Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 43, Issue 4
Displaying 1-25 of 25 articles from this issue
Current Topics -Recent Advances in Research on Particulate Formulations such as Lipoproteins, Liposomes, Extracellular Vesicles, and iPS-Derived Cells
  • Tatsuhiro Ishida, Shigeru Kawakami, Ken-ichi Hosoya
    2020 Volume 43 Issue 4 Pages 575
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Editor's pick

    The 34th Annual Meeting of the Academy of Pharmaceutical Sciences and Technologies, Japan (APSTJ) was held in Toyama, Japan, May 16–18, 2019. In this meeting, a joint symposium was held with the Pharmaceutical Society of Japan and APSTJ. The theme of the symposium was “Recent Advances in Research on Particulate Formulations such as Lipoproteins, Liposomes, Extracellular Vesicles, and iPS Derived Cells.” The four invited speakers provide their review articles in the Current Topics of this issue.

Current Topics: Reviews
  • Yoshinobu Takakura, Akihiro Matsumoto, Yuki Takahashi
    2020 Volume 43 Issue 4 Pages 576-583
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Small extracellular vesicles (sEVs), including exosomes as typical example, are cell-derived vesicles comprising lipid bilayer with a diameter approximately 100 nm. sEVs are endogenous delivery vehicles that deliver their contents such as nucleic acids and proteins to recipient cells. Because of their potential nature as endogenous delivery vehicles, therapeutic applications of sEVs as delivery systems of various drugs are expected. To develop sEV-based therapeutics, a variety of challenges should be overcome. In this review, we summarize the current status and future perspectives of therapeutic applications of sEVs. Several pharmaceutical and pharmacokinetic challenges will be discussed.

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  • Ikramy A. Khalil, Mahmoud A. Younis, Seigo Kimura, Hideyoshi Harashima
    2020 Volume 43 Issue 4 Pages 584-595
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    The last few years have witnessed a great advance in the development of nonviral systems for in vivo targeted delivery of nucleic acids. Lipid nanoparticles (LNPs) are the most promising carriers for producing clinically approved products in the future. Compared with other systems used for nonviral gene delivery, LNPs provide several advantages including higher stability, low toxicity, and greater efficiency. Additionally, systems based on LNPs can be modified with ligands and devices for controlled biodistribution and internalization into specific cells. Efforts are ongoing to improve the efficiency of lipid-based gene vectors. These efforts depend on the appropriate design of nanocarriers as well as the development of new lipids with improved gene delivery ability. Several ionizable lipids have recently been developed and have shown dramatically improved efficiency. However, enhancing the ability of nanocarriers to target specific cells in the body remains the most difficult challenge. Systemically administered LNPs can access organs in which the capillaries are characterized by the presence of fenestrations, such as the liver and spleen. The liver has received the most attention to date, although targeted delivery to the spleen has recently emerged as a promising tool for modulating the immune system. In this review, we discuss recent advances in the use of LNPs for cell-specific targeted delivery of nucleic acids. We focus mainly on targeting liver hepatocytes and spleen immune cells as excellent targets for gene therapy. We also discuss the potential of endothelial cells as an alternate approach for targeting organs with a continuous endothelium.

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  • Ryosuke Fukuda, Tatsuya Murakami
    2020 Volume 43 Issue 4 Pages 596-607
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Lipoproteins are naturally occurring nanoparticles and their main physiological function is the promotion of lipid metabolism. They can be prepared in vitro for use as drug carriers, and these reconstituted lipoproteins show similar biological activity to their natural counterparts. Some lipoproteins can cross the blood-retinal barrier and are involved in intraocular lipid metabolism. Drug-loaded lipoproteins can be delivered to the retina for the treatment of posterior eye diseases. In this review, we have discussed the therapeutic applications of lipoproteins for eye diseases and introduced the emerging animal models used for the evaluation of their therapeutic effects.

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  • Sayaka Deguchi, Kazuo Takayama, Hiroyuki Mizuguchi
    2020 Volume 43 Issue 4 Pages 608-615
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Liver transplantation and hepatocyte transplantation are effective treatments for severe liver injuries, but the donor shortage is a serious problem. Therefore, hepatocyte-like cells generated from human induced pluripotent stem (iPS) cells with unlimited proliferative ability are expected to be a promising new transplantation resource. The technology for hepatic differentiation from human iPS cells has made great progress in this decade. The efficiency of hepatic differentiation now exceeds 90%, making it possible to produce nearly homogeneous hepatocyte-like cells from human iPS cells. Because there is little contamination of undifferentiated cells, there is a lower risk of teratoma formation. To date, the transplantation of human iPS cell-derived hepatocyte-like cells has been shown to have therapeutic effects using various liver injury model mice. Currently, studies are underway using model animals larger than mice. The day when human iPS cell-derived hepatocyte-like cells can be used as cellular medicine is surely approaching. In this review, we introduce the forefront of regenerative medicine applications using human iPS cell-derived hepatocyte-like cells.

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Communication to the Editor
  • Daisuke Yasuda, Haruki Torii, Rumiko Shimizu, Yoshinori Hiraoka, Noria ...
    2020 Volume 43 Issue 4 Pages 616-618
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic seatohepatitis (NASH) is one of the major health problems world wide, because of increased abdominal obesity. To date, specific and effective medications to treat or prevent NAFLD/NASH have not been established. To identify appropriate molecular targets for that purpose, suitable animal models of NAFLD/NASH have been explored. A choline-deficient amino acid-defined high fat diet (CDAHFD)-induced mouse model of NASH has been developed. However, its relevance to human NASH, including serum lipid profiles, have not been clearly defined. In this study, we have revealed that mice fed CDAHFD showed significantly lowerd serum total cholesterol and triglyceride (TG) levels, in addition to reduced body weight (BW). Furthermore, hepatic microsomal triglyceride transfer protein (MTP) expression was significantly downregulated in CDAHFD-fed mice. Thus, the current CDAHFD-fed mouse model has points that are distinct from human NAFLD/NASH, in general, which is based upon abdominal obesity.

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Regular Articles
  • Ji Hye Yang, Chang-Su Na, Sam Seok Cho, Kyu Min Kim, Ji Hyun Lee, Xi-Q ...
    2020 Volume 43 Issue 4 Pages 619-628
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
    Advance online publication: January 31, 2020
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    Supplementary material

    Neoagarooligosaccharides (NAOS) are generated by β-agarases, which cleave the β-1,4 linkage in agarose. Previously, we reported that NAOS inhibited fat accumulation in the liver and decreased serum cholesterol levels. However, the hepatoprotective effect of NAOS on acute liver injury has not yet been investigated. Thus, we examined whether NAOS could activate nuclear factor (NF)-E2-related factor 2 (Nrf2)–antioxidant response element (ARE) and upregulates its target gene, and has hepatoprotective effect in vivo. In hepatocytes, phosphorylation and subsequent nuclear translocation of Nrf2 are increased by treatment with NAOS, in a manner dependent on p38 and c-Jun N-terminal kinase (JNK). Consistently, NAOS augmented ARE reporter gene activity and the antioxidant protein levels, resulting in increased intracellular glutathione levels. NAOS antagonized tert-butylhydroperoxide-induced reactive oxygen species (ROS) generation. Moreover, NAOS inhibited acetaminophen (APAP)-induced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and significantly decreased hepatocyte degeneration and inflammatory cell infiltration. Moreover, ROS production and glutathione depletion by APAP were reversed by NAOS. APAP-mediated apoptotic signaling pathways were also inhibited in NAOS-treated mice. Upregulalted hepatic expression of genes related to inflammation by APAP were consistently diminished by NAOS. Collectively, our results demonstrate that NAOS exhibited a hepatoprotective effect against APAP-mediated acute liver damage through its antioxidant capacity.

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  • Junji Nishioka, Keiichi Hiramoto, Koji Suzuki
    2020 Volume 43 Issue 4 Pages 629-638
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
    Advance online publication: January 24, 2020
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    Supplementary material

    Sparassis crispa (SC; Japanese name: Hanabiratake) is a mushroom with high β(1-3)-glucan content. We here studied the effects of SC and lactic acid bacteria-fermented SC (SCL) on innate immunity. In in vivo studies using mice, oral administration of SC or SCL enhanced the accumulation of macrophages, neutrophils, natural killer (NK) cells, and C–C chemokine receptor type 2- or phospho-Syk-expressing cells in the jejunum epithelial villi and spleen, with significantly higher cell numbers in the SCL group than in the SC group. In addition, mRNA levels of genes encoding tissue factor (TF) and tumor necrosis factor (TNF)-α were increased in monocytes/macrophages from the peritoneal cavity of mice orally administered SCL. In in vitro studies using cultured human monocytes, SC and SCL enhanced the expression of gees involved in blood coagulation and inflammation, as well as those encoding various innate immune-related factors, such as TF, TNF-α, plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1β, IL-8, IL-12β, and IL-17, in a dose-dependent manner. In particular, the expression levels of all these factors in monocytes were significantly higher with SCL treatment than with SC treatment. SCL significantly enhanced the phagocytosis of pH-sensitive fluorescent dye-labeled Escherichia coli by human monocytes compared to SC. The effect of SCL on phagocytosis was significantly reduced to approximately 30% by pre-digestion of SCL with β-glucanase, suggesting that β(1-3)-glucan in SCL is a major contributor to the effect. These data suggest that oral administration of SCL significantly enhances innate immunity in mice and possibly humans.

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  • Haidong Zhang, Hui Ma, Wenling Zhang, Deyi Duan, Guangting Zhu, Wei Ca ...
    2020 Volume 43 Issue 4 Pages 639-648
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    Sema3C has been reported to promote glioma stem cells self-renewal and glioblastoma growth. However, the prognostic value and the regulatory mechanism for its abnormal expression in glioma remain poorly understood. In the current study, the immunohistochemistry results demonstrated that Sema3C was overexpressed in 169 of 216 (78.2%) interpretable glioma patients compared with 3 of 15 (20.0%) interpretable non-neoplastic brain cases (p = 0.0001). Sema3C overexpression was significantly associated with histologic type (p = 0.008), high Ki67 labeling index (p = 0.02), tumor grade (p = 0.002) and wild type IDH1 (p = 0.0001). Importantly, its overexpression predicts the shorter overall survival of glioma patients (p = 0.0017), especially the ones with high grade (p = 0.0124). Functionally, Sema3C silencing significantly reduced the proliferation and invasion of glioma cells, indicating an oncogenic role of Sema3C in glioma in vitro. To elucidate the reason accounting for its overexpression, it is identified miR-142-5p as a tumor suppressor that directly targets Sema3C in glioma cells. miR-142-5p and Sema3C were co-regulators of epithelial–mesenchymal transition. Clinically, miR-142-5p expression was conversely related with Sema3C expression in glioma samples. Together, we identified that Sema3C could promote the progression of glioma and its expression was negatively regulated by miR-142-5p in vitro. Thus, the miR-142-5p-Sema3C axis plays importantly in glioma and holds potential to be therapeutic targets as well.

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  • Nurhanani Razali, Hirofumi Hohjoh, Tomoaki Inazumi, Bishnu Devi Maharj ...
    2020 Volume 43 Issue 4 Pages 649-662
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naïve T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D2 and thromboxane B2, a metabolite of thromboxane A2, in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1- and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naïve T cells in the thymus.

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  • Shigeru Ishida, Ken Masuguchi, Takehiro Kawashiri, Toshikazu Tsuji, Hi ...
    2020 Volume 43 Issue 4 Pages 663-668
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Hypersensitivity reactions, including anaphylaxis, are common side effects associated with docetaxel treatment in breast cancer patients. However, preventive measures have not yet been established. In this study, we retrospectively analyzed the risk factors for developing anaphylaxis in 182 female breast cancer patients treated with docetaxel. We found that 6.6% of all patients (n = 12) experienced anaphylaxis. Multivariate analyses indicated that concentration of docetaxel higher than 0.275 mg/m2/mL, docetaxel dose rate higher than 1.15 mg/m2/min, and white blood cell count less than 4290 cells/mL are risk factors for developing docetaxel-related anaphylaxis. In particular, concentrations of docetaxel or doses per administration time were associated with a high odds ratio (11.88 or 11.60) for docetaxel-related anaphylaxis. Moreover, patients receiving doses in 250 mL volume experienced anaphylaxis more frequently than those receiving doses in 500 mL (7.0 vs. 0.9%, p = 0.0236). Additionally, patients receiving treatments over 60 min tended to experience anaphylaxis more frequently than those who were treated over 90 min (6.7 vs. 1.1%, p = 0.0637). The present results indicate that high docetaxel concentrations, high dose rates, and low white blood cell counts are risk factors for developing docetaxel-related anaphylaxis, and administering docetaxel diluted in 500 mL over 90 min may limit docetaxel-induced hypersensitivity reactions.

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  • Yosuke Ando, Takahiro Hayashi, Hideyo Shiouchi, Chihiro Tanaka, Kaori ...
    2020 Volume 43 Issue 4 Pages 669-674
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
    Advance online publication: February 07, 2020
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    Despite in vivo studies suggesting that obesity increases carboplatin (CBDCA) bone marrow toxicity, the American Society of Clinical Oncology recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer. Accordingly, the present study retrospectively investigated the effect of body mass index (BMI) on bone marrow toxicity in patients with gynecological cancer who underwent paclitaxel and carboplatin (TC) therapy after eliminating the effect of the target area under the curve (AUC). Risk factors for CBDCA bone marrow toxicity were also identified. A total of 110 patients with primary gynecological cancer or gynecological cancer of unknown primary origin who underwent TC therapy with a target AUC of 5–6 were included herein. Patients with a BMI of ≥25 and <25 kg/m2 were assigned to the obesity and control groups, respectively, and evaluated according to changes in hematological test values (platelet, white blood cell, and hemoglobin counts) starting from initial TC therapy administration until 21 d after the second treatment course. The obesity group had a significantly higher thrombocytopenia rate than the control group. Risk factors for thrombocytopenia ≥ grade 2 included BMI ≥25 kg/m2. Among patients with primary gynecological cancer or gynecological cancer of unknown primary origin who had a BMI of ≥25 kg/m2, those receiving CBDCA may be at increased risk for thrombocytopenia ≥ grade 2 when the dosage is calculated using the Calvert formula with the creatinine clearance level.

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  • Yasufumi Katanasaka, Yusuke Miyazaki, Yoichi Sunagawa, Masafumi Funamo ...
    2020 Volume 43 Issue 4 Pages 675-681
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Previous studies have shown that green tea catechins (GTCs) have beneficial effects on obesity and metabolic syndromes. In this study, we prepared kosen-cha from green tea using high pressure extraction, to reduce the astringent taste of the green tea. We identified a large quantity of polymerized GTCs in kosen-cha. To investigate the effects of kosen-cha containing polymerized GTCs in obese Japanese patients, we designed an open-label pilot study in which 6 obese subjects (body mass index (BMI) >25 kg/m2) were administered kosen-cha (5 g/L/d) for 12 weeks. Body composition, serum lipids, insulin resistance, vascular functions, and cardiac hypertrophy were measured before and 12 weeks after kosen-cha administration. Kosen-cha showed no significant adverse effects on the patients. Body weights, BMI, waist circumferences, serum triglyceride (TG) levels, and homeostasis model assessment as an index of insulin resistance (HOMA-IR) levels were significantly decreased after the 12 weeks of administration. Flow-mediated dilation (FMD) (p = 0.0214), brachial-ankle pulse wave velocity (baPWV)(p = 0.0141), left ventricular mass indexes (p = 0.0120), and plasma brain natriuretic peptide (BNP) (p = 0.0144) were significantly improved. Overall, kosen-cha reduced obesity and improved insulin resistance, vascular function, and cardiac hypertrophy, indicating its preventive potential in obesity and metabolic syndrome.

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  • Yukiko Nakagawa, Takuya Suzuki, Yukio Suga, Tsutomu Shimada, Yoshimich ...
    2020 Volume 43 Issue 4 Pages 682-687
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    We previously showed that adhesive aggregates were formed when levofloxacin hydrate tablets and lansoprazole orally disintegrating (OD) tablets were suspended in water in the clinical context. In this study, we have clarified the factors causing aggregate formation, focusing on the role of pharmaceutical additives and electrostatic interaction. Co-suspension of enteric-coated proton pump inhibitor (PPI) esomeprazole magnesium hydrate with levofloxacin resulted in aggregate formation, whereas the non-enteric-coated PPI vonoprazan fumarate did not. A comparison of pharmaceutical additive in the two PPIs highlighted polysorbate 80 and methacrylic acid copolymer LD as candidates causing aggregation. When these pharmaceutical additives were added to levofloxacin, only methacrylic acid copolymer LD induced aggregate formation. Since levofloxacin is zwitterionic, we examined another zwitterionic ingredient, ampicillin sodium, and found that it also formed aggregates with methacrylic acid copolymer LD, while benzylpenicillin sodium, which is not zwitterionic, did not form aggregates. When we next examined a series of zwitterionic quinolone antimicrobial drugs, we found that ofloxacin, which is highly soluble, formed aggregates with lansoprazole OD tablets, whereas poorly soluble quinolone antimicrobial drugs did not form aggregates. Further, although cefepime hydrochloride and cephalexin did not form aggregates with methacrylic acid copolymer LD in tap water, aggregates were formed when a suspension of cefepime hydrochloride or cephalexin with methacrylic acid copolymer LD was adjusted to pH 7.0. Our results indicate that electrostatic interaction between zwitterionic ingredients and methacrylic acid copolymer LD can result in aggregate formation under conditions where the drug and methacrylic acid copolymer LD are both sufficiently soluble.

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    Editor's pick

    Interactions between drugs and pharmaceutical additives can cause problems when mixing multiple drugs in clinical settings. One example is aggregate formation between levofloxacin hydrate tablets and lansoprazole orally disintegrating tablets. Nakagawa et al investigated the factors involved in this aggregation, focusing on the role of pharmaceutical additives and electrostatic interaction. Levofloxacin, which is zwitterionic, formed aggregates with methacrylic acid copolymer LD, one of the pharmaceutical additives of lansoprazole orally disintegrating tablet. Other zwitterionic ingredients, including ampicillin, meropenem, cefepime, and cephalexin, also formed aggregates with methacrylic acid copolymer LD.

  • Hiroaki Watanabe, Satoshi Yamaori, Shinobu Kamijo, Kaori Aikawa, Shige ...
    2020 Volume 43 Issue 4 Pages 688-692
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Sesamin is a major lignan in sesame seeds, and a recent meta-analysis of controlled trials indicated that sesamin intake decreases blood pressure. The antihypertensive effect of sesamin has been suggested to be due to sesamin-mediated suppression of 20-hydroxyeicosatetraenoic acid production catalyzed by CYP4F2. However, the detailed mechanism underlying inhibition of CYP4F2 function by sesamin remains unclear. In this study, the effects of sesamin on catalytic activity of CYP4F2 were investigated in vitro. Sesamin inhibited luciferin-4F2/3 O-dealkylase activity of recombinant human CYP4F2 with an IC50 value of 0.381 µM. When preincubated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) for 20 min, sesamin potentiated the inhibition of CYP4F2 activity. Moreover, kinetic analysis of the inactivation revealed that sesamin showed a preincubation time- and concentration-dependent inhibition of CYP4F2 activity yielding a maximal inactivation rate constant (kinact) value of 0.354 min−1 and half-maximal inhibitory concentration (KI) value of 1.12 µM. The inactivation of CYP4F2 by sesamin required NADPH. These results indicated that sesamin is a mechanism-based inactivator of human CYP4F2.

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    Editor's pick

    Sesamin is a major lignan in sesame seeds, and a recent meta-analysis of controlled trials showed that sesamin consumption reduces blood pressure. The antihypertensive effect of sesamin was suggested to be caused by suppression of cytochrome P450 4F2 (CYP4F2)-mediated 20-hydroxyeicosatetraenoic acid production. However, the detailed mechanism underlying inhibition of CYP4F2 function by sesamin was unclear. The article by Watanabe et al. characterized the in vitro inhibitory effects of sesamin on human CYP4F2 activity. The results indicated that sesamin is a mechanism-based inactivator of CYP4F2.

  • Saki Ishii, Yuichi Muraki, Yoshiki Kusama, Tetsuya Yagi, Ryota Goto, A ...
    2020 Volume 43 Issue 4 Pages 693-696
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    In Japan, there is no national surveillance study of Clostridioides (Clostridium) difficile infection (CDI), and details about the epidemiology and treatment status of CDI are unknown. Additionally, clinical practice guidelines (CPGs) for CDI are published by four different institutions. All CPGs recommend that the antimicrobials, vancomycin (VCM) and metronidazole (MNZ), should be selected according to disease severity. However, the trends for VCM and MNZ use in Japan remain unclear. Therefore, this study was aimed at clarifying the secular trends for VCM and MNZ use based on sales data from 2006 to 2015 and discussing its impact on CDI status and drug costs. This is the first study to clarify the antibiotic use trends for CDI treatment. We found that the total use increased over time (r = 0.0013, Pfor trend < 0.0001). While VCM use significantly decreased (r = −0.0003, Pfor trend = 0.0002), MNZ use increased (r = 0.0017, Pfor trend < 0.0001). These results show that although treatment for CDI was in line with CPGs, CDI incidence might be on an increasing trend. Additionally, despite the increased total use, the total drug costs decreased by 55% (&#36; 25 million) from 2006 to 2015. It was also surmised that CDI treatment in compliance with CPGs would lead to a reduction in drug costs. Hence, to understand the epidemiology of CDI, it is important to continuously investigate the use of drugs used for CDI therapy.

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  • Tatsushi Yuri, Yusuke Kono, Tomofumi Okada, Tomohiro Terada, Seiji Miy ...
    2020 Volume 43 Issue 4 Pages 697-706
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    5-Aminosalicylic acid (5-ASA) is used as first line therapy for symptom remission and maintenance of inflammatory bowel disease (IBD). Because 5-ASA is well absorbed from the small intestine when orally administered, several 5-ASA formulations for selective delivery to the colon have been developed and used in clinical practice. However, its delivery efficiency to local inflamed colonic sites remains low. Intestinal H+-coupled oligopeptide transporter 1 (PEPT1) expression in the colon is low, whereas its expression is induced in the colon under chronic inflammation conditions, such as IBD. Therefore, we considered that PEPT1 would be a target transporter to improve 5-ASA delivery efficiency to local colonic lesions. We evaluated the transport characteristics of dipeptide-like 5-ASA derivatives, which were coupling glycine (Gly), lysine, glutamic acid (Glu), valine (Val) and tyrosine to amino or carboxyl group of 5-ASA, in Caco-2 cells. [3H]Glycylsarcosine (Gly-Sar) uptake into Caco-2 cells was inhibited by all 5-ASA derivatives. In addition, 5-ASA derivatives (Gly-ASA, Glu-ASA and Val-ASA), which were coupled by glycine, glutamic acid and valine to amino group of 5-ASA, were taken up in a pH- and concentration-dependent manner and their uptake was inhibited by excess Gly-Sar. Two-electrode voltage-clamp experiment using human PEPT1 expressing Xenopus oocytes showed that Gly-ASA, Glu-ASA and Val-ASA induced marked currents at pH 6.0. Taken together, these results showed that these 5-ASA derivatives are transportable substrates for PEPT1.

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    Editor's pick

    5-Aminosalicylic acid (5-ASA) is used as first line therapy for inflammatory bowel disease (IBD). However, a very high 5-ASA dose is required for IBD treatment because 5-ASA formula is relatively low delivery efficacy to local inflamed colonic sites. In this report, Yuri et al. focused on an intestinal H+-coupled oligopeptide transporter 1 (PEPT1) which is induced in the colon under IBD condition, and demonstrated that the newly synthesized dipeptide-like 5-ASA derivatives, which are coupling glycine, glutamic acid and valine to amino group of 5-ASA, were transportable substrates for PEPT1.

  • Minwoo Hwang, Jeong Nam Kim, Jong Rok Lee, Sang Chan Kim, Byung Joo Ki ...
    2020 Volume 43 Issue 4 Pages 707-715
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Chaihu-Shugan-San (CSS) has been widely used as an alternative treatment for gastrointestinal (GI) diseases in East Asia. Interstitial cells of Cajal (ICCs) are pacemakers in the GI tract. In the present study, we examined the action of CSS on pacemaker potentials in cultured ICCs from the mouse small intestine in vitro and on GI motility in vivo. We used the electrophysiological methods to measure the pacemaker potentials in ICCs. GI motility was investigated by measuring intestinal transit rates (ITR). CSS inhibited the pacemaker potentials in a dose-dependent manner. The capsazepine did not block the effect of CSS. However, the effects of CSS were blocked by glibenclamide. In addition, NG-nitro-L-arginine methyl ester (L-NAME) also blocked the CSS-induced effects. Pretreatment with SQ-22536 or with KT-5720 did not suppress the effects of CSS; however, pretreatment with ODQ or KT-5823 did. Furthermore, CSS significantly suppressed murine ITR enhancement by neostigmine in vivo. These results suggest that CSS exerts inhibitory effects on the pacemaker potentials of ICCs via nitric oxide (NO)/cGMP and ATP-sensitive K+ channel dependent and transient receptor potential vanilloid 1 (TRPV1) channel independent pathways. Accordingly, CSS could provide the basis for the development of new treatments for GI motility dysfunction.

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  • Jing Liu, Tao Zhu, Qingqing Niu, Xiaoxing Yang, Hao Suo, Hao Zhang
    2020 Volume 43 Issue 4 Pages 716-724
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    The purpose of this study was to investigate the preventive effect and mechanism of Dendrobium alkaloids (DNLA) on oxidative stress-related death in neuronal cells. Our results demonstrated that DNLA has a direct neuroprotective effect through oxidative stress in N2A cells induced by hydrogen peroxide (H2O2). CCK8, lactate dehydrogenase (LDH), intracellular Ca2+, intracellular reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were used to evaluate the mechanism of DNLA neutralization by H2O2-induced injury. Results presented in the paper indicate that treatment with DNLA (35 ng/mL) significantly attenuated decreases in cell viability, release of LDH, and apoptosis after H2O2-induced neuronal injury. Furthermore, DNLA significantly reduced intracellular Ca2+ up-regulation, ROS production, and inhibited mitochondrial depolarization. Moreover, DNLA treatment significantly downregulated expressions of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, nitric oxide synthase, janus kinase–signal transducer and activators of transcription (JAK–STATs) signaling in N2A cells, all of which were H2O2-induced. Taken together, our findings suggested that DNLA may inhibit the expression of pro-inflammatory and pro-apoptotic factors by blocking JAK–STATs signaling after oxidative stress injury. This research provides a potential experimental basis for further application of DNLA to prevent various human nervous system diseases caused by oxidative stress.

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  • Haruka Fujikawa, Taise Kawakami, Ryunosuke Nakashima, Aoi Nasu, Shunsu ...
    2020 Volume 43 Issue 4 Pages 725-730
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
    Advance online publication: January 31, 2020
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    Epithelial sodium channel (ENaC) is an amiloride-sensitive sodium ion channel that is expressed in epithelial tissues. ENaC overexpression and/or hyperactivation in airway epithelial cells cause sodium over-absorption and dysregulated ciliary movement for mucus clearance; however, the agents that suppress constitutive airway ENaC activation are yet to be clinically available. Here, we focused on macrolides, which are widely used antibiotics that have many potential immunomodulatory effects. We examined whether macrolides could modulate constitutive ENaC activity and downstream events that typify cystic fibrosis (CF) and chronic obstructive pulmonary diseases (COPD) in in vitro and in vivo models of ENaC overexpression. Treatment of ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o- cells) with three macrolides (erythromycin, clarithromycin, azithromycin) confirmed dose-dependent suppression of ENaC function. For in vivo studies, mice harboring airway specific βENaC overexpression (C57BL/6J-βENaC-transgenic mice) were treated orally with azithromycin, a well-established antimicrobial agent that has been widely prescribed. Azithromycin treatment modulated pulmonary mechanics, emphysematous phenotype and pulmonary dysfunction. Notably, a lower dose (3 mg kg−1) of azithromycin significantly increased forced expiratory volume in 0.1 s (FEV0.1), an inverse indicator of bronchoconstriction. Although not statistically significant, improvement of pulmonary obstructive parameters such as emphysema and lung dysfunction (FEV0.1%) was observed. Our results demonstrate that macrolides directly attenuate constitutive ENaC function in vitro and may be promising for the treatment of obstructive lung diseases with defective mucociliary clearance, possibly by targeting ENaC hyperactivation.

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  • Kota Kikuchi, Yu Fujita, Xuefeng Shen, Junjun Liu, Tomoki Terakawa, Da ...
    2020 Volume 43 Issue 4 Pages 731-735
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Alzheimer’s disease (AD) is characterized by the formation of extracellular amyloid plaques containing the amyloid β-protein (Aβ) within the parenchyma of the brain. Aβ is considered to be the key pathogenic factor of AD. Recently, we showed that Angiotensin II type 1 receptor (AT1R), which regulates blood pressure, is involved in Aβ production, and that telmisartan (Telm), which is an angiotensin II receptor blocker (ARB), increased Aβ production via AT1R. However, the precise mechanism underlying how AT1R is involved in Aβ production is unknown. Interestingly, AT1R, a G protein-coupled receptor, was strongly suggested to be involved in signal transduction by heterodimerization with β2-adrenergic receptor (β2-AR), which is also shown to be involved in Aβ generation. Therefore, in this study, we aimed to clarify whether the interaction between AT1R and β2-AR is involved in the regulation of Aβ production. To address this, we analyzed whether the increase in Aβ production by Telm treatment is affected by β-AR antagonist using fibroblasts overexpressing amyloid precursor protein (APP). We found that the increase in Aβ production by Telm treatment was decreased by the treatment of β2-AR selective antagonist ICI-118551 more strongly than the treatment of β1-AR selective antagonists. Furthermore, deficiency of AT1R abolished the effect of β2-AR antagonist on the stimulation of Aβ production caused by Telm. Taken together, the interaction between AT1R and β2-AR is likely to be involved in Aβ production.

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Notes
  • Yusuke Kono, Kazuha Yokoyama, Motofumi Suzuki, Hideo Takakura, Mikako ...
    2020 Volume 43 Issue 4 Pages 736-741
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    Stimuli-responsive liposomes are promising drug carriers for cancer treatment because they enable controlled drug release and the maintenance of desired drug concentrations in tumor tissue. In particular, near-IR (NIR) light is a useful stimulus for triggering drug release from liposomes based on its advantages such as deep tissue penetration and safety. Previously, we found that a silicon phthalocyanine derivative, IR700, conjugated to antibodies, can induce the rupture of the cell membrane following irradiation by NIR light. Based on this finding, we constructed IR700-modified liposomes (IR700 liposomes) and evaluated their drug release properties triggered by NIR light. IR700 liposomes released substantial amounts of encapsulated calcein following irradiation by NIR light. Drug release was substantially suppressed by the addition of sodium azide, suggesting that liposomal membrane permeabilization was mediated by singlet oxygen generated from IR700. Moreover, calcein release from IR700 liposomes triggered by NIR light was promoted under conditions of deoxygenation and the presence of electron donors. Thus, membrane disruption should be induced by the physical change of IR700 from highly hydrophilic to hydrophobic as we previously described, although singlet oxygen can cause a certain level of membrane disruption under normoxia. We also observed that doxorubicin-encapsulated IR700 liposomes exhibited significant cytotoxic effects against CT-26 murine colon carcinoma cells following NIR light exposure. These results indicate that IR700 liposomes can efficiently release anti-cancer drugs following NIR light irradiation even under hypoxic conditions and, therefore, they would be useful for cancer treatment.

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  • Kohei Izawa, Keisuke Shirakura, Koji Kakiuchi, Nobuaki Funahashi, Naok ...
    2020 Volume 43 Issue 4 Pages 742-746
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    Roundabout4 (Robo4) is an endothelial cell-specific protein that stabilizes the vasculature in pathological angiogenesis and inflammation. We previously determined a 3-kb Robo4 promoter and demonstrated the importance of the upstream region for nuclear factor-kappaB (NF-κB)-mediated promoter activation induced by tumor necrosis factor α (TNFα). This region contains unique genomic features, including promoter region-specific DNA hypermethylation and chromatin condensation; however, the function of the region remains poorly understood. In this study, we analyzed the DNA sequences of the region and identified a motif for polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation assay indicates the binding of the PRC2 component, SUZ12, to the motif. A mutation in the motif decreased DNA methylation in embryonic stem cells and increased Robo4 promoter activity in endothelial cells. An inhibitor for the PRC2 component, EZH2, induced the promoter activity and expression of Robo4 in endothelial cells treated with or without TNFα. Taken together, these results indicate that the PRC2 components maintain DNA hypermethylation and suppress Robo4 expression via the PRC2 binding motif in the upstream promoter.

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  • Saeka Kinouchi, Miku Sato, Haruna Furukawa, Takeshi Sato
    2020 Volume 43 Issue 4 Pages 747-751
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
    Advance online publication: February 04, 2020
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    Our previous study demonstrated that downregulation of transcription factor Specificity protein (Sp) 1 suppresses the malignant potentials of A549 human lung cancer cell line with the reduced β4-galactosylation of highly branched N-glycans on cell surface glycoproteins. The reduced β4-galactosylation was brought about by the decreased expression of the β4-galactosyltransferase 1 (β4GalT1) gene. Herein, we examined whether the reduced β4-galactosylation by decreasing the β4GalT1 gene expression suppresses the malignant potentials of A549 cells. In the β4GalT1-downregulated cells, the β4-galactosylation of highly branched N-glycans was reduced in several glycoproteins such as lysosome-associated membrane protein-1 and E-cadherin. The anchorage-independent growth and migratory ability of the β4GalT1-downregulated cells decreased when compared with the control cells. Furthermore, the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) decreased in the β4GalT1-downregulated cells. These results indicate that downregulation of the β4GalT1 gene decreases the β4-galactosylation of highly branched N-glycans and the phosphorylation of p44/42 MAPK, and suppresses the malignant potentials of A549 cells.

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  • Satoshi Dote, Daisuke Yamaguchi, Daiki Hira, Satoshi Noda, Yuka Kobaya ...
    2020 Volume 43 Issue 4 Pages 752-756
    Published: April 01, 2020
    Released on J-STAGE: April 01, 2020
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    Supplementary material

    Hypothyroidism is a well-established toxicity of small-molecule anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors. However, its association with anti-VEGF biologics is uncertain. The aim of this study was to investigate the incidence, time course, clinical features, and severity of thyroid dysfunction in patients receiving ramucirumab (an antiangiogenic VEGF receptor 2-binding monoclonal antibody). After retrospectively reviewing electronic medical records from September 2015 to December 2018 at Kyoto-Katsura Hospital, we identified 38 patients who received ramucirumab and had thyroid function testing available to review (case series). We also evaluated the change of thyroid-stimulating hormone (TSH) level during ramucirumab chemotherapy in 16 out of 38 patients who were regularly confirmed TSH (descriptive study). A total of 14 (36.8%) patients developed thyroid dysfunction (TSH >10 mU/L) after ramucirumab chemotherapy. Thyroid autoantibodies were detected in one of the 10 patients (10.0%) who were tested for thyroid autoantibodies. The median time to onset of thyroid dysfunction after ramucirumab initiation was 275 (range, 63–553) days. Levothyroxine replacement was needed in 10 (71.4%) patients. Sixteen patients had thyroid function regularly monitored; the mean TSH level was significantly increased after ramucirumab chemotherapy compared with that at baseline (10.7 ± 10.0 mU/L vs. 4.1 ± 2.8 mU/L; p < 0.01). Our findings indicate that ramucirumab can result in thyroid dysfunction. We propose that thyroid function testing should be performed regularly to detect hypothyroidism and guide its management in patients receiving ramucirumab chemotherapy.

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