomethacin (10−5 M) was similar in the vehicle- and TAK-242-treated groups. The productions of thromboxane (TX) B2 in cultured medium in the presence of ACh (10−5 M) were lower in the TAK-242-treated group than in the vehicle-treated group. These data suggested that TAK-242 could augment endothelium-dependent relaxation by partly suppressing vasoconstrictor TXA2 or increasing NO signaling. TLR4 inhibition may be a novel therapeutic strategy to assist in the management of diabetes-associated vascular complications.

    Graphical Abstract Fullsize Image
  • Subha Sankar Paul, Eizo Takahashi, Goutam Chowdhury, Shin-ichi Miyoshi ...
    2020 年 43 巻 8 号 p. 1288-1291
    発行日: 2020/08/01
    公開日: 2020/08/01
    [早期公開] 公開日: 2020/06/09
    ジャーナル フリー HTML

    It has been well known that Vibrio cholerae inhabit in environmental water. As many patients infected with cholera toxin-producing V. cholerae O1 (toxigenic V. cholerae O1) emerge in Kolkata, India, it has been thought that toxigenic V. cholerae O1 is easily detected in environmental water in Kolkata. However, we could not isolate toxigenic V. cholerae O1 from environmental water in Kolkata, though NAG Vibrio (generic name of V. cholerae non-O1/non-O139) is constantly detected. To clear the reason for the non-isolation of toxigenic V. cholerae O1, we examined the viability of V. cholera O1 and NAG Vibrios in the artificial low ionic strength aquatic solution. We found that the viability of toxigenic V. cholerae O1 in the solution is low, but that of NAG Vibrios is high. Subsequently, we examined the viability of NAG Vibrios possessing cholera toxin gene (ctx) in the same condition and found that the viability of these NAG Vibrios is low. These results indicate that the existence of ctx in V. cholerae affects the viability of V. cholerae in the aquatic solution used in this experiment. We thought that there was closely relation between the low viability of toxigenic V. cholerae O1 in the artificial low ionic strength aquatic solution and the low frequency of isolation of the strain from environmental water.

    Graphical Abstract Fullsize Image
feedback
Top