Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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  • Yang Zhang, Jun Zhao, Juan Jing, Ruitao Zhang, Xuejiao Zhou, Jianyi Ga ...
    2021 Volume 44 Issue 2 Pages 162-168
    Published: February 01, 2021
    Released: February 01, 2021
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    Folic acid (FA) affect human physiology and drug metabolism. Up to now, the effect of microgravity on the pharmacokinetics of FA remains unclear. The pharmacokinetics of FA in Sprague–Dawley (SD) rats are laying a foundation for safe medicine administration of astronauts. Proteins expression of such FA metabolic enzymes as Methyltetrahydrofolate reductase (MTHFR), Cystathionine beta synthase (CBS) and Methionine synthase (MS) in a variety of organs was analyzed with Western-Blot, and mRNA expression was detected by RT-PCR. The plasma concentration–time profile of FA in normal or tail-suspended SD rats was acquired by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after oral administration of FA. Area under curve (AUC) and Cmax of FA in SD rats decreased significantly with extending period of tail-suspension. In terms of expressed level of metabolic enzymes over four suspension terms, as well as the level of the corresponding mRNAs, the following regularities were found: an obvious sharp decline of MTHFR tissue in kidney, a time-dependent increase of CBS in liver tissue and duodenum tissues, the resemblance of MS fluctuation to that of CBS in tested tissues. A four-week simulated microgravity of SD rats exhibits an unequivocal diminish of bioavailability of FA, and simulated microgravity shows a varying effect on the expression of FA-metabolizing enzyme in a variety of tissues.

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  • Jianhui Ren, Jiquan Guo, Shuguang Zhu, Qiyou Wang, Ruiping Gao, Chunhe ...
    2021 Volume 44 Issue 2 Pages 169-180
    Published: February 01, 2021
    Released: February 01, 2021
    [Advance publication] Released: November 25, 2020
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    Chronic stress-induced brain injury (CSBI) is the organic damage of brain tissue caused by long-term psychological and environmental stress. However, there is no effective drug for the treatment of CSBI. The present study aimed to investigate possible mechanisms of CSBI and to explore related therapeutic targets. A rat model of CSBI was established by combining chronic restraint and cold water immersion. Our CSBI model was validated via Nissl staining, Western blotting, and behavioral tests. RNA sequencing (RNA-seq) was used to identify differentially expressed genes (DEGs) within brain tissue during CSBI. Both Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to determine signaling pathways associated with CSBI-induced DEGs. Agonists/antagonists were used to validate the pharmacodynamics of potential therapeutic targets. A combination of chronic restraint and cold water immersion successfully induced a rat model of CSBI, as indicated by various markers of brain injury and cell apoptosis that were verified via Nissl staining, Western blotting, and behavioral tests. RNA-seq analysis identified 1131 DEGs in CSBI rats. Of these DEGs, 553 genes were up-regulated and 778 genes were down-regulated. GO and KEGG pathway analyses revealed that significant DEGs were predominantly related to membrane-bound ion channels, among which the potassium channel function was found to be significantly affected. Pharmacological experiments revealed that retigabine, a voltage-gated potassium channel opener, demonstrated a protective effect in CSBI rats. Taken together, our findings suggest that potassium channel function is disrupted in CSBI, and that potassium channel regulators may function as anti-CSBI drugs.

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  • Kana Ohashi, Koji Shibasaki, Hayaki Nakazawa, Ryotaro Kunimasa, Kazuki ...
    2021 Volume 44 Issue 2 Pages 181-187
    Published: February 01, 2021
    Released: February 01, 2021
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    Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca2+-permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3+/Pdgfra+ OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30–100 µM) increased the Ca2+ concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd3+ (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3+ OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.

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    Editor’s picks

    Transient receptor potential melastatin 3 (TRPM3) is Ca2+-permeable channel that is highly expressed in the brain and activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Here, it is shown that TRPM3 was expressed in cultured rat oligodendrocyte precursor cells (OPCs) and activated by PS, resulting in extracellular Ca2+ influx. Moreover, TRPM3 expression was increased by treatment with tumor necrosis factor a. In demyelinated lesions of endothelin-1-induced ischemic rat model (lacunar infarction model), TRPM3 was upregulated in OPCs, a type of glial cells that differentiate into myelinating oligodendrocytes. These imply that TRPM3 is involved in the regulation of specific behaviors of OPCs in inflammatory pathological conditions. Scale bar shows 200 mm.

  • Hiroki Shioya, Yuichi Inagaki, Kenji Hiraizumi, Tomohiro Hoshino, Haru ...
    2021 Volume 44 Issue 2 Pages 188-196
    Published: February 01, 2021
    Released: February 01, 2021
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    Supplementary material

    ONO-4641, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid (ceralifimod), is a second-generation sphingosine 1-phosphate receptor agonist selective for sphingosine 1-phosphate receptors 1 and 5, and has clinical effects in multiple sclerosis. The objective of the present study was to explore other potential indications for ONO-4641 based on its immunomodulatory effects. ONO-4641 was tested in non-obese diabetic (NOD) mice, an animal model of spontaneous type 1 diabetes mellitus, an autoimmune disease with unmet medical needs. ONO-4641 at a dose of 0.1 mg/kg prevented the onset of diabetes mellitus in NOD mice. Furthermore, ONO-4641 at doses of 0.03 and 0.1 mg/kg decreased diabetic prevalence in NOD mice after the onset of diabetes mellitus in a dose-dependent manner. Histopathological analysis demonstrated that insulin-positive areas in the islets of mice administered 0.03 and 0.1 mg/kg ONO-4641 showed a tendency of high values although they were not significantly different from the Control group, which was treated with vehicle. These observations suggest ONO-4641 may delay the onset and progression of type 1 diabetes mellitus.

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  • Kazuki Kitabatake, Toshiyuki Kaji, Mitsutoshi Tsukimoto
    2021 Volume 44 Issue 2 Pages 197-210
    Published: February 01, 2021
    Released: February 01, 2021
    [Advance publication] Released: December 01, 2020
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    Glioblastoma is the most common malignant tumor of the central nervous system and is treated with a combination of surgery, radiation and chemotherapy. However, the tumor often acquires radiation resistance, which is characterized by an increased DNA damage response (DDR). Here, we show that CD73, which generates extracellular adenosine from ATP, and A2B receptor, which is activated by adenosine, are involved in the γ-radiation-induced DDR and the enhanced migration ability of human glioblastoma cell line A172. To investigate DDR, we evaluated ataxia telangiectasia mutated (ATM) activation and focus formation of histone H2A isoform γ (γH2AX) and p53-binding protein 1 (53BP1) in the nucleus of A172 cells after γ-irradiation. Antagonists of A2B receptor and CD73, or knockdown with small interfering RNA (siRNA), suppressed γ-radiation-induced DDR and promoted γ-radiation-induced cell death, as well as suppressing γ-radiation-induced cell migration and actin remodeling. These results suggest that activation of A2B receptor by extracellular adenosine generated via CD73 promotes γ-radiation-induced DDR, leading to recovery from DNA damage, and also enhances cell migration and actin remodeling. The CD73-A2B receptor pathway may be a promising target for overcoming radiation resistance and the acquisition of malignant phenotypes during radiotherapy of glioblastoma.

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    Editor’s picks

    The article by Kitabatake et al. suggested a novel mechanism of radiation resistance and radiation-induced acquisition of malignant profile in glioblastoma. Authors have shown that CD73, an enzyme that metabolizes extracellular ATP to adenosine, and activation of adenosine A2B receptor (CD73-A2B receptor pathway) are involved in radiation-induced DNA damage response, cell death, and enhancement of cell migration in A172 cells. These findings proposed that the CD73-A2B receptor pathway contributes to the resistance of the antitumor effect of radiation in glioblastoma and could be a novel molecular target to improve the efficiency of radiation therapy for glioblastoma.

  • Shuai Xiao, Yanshan Dong, Kunkun Hu, Dingbang Hu, Li Zhou, Yefu Wang
    2021 Volume 44 Issue 2 Pages 211-218
    Published: February 01, 2021
    Released: February 01, 2021
    [Advance publication] Released: December 04, 2020
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    Supplementary material

    Subtilisin NAT, a Bacillus subtilisin, is widely applied as a functional food and considered to be one of the most exploitable potential oral thrombolytic agents. Subtilisin QK, another Bacillus subtilisin, is a serine protease fermented by Bacillus subtilis 02 and has a better thrombolytic effect. Therefore, subtilisin QK is typically used for evaluating the safety of Bacillus subtilisins. Here, we conduct several good laboratory practice (GLP)-compliant studies in non-rodent animal, i.e., in Beagle dogs, including acute toxicity, subchronic toxicity, and safety pharmacology studies. No adverse effects were evident in the acute and 28-d subchronic toxicity studies at doses up to 40000 FU/kg and 16000 FU/kg/d, respectively. In evaluating the pharmacological safety of up to 2000FU/kg subtilisin QK, we found no significant differences between the electrocardiograms, blood pressures, and respiration of beagle dogs. These findings suggest the safety of Bacillus subtilisin, providing reliable pharmacological and toxicological data for its development and popularization as a functional food and drug.

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  • Chiaki Kawabata, Yusuke Kawai, Takahiko Tamura
    2021 Volume 44 Issue 2 Pages 219-224
    Published: February 01, 2021
    Released: February 01, 2021
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    Baculovirus vectors (BVs) are safely able to transduce foreign genes and express them in mammalian cells. However, the transduction activity of BVs is strongly reduced by the attack of serum complement, which is one of the major obstacles in the use of BVs for in vivo gene transfer. One strategy to overcome this problem is the display of complement regulatory proteins (CRPs) on BV virions. We previously developed CD46-decay accelerating factor (DAF)-CD59 triple fusion type BV showing potent complement resistance. We also developed BVs expressing Plasmodium circumsporozoite protein (CSP) to enhance transduction efficacy in hepatic cells. In this study, we investigated the combination of CSP and CRPs in a BV system to evaluate transduction efficacy along with complement resistance. To accomplish the combination of CSP and CRPs, we generated insect Sf9 cells stably expressing CRPs, to which CSP type BV was infected. The BVs collected from these infected cells were confirmed to possess both CSP and CRPs in virions. We demonstrated that CSP-CD46-DAF-CD59 type BV, containing both CSP and CD46-DAF-CD59, showed a significant increase in transduction efficacy in human hepatoma HepG2 cells under intact serum exposure compared with control type BV or CSP type BV, retaining both advantages of CSP and CD46-DAF-CD59. Collectively, these results demonstrated that the utilization of stably expressing Sf9 cells to introduce the protein products of interest, e.g., CRPs into BVs, would be useful strategy to generate BVs with novel functions such as resistance against serum complement attack.

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  • Karin Endo, Yoko Niki, Yukihiro Ohashi, Hitoshi Masaki
    2021 Volume 44 Issue 2 Pages 225-231
    Published: February 01, 2021
    Released: February 01, 2021
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    The dermis is mainly constructed by type I collagen fibers, which provide mechanical strength to the skin by building a frame-like structure, and by elastic fibers, which provide elasticity to respond to movements of the skin. The depletion of collagen fibers and the disappearance of oxytalan fibers, which are a type of elastic fiber, are characteristic changes in photoaged skin. Prostaglandin E2 (PGE2) is one of the chemical mediators involved in inflammation and is responsible for sunburn. Furthermore, it has been reported that PGE2 attenuates the production of collagen and the expression of elastic fiber-related factors in fibroblasts. Tranexamic acid (TXA), which is an anti-inflammatory medicine that inhibits plasmin, reduces the level of PGE2 secreted following UV exposure or after inflammatory stimulation. However, few reports have verified TXA as an anti-skin aging agent. In this study, we examined the potential of TXA as an anti-skin aging agent using repetitively UVA-irradiated fibroblasts as a model for fibroblasts located in chronically sun-exposed dermis. Repetitively UVA-irradiated fibroblasts had higher secretion levels of PGE2. In addition, fibroblasts repetitively irradiated with UVA or treated with PGE2 produced disrupted collagen and fibrillin-1 fibers. Treatment with TXA improved the formation of both types of fibers by repetitively UVA-irradiated fibroblasts by restoring the expression of fiber-related proteins at the mRNA and protein levels. Thus, these results demonstrate that TXA has potential as an anti-photoaging agent.

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  • Dijun Ou, Wenbin Ding, Changjun Tong, Weihong Yi
    2021 Volume 44 Issue 2 Pages 232-237
    Published: February 01, 2021
    Released: February 01, 2021
    [Advance publication] Released: December 02, 2020
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    Osteoarthritis (OA) is a chronic joint disease with high prevalence. However, effective treatment options for OA are still lacking. It was previously reported that LINC00473 was upregulated in patients with OA and upregulated LINC00473 might be associated with the progression of OA; however, the role of LINC00473 in OA remains to be investigated. CHON-001 human chondrocyte cells stimulated with 10 ng/mL interleukin (IL)-1β were utilized to mimic OA in vitro. Protein expression, cell apoptosis and cell proliferation of CHON-001 cells were investigated by Western blot, Annexin V and propidium iodide (PI) double staining, cell counting-8 kit assay and immunofluorescence staining respectively. The result indicated IL-1β triggered viability decrease and apoptosis in CHON-001 cells, which was alleviated by LINC00473 knockdown. Meanwhile, IL-1β-induced upregulation of cleaved caspase 3 and Bax were ameliorated by LINC00473 knockdown. Likewise, IL-1β-induced downregulation of X-linked inhibitor of apoptosis protein was alleviated by LINC00473 knockdown. In addition, LINC00473 knockdown protected CHON-001 cells against IL-1β by inhibiting the methylation of LIM mineralization protein (LMP)-1 gene. Moreover, c-Jun N-terminal kinase (JNK)/nuclear factor-kappaB (NF-κB) signaling pathway was proved to be involved in the cell protective effect of LINC00473 knockdown in IL-1β treated CHON-001 cells. Taken together, LINC00473 knockdown defended CHON-001 cells from IL-1β induced cell injury via inhibition of the methylation of LMP-1. Thus, LINC00473 might possibly act as a novel therapeutic target for OA.

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  • Yohei Kawano, Maho Katsuyama, Masashi Nagata, Maki Obana, Satoshi Naka ...
    2021 Volume 44 Issue 2 Pages 238-244
    Published: February 01, 2021
    Released: February 01, 2021
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    Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant. MTZ is reportedly associated with an increased risk of bleeding. However, the underlying mechanism remains unclear. In this study, we investigated the antiplatelet effect of MTZ in mice via light transmission aggregometry to elucidate the mechanism of MTZ-induced bleeding. The results of the ex vivo study showed that the oral administration of MTZ (20 or 100 mg/kg) significantly suppressed platelet aggregation mediated by the synergic interaction of 5-hydroxytryptamine (5-HT) and adrenaline. Additionally, MTZ significantly suppressed platelet aggregation, mediated by the synergic interaction of ADP and 5-HT or adrenaline. Similar results were obtained in vitro, under the condition of 5-HT- and adrenaline-induced platelet aggregation. Overall, the results suggest that MTZ exerts antiplatelet effect by co-blocking 5-HT2A and α2-adrenergic receptors on platelets and suppresses platelet aggregation mediated by ADP, increased by either 5-HT or adrenaline. Thus, a detailed monitoring of bleeding is recommended for patients taking MTZ.

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  • Yue Gong, Hong Xu Li, Rui Hong Guo, Wahyu Widowati, Young Ho Kim, Seo ...
    2021 Volume 44 Issue 2 Pages 245-250
    Published: February 01, 2021
    Released: February 01, 2021
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    Supplementary material

    Piper crocatum Ruiz & Pav. (P. crocatum), a traditional medicinal plant, has been shown to possess various pharmacological activities, including anticancer activity, antioxidant activity, antibacterial activity, anti-hyperglycemic activity, anti-allergic inflammatory activity and others. To identify the potential anti-allergic inflammatory effective constituents of P. crocatum, 13 single compounds were isolated from the methanol extract of P. crocatum leaves, and their structures were identified by contrasting their NMR spectroscopic data and previously published papers. First, the anti-allergic inflammatory activities of these single compounds were examined by accessing immune function related biomarkers such as nitric oxide (NO) and β-hexosaminidase. We found that the methanol extract and catechaldehyde (compound 1) potently suppressed NO production. Additionally, Western blot analysis showed that P. crocatum methanol extract and compound 1 suppressed the production of NO by reducing inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Consistent with these observations, P. crocatum methanol extract and compound 1 remarkably decreased β-hexosaminidase release from RBL-2H3 cells stimulated with 2,4-dinitrophenylated bovine serum albumin (DNP-BSA)-specific immunoglobulin E (IgE) antibodies. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay indicated that P. crocatum methanol extract and compound 1 exhibited no cytotoxicity to RAW264.7 and RBL-2H3 cells. Based on these findings, compound 1 is suggested as an active anti-allergic inflammatory component of P. crocatum.

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  • Mona M. Elkhatib, Amir I. Ali, Ali S. Al-badrawy
    2021 Volume 44 Issue 2 Pages 251-258
    Published: February 01, 2021
    Released: February 01, 2021
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    Multiple daily injections of insulin for diabetes cause many hazards for diabetic patients. Oral noninvasive insulin delivery could be more convenient and less painful than parenteral route. In past decades transdermal iontophoresis had been studied for insulin delivery across the skin with or without chemical permeation enhancers. However, the results of these studies were not efficacious and serum insulin levels were not therapeutically effective. In the present study an advanced technology “gut iontophoresis” for insulin delivery across the gut wall was compared with traditional oral insulin delivery in the form of nanoparticles. In vitro application of electric current to the intestinal membrane could enhance the flux of insulin nanoparticles (3.4 fold enhancement of insulin transport) from the donor to the receptor compartment in the Franz cell. In vivo iontophoresis of insulin nanoparticles through the gut wall would produce intense hypoglycemia (57% glycemia drop in 3 h) without damage of the intestinal tissues. Cell viability assay indicated that 50–500 µg/mL nanoparticles had no toxic effect on Caco-2 cells. Nanoparticles gut iontophoresis could be a promising non-invasive technique for oral insulin delivery.

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    Editor’s picks

    Most of therapeutic peptides like insulin are administered parenteral because of rapid hydrolysis and enzymatic degradation after oral administration. Many techniques have been investigated for overcoming the problems and meeting the shortage of current conventional dosage forms such as iontophoresis.In this study, authors investigated if iontophoresis can be used to enhance permeation of insulin nanoparticles across the intestinal membrane and thus enhance the oral delivery of insulin.Gut iontophoresis is a promising technology that can substantially improve the transport of insulin nanoparticles across the intestinal membrane barrier.

  • Keishi Yamasaki, Koji Nishi, Kenji Tsukigawa, Kazuaki Taguchi, Masaki ...
    2021 Volume 44 Issue 2 Pages 259-265
    Published: February 01, 2021
    Released: February 01, 2021
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    Supplementary material

    Nafamostat mesilate (NFM) is used as an anticoagulant during hemodialysis in patients who have had complications due to hemorrhages. The formation of precipitates, which could lead to the interruption of hemodialysis has been reported when NFM is infused into blood during hemodialysis. We report herein on an examination of possible factors that could cause this. The effects of electrolytes such as phosphates, citrates or succinates on the formation of precipitates were examined by mixing NFM with aqueous solutions or plasma that contained these electrolytes. The formation of precipitates was observed in all electrolyte solutions when higher concentrations of NFM were mixed at around physiological pH. In the case of plasma, precipitates were observed when solutions containing higher concentrations of NFM were mixed with plasma that contained phosphate and citrate. In addition, the formation of precipitates under dynamic conditions where NFM was infused into flowing electrolyte solutions was also evaluated. The data suggested that such precipitates might be formed and disrupt the blood flow and/or an NFM infusion when NFM is infused into blood flowing in the hemodialysis circuit. The findings presented herein suggest the serum levels of anionic electrolytes (e.g., phosphate), the type of excipients present in pharmaceutical products (e.g., succinic acid or citric acid), the concentration of NFM used for the infusion or the rates of NFM infusion and blood flow are all factors that could affect precipitate formation during NFM infusions for hemodialysis.

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  • Hidenori Ando, Kiyoshi Eshima, Tatsuhiro Ishida
    2021 Volume 44 Issue 2 Pages 266-270
    Published: February 01, 2021
    Released: February 01, 2021
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    Extracellular pH (pHe) of tumor cells is characteristic of tumor microenvironment (TME). Acidic TME impairs the responses of tumors to some anti-cancer chemotherapies. In this study, we showed that daily oral dosing of sodium potassium citrate (K/Na citrate) increased blood HCO3 concentrations, corresponding to increase of HCO3 concentrations and pHs in urine, and neutralized the tumor pHe. Neutralization of acidic TME by alkaline substance like HCO3, an active metabolite of K/Na citrate, well potentiated the therapeutic effect of anticancer agent TS-1®, an orally active 5-fuluoro-uracil derivative, in Panc-1 pancreatic cancer-xenograft murine model. Neutralization of acidic TME by using an alkaline K/Na citrate is a smart approach for enhancement of the therapeutic effects of anticancer agents for pancreatic cancer in the end stage.

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    Editor’s picks

    Acidified extracellular pH (pHe) characterized of tumor microenvironment (TME) impairs the responses of tumors to anti-cancer chemotherapies. In this study, the authors showed that daily oral dosing of sodium potassium citrate (K/Na citrate) increased blood bicarbonate concentrations and then neutralized the tumor pHe. In addition, this tumor neutralization potentiated the therapeutic effect of anticancer agent TS-1 on Panc-1 pancreatic cancer-xenograft murine model. The authors strongly propose that the neutralization of acidic TME by oral dosing of K/Na citrate must be a smart approach for enhancing the therapeutic effects of anticancer agents for pancreatic cancer in the end stage.

Notes
  • Hiroko Nakamura, Takehiro Kawashiri, Daisuke Kobayashi, Mayako Uchida, ...
    2021 Volume 44 Issue 2 Pages 271-274
    Published: February 01, 2021
    Released: February 01, 2021
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    Supplementary material

    The anticancer agents including oxaliplatin, paclitaxel, and bortezomib cause severe peripheral neuropathy. The Kampo medicine Sokeikakketsuto (SOKT) has been widely used to treat several types of pain. In this study, the analgesic effects of SOKT on oxaliplatin-, paclitaxel-, and bortezomib-induced peripheral neuropathy were investigated in rat models. Rats were treated with oxaliplatin (4 mg/kg, intraperitoneally (i.p.), twice a week for four weeks), paclitaxel (4 mg/kg, i.p., twice a week for two weeks), or bortezomib (0.2 mg/kg, i.p., twice a week for two weeks). SOKT (0.3 or 1.0 g/kg) or duloxetine hydrochloride (30 mg/kg, as a positive control) was administered orally after neuropathy developed. Mechanical allodynia and cold hyperalgesia were assessed using the von Frey test and the acetone test, respectively. These tests were performed immediately before and 30, 60, 90, and 120 min after the administration of the drugs. Repeated treatment of oxaliplatin induced mechanical allodynia and cold hyperalgesia. A single administration of SOKT (1 g/kg, per os (p.o.)), as well as duloxetine, temporarily reversed both the mechanical allodynia and the cold hyperalgesia. Repeated administration of paclitaxel and bortezomib also induced the mechanical allodynia. SOKT and duloxetine reversed the mechanical allodynia caused by bortezomib, but not by paclitaxel. SOKT might have the potential to become a new drug to relieve the symptom of oxaliplatin- or bortezomib-induced peripheral neuropathy.

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  • Genki Yasuda, Masaki Kobayashi, Atsuhito Kubota, Katsuya Narumi, Ayako ...
    2021 Volume 44 Issue 2 Pages 275-278
    Published: February 01, 2021
    Released: February 01, 2021
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    Supplementary material

    α-Defensin 5 has a particularly broad antibacterial spectrum; it eliminates pathogenic microorganisms and regulates intestinal flora. Although Caco-2 cells are similar to small intestinal cells, it is unclear whether they secrete α-defensin 5. Therefore, we investigated whether Caco-2 cells secrete α-defensin 5 and determined the secretion mechanism using cells from three cell banks (ATCC, DSMZ, and RIKEN). The Caco-2 cell proliferation rate increased with the number of culture days, irrespective of cell bank origin. On the other hand, the alkaline phosphatase activity, which affects cell differentiation and the mRNA levels of several cytokines, such as interleukin 8 (IL-8), IL-6, IL-1β, tumor necrosis factor-α (TNF-α), and IL-2, in the Caco-2 cells fluctuated with the number of culture days, and differed for each cell bank. α-Defensin 5 secretion was detected in all three cell bank Caco-2 cells; particularly, the ATCC Caco-2 cells grew linearly depending on the cell culture day as well as the levels of IL-8 and TNF-α mRNA. This suggested that α-defensin 5 secretion in the ATCC Caco-2 cells was associated with fluctuations in the mRNA levels of various cytokines, such as IL-8 and TNF-α. In conclusion, Caco-2 cells may be a simple model for screening health food components and drugs that affect α-defensin 5 secretion.

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    Editor’s picks

    α-Defensin 5 has a particularly broad antibacterial spectrum, eliminates pathogenic microorganisms and regulates intestinal flora. There are few reports of measuring the secretory capacity of α-defensin 5 in vitro. In this study, author found Caco-2 cells, which are gastrointestinal model cells, secreted α-defensin 5 and examined the relationship between α-defensin 5 secretion and cytokines mRNA levels such as TNF-α. These results suggest that Caco-2 cells may be a simple model for screening health food components and drugs that affect α-defensin 5 secretion.

  • Kazuyuki Niki, Maki Yasui, Maika Iguchi, Tomomi Isono, Hiroto Kageyama ...
    2021 Volume 44 Issue 2 Pages 279-282
    Published: February 01, 2021
    Released: February 01, 2021
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    Taking bitter-tasting drugs can be stressful for children who have underdeveloped swallowing skills and do not understand the meaning of medication. Furthermore, the senses of vision and smell are known to majorly influence taste. This pilot study was aimed at determining the effect of visual stimulation by immersive virtual reality (iVR) on taste and the safety of this approach for developing a new method to assist children with taking medication. Ten subjects participated in this study, and their mean (standard deviation (S.D.)) age was 21.8 (0.8) years. The subjects tasted the bitter aqueous solution (quinine 0.00375%) while viewing two different VR images (strawberry sponge cake and orange juice) alternately and received sensory tests immediately after the tasting and again 30 s later. In addition, nausea was assessed 30 s after tasting for each VR image. The primary endpoint was the difference in sensory test scores immediately after the tasting and 30 s later, between the two images. There were no significant differences in the sensory test scores between the placebo and either strawberry sponge cake or orange juice immediately after tasting. However, 30 s after tasting, the scores changed significantly to a tendency to perceive sweetness from the strawberry sponge cake and orange juice images compared with the placebo. No subject experienced nausea. Therefore, the findings of this study suggest that displaying images of sweet foods by using iVR to stimulate visual perception could safely reduce the sense of bitterness.

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  • Congyun Jin, Yoshihiro Matsui, Atsushi Yonezawa, Satoshi Imai, Takashi ...
    2021 Volume 44 Issue 2 Pages 283-286
    Published: February 01, 2021
    Released: February 01, 2021
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    Riboflavin (vitamin B2) plays an important role in cellular growth and function. Riboflavin transporter 2 (RFVT2) is widely expressed in several tissues, especially in the brain and salivary glands, and plays an important role in the tissue disruption of riboflavin. During the last 10 years, mutations in SLC52A2 have been documented in patients with a rare neurological disorder known as Brown–Vialetto–Van Laere syndrome. However, no suitable animal model of this disease has been reported. Here, we aimed to clarify the physiological role of RFVT2 using Slc52a2-mutant mice. The appearance, body weight, and plasma riboflavin concentration of Slc52a2 heterozygous mutant (Slc52a2+/−) mice were similar to those of wild-type (WT) mice. However, intercrossing between Slc52a2+/− mice failed to generate Slc52a2 homozygous mutant (Slc52a2−/−) mice. This suggested that Slc52a2 gene deficiency results in early embryonic lethality. Our findings suggested that RFVT2 is essential for growth and development, and its deletion may influence embryonic survival.

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  • Hajime Hiyama, Aya Ozawa, Bunsho Makino, Yosuke Yoshioka, Ryo Ohsawa
    2021 Volume 44 Issue 2 Pages 287-291
    Published: February 01, 2021
    Released: February 01, 2021
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    Supplementary material

    Dried terrestrial stems of Ephedra sinica are called ‘Ephedra herb,’ whose pharmacological effects are due mainly to two major ingredients, (−)-ephedrine and (+)-pseudoephedrine (total alkaloids which are defined in Japanese Pharmacopoeia (TA)). Ephedra herb is an important crude drug in Japan. However, E. sinica is widely distributed in arid areas of northeastern China and Mongolia. Recently, E. sinica has started to be cultivated in Japan. This study aimed to assess the validity of selection breeding on TA content of E. sinica in several locations in Japan. In this experiment, we grew approximately 350 seedlings and divided them randomly into seven groups. Nearly fifty plants were cultivated at each of seven locations. In Ibaraki, Yamanashi, and Shizuoka, average TA content of whole samples satisfied the criteria for Ephedra herb defined in Japanese Pharmacopoeia (7.0 mg/g of dry weight (DW)). Plants with high and intermediate TA content at four locations were selected and transplanted to Ibaraki. There were significant differences in TA content between selected plants with high and intermediate TA content before and after transplanting (p < 0.05). TA content of high-TA plants was significantly higher than that of control plants cultivated continuously at Ibaraki (p < 0.05). These results suggest that the selection on content of ephedrine alkaloids in E. sinica under various locations in Japan is valid, and high- TA E. sinica plants can be selected at various locations.

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