Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Advance online publication
Showing 1-7 articles out of 7 articles from Advance online publication
  • Akio Negishi, Shinji Oshima, Norimitsu Horii, Mizue Mutoh, Naoko Inoue ...
    Article ID: b20-00986
    Published: 2021
    [Advance publication] Released: May 07, 2021

    The “INTERACTIONS” section of package inserts aims to provide alert-type warnings in clinical practice; however, these also include many drug–drug interactions that occur rarely. Moreover, considering that drug–drug interaction alert systems were created based on package inserts, repeated alerts can lead to alert fatigue. Although investigations have been conducted to determine prescriptions that induce drug–drug interactions, no studies have focused explicitly on the adverse events induced by drug–drug interactions. We, therefore, sought to investigate the true occurrence of adverse events caused by drug pair contraindications for coadministration in routine clinical practice. Toward this, we created a list of drug combinations that were designated as “contraindications for coadministration” and extracted the cases of adverse drug events from the Japanese Adverse Drug Event Report database that occurred due to combined drug usage. We then calculated the reporters’ recognition rate of the drug–drug interactions. Out of the 2,121 investigated drug pairs, drug–drug interactions were reported in 43 pairs, 23 of which included an injected drug and many included catecholamines. Warfarin potassium and miconazole (19 reports), azathioprine and febuxostat (11 reports), and warfarin potassium and iguratimod (six reports) were among the 20 most-commonly reported oral medication pairs that were contraindicated for coadministration, for which recognition rates of drug–drug interactions were high. Although these results indicate that only a few drug pair contraindications for coadministration were associated with adverse drug events (43 pairs out of 2,121 pairs), it remains necessary to translate these findings into clinical practice.

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  • Ya li Yang, Zhan wen Lin, Pei ting He, Hua Nie, Qian yin Yao, Sheng yu ...
    Article ID: b20-00959
    Published: 2021
    [Advance publication] Released: April 29, 2021

    Background Astragalus Polysaccharide (APS) had shown great promise in anti-tumour activities in our previous studies. The present study was designed to investigate whether APS has synergistic effect with cisplatin on the growth-inhibitory of human nasopharyngeal carcinoma cell lines and the possible mechanism. Methods Here, nasopharyngeal carcinoma cell lines (CNE-1) were divided into CNE-1 group, Cisplatin treatment group (2 μg/ml Cisplatin), APS treatment group (200 μg/ml APS) and combination group (2 μg/ml Cisplatin and 200 μg/ml APS). The proliferation inhibition rate of CNE-1 cells was determined by CCK-8 method after treatment with different concentrations of APS for 24, 48, and 72 h. Apoptosis rates and cell cycle retardation of cells were detected by flow cytometry. Cell migration and invasion was evaluated by transwell assay. Western blotting and qRT-PCR were performed to detect the expression of Bcl-2, Bax, Caspase-3, matrix metalloproteinase-2(MMP-2), p53 and matrix metalloproteinase-9(MMP-9) proteins in CNE-1 cells. Results APS have an inhibition on the proliferation of CNE-1 cells with time and dose dependence manner. Both the APS and combination therapy could promote apoptosis of CNE-1 cells, with the count of cells increased in G0/G1 and S phase while decreased in G2/M phase, and inhibited the migration and invasion of CNE-1 cells. Moreover, co-administration of Cisplatin and APS was more efficacious for the antitumor effect than either agent alone, as evidenced by the significant decrease in MMP-9 level and increase in p53. Conclusion APS, in combination with cisplatin, had significantly synergistic growth-inhibitory effect on nasopharyngeal carcinoma cell lines, which may be related to cell cycle and migration induction.

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  • Keita Kitamura, Kenta Umehara, Ryo Ito, Yoshiyuki Yamaura, Takafumi Ko ...
    Article ID: b21-00218
    Published: 2021
    [Advance publication] Released: April 24, 2021

    In vitro blood-brain barrier (BBB) models are essential research tools for use in developing brain-targeted drugs and understanding the physiological and pathophysiological functions of the BBB. To develop BBB models with better functionalities, three-dimensional (3D) culture methods have gained significant attention as a promising approach. In this study, we report on the development of a human conditionally immortalized cell-based multicellular spheroidal BBB (hiMCS-BBB) model. After being seeded into non-attachment culture wells, HASTR/ci35 (astrocytes) and HBPC/ci37 cells (brain pericytes) self-assemble to form a spheroid core that is then covered with an outer monolayer of HBMEC/ci18 cells (brain microvascular endothelial cells). The results of immunocytochemistry showed the protein expression of several cellular junction and BBB-enriched transporter genes in HBMEC/ci18 cells of the spheroid model. The permeability assays showed that the hiMCS-BBB model exhibited barrier functions against the penetration of dextran (5 kDa and 70 kDa) and rhodamine123 (a P-glycoprotein substrate) into the core. On the other hand, facilitation of 2-NBDG (a fluorescent glucose analog) uptake was observed in the hiMCS-BBB model. Furthermore, tumor necrosis factor-alpha treatment elicited an inflammatory response in HBMEC/ci18 cells, thereby suggesting that BBB inflammation can be recapitulated in the hiMCS-BBB model. To summarize, we have developed an hiMCS-BBB model that possesses fundamental BBB properties, which can be expected to provide a useful and highly accessible experimental platform for accelerating various BBB studies.

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  • Masato Maruyama, Yousuke Nakano, Takuya Nishimura, Ryoichi Iwata, Sato ...
    Article ID: b20-00868
    Published: 2021
    [Advance publication] Released: April 23, 2021

    Glioblastoma multiforme (GBM) is the most prevalent malignant primary brain tumor with a high recurrence rate. Despite multimodal therapy including surgical resection, chemotherapy, and radiotherapy, the median survival time after the initial diagnosis of GBM is approximately 14 months. Since cancer stem cells (CSCs) are considered the leading cause of cancer recurrence, glioblastoma stem cell-targeted therapy is a promising strategy for the treatment of GBM. However, because CSC heterogeneity has been implicated in the difficulties of CSC-target therapy, more in-depth knowledge of CSC biology is still required to develop novel therapies.

    In this study, we established single cell-derived tumorspheres from human glioblastoma U87MG cells. One of these tumorspheres, P4E8 clone, showed CSC-like phenotypes, such as self-renewal capacity, expression of CSC markers, resistance to anti-cancer agents, and in vivo tumorigenicity. Therefore, we used P4E8 cells as a cell-based model of glioblastoma stem cells (GSCs). Gene expression analysis using microarray indicated that the most highly expressed genes in P4E8 cells compared to the parental U87MG were PC3-secreted microprotein (MSMP). Furthermore, MSMP was expressed in patient-derived GSCs and human glioma tissues at the protein level, implying that MSMP might contribute to glioma development and progression.

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  • Yancai Liu, Xuegang Liu, Shan Yang
    Article ID: b21-00163
    Published: 2021
    [Advance publication] Released: April 08, 2021

    microRNA-221 (miRNA-221) is upregulated in several malignant tumors and is associated with poor patient prognosis. Therefore, the present study aimed to investigate the role and underlying mechanism of miRNA-221 in doxorubicin (DOX) resistance in osteosarcoma cells. We constructed DOX-resistant Saos-2/DOX cells and treated them with DOX. Cell viability was determined by performing an MTT assay. Cells were transfected with either miRNA-221 mimic or miRNA-221 inhibitor; real-time quantitative reverse transcription PCR was performed to detect the expression of miRNA-221. Flow cytometry and TUNEL staining were used to detect cell apoptosis. The immunofluorescence method was also used to detect cell Stat3 protein expression distribution. In addition, western blotting was used to detect changes in the expression of each protein. We found that miRNA-221 was upregulated in Saos-2/DOX cells. Moreover, the miRNA-221 mimic induced DOX resistance in Saos-2 cells, whereas the miRNA-221 inhibitor enhanced DOX sensitivity in Saos-2/DOX cells. The miRNA-221 mimic upregulated the expression of phosphorylated-Stat3, P-gp, and Bcl-2 proteins in Saos-2 cells and induced the entry of Stat3 into the nucleus, whereas the miRNA-221 inhibitor exerted the opposite effect. Pretreatment with the Stat3 chemical inhibitor, STAT3-IN-3, significantly inhibited the upregulation of P-gp and Bcl-2 protein expression induced by the miRNA-221 mimic in Saos-2 cells; it also caused the Saos-2 cells to overcome DOX resistance induced by the miRNA-221 mimic. Thus, miRNA-221 increased the expression of P-gp and Bcl-2 by activating the Stat3 pathway to promote DOX resistance in osteosarcoma cells, indicating a potential use of miRNA-221 in osteosarcoma treatment.

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  • Chi Liu, Liang Chen, Wanchen Wang, Dengke Qin, Chuanlong Jia, Mingjie ...
    Article ID: b20-00807
    Published: 2021
    [Advance publication] Released: March 17, 2021

    Emodin(1,3,8-trihydroxy-6-methylanthraquinone), as an active ingredient in rhubarb roots and rhizomes, has been reported to possess various pharmacological properties including anti-tumor effects. Recent studies have confirmed that emodin inhibited cell proliferation and induced apoptosis of cancer cells. However, the inhibitory effect of emodin on the migration and invasion of melanoma cells and its underlying mechanism are still unclear. In the study, we observed the impercipient effects of emodin in B16F10 and A375 melanoma cells with strong metastatic abilities, focusing on the functions and mechanisms of migration and invasion of B16F10 and A375 melanoma cells. CCK-8,colony formation test and Annexin V-FITC / PI staining tests confirmed that emodin possessed anti-proliferative and pro-apoptotic activities in B16F10 and A375 cells. The inhibitory effects on the migration and invasion of B16F10 and A375 cells were proved by wound healing assay and Transwell methods. Moreover, immunofluorescence array approved the decrease in protein expression of MMP-2/-9 by emodin, and western blot analyses revealed that emodin could increase the Bax/Bcl-2 radio and inhibit the MMP-2/-9 protein expression and Wnt/β-catenin pathway in a dose-depended manner. BML-284, as an agonist of Wnt/β-catenin signaling pathway, reversed the effects of emodin on cell growth, migration and invasion in B16F10 cells. These findings may suggest that emodin treatment can be a promising therapeutic strategy for melanoma with highly metastatic abilities.

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  • Jun Ho Kim, Jin Hyup Lee, Young Jun Kim
    Article ID: b15-00585
    Published: 2016
    [Advance publication] Released: November 06, 2015
    This article has been retracted by the Editorial Committee of The Pharmaceutical Society of Japan because it contains scientific misconduct. Although the data published in this article were generated in part by the first author, the authors violated authorship and sponsorship protocol.
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