Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
早期公開論文
早期公開論文の15件中1~15を表示しています
  • Tsuyoshi Aoyama, Yoshihiko Shibayama, Tatsuhiko Furukawa, Mitsuru Suga ...
    論文ID: b19-00185
    発行日: 2019年
    [早期公開] 公開日: 2019/08/20
    ジャーナル フリー 早期公開

    Tyrosine kinase inhibitors (TKIs) are used as the first choice for chronic myeloid leukemia (CML) pharmacotherapeutics. Some patients taking these drugs showed good therapeutic reactivity despite the disappearance of drugs from blood. We investigated whether these drugs have sustained effects even after their disappearance and whether their effects depend on their amounts of intracellular accumulation. Cell proliferation after exposure of K562 cells or Multidrug resistance-1 (MDR-1)-transfected K562 cells was determined by a cell counting kit-8 assay. The intracellular accumulation amount of the drug showing a sustained cytostatic effect was measured by ultra performance liquid chromatography-mass spectrometry. Cell viability decreased in a culture time-dependent manner after washing out nilotinib and dasatinib. The sustained cytostatic effect of dasatinib, but not that of nilotinib, correlated with the intracellular accumulation level. In contrast, imatinib showed continuous a cytostatic effect after drug washout for long-term exposure but not after drug washout for short-term exposure. These results suggest that a good response in patients with a low serum concentration of imatinib, nilotinib or dasatinib may be due to the cytostatic effect of that drug continues even after its disappearance in plasma.

  • Miki Matsui, Junpei Konishi, Takahiro Suzuki, Chihiro Sekijima, Noriko ...
    論文ID: b19-00044
    発行日: 2019年
    [早期公開] 公開日: 2019/08/09
    ジャーナル フリー 早期公開

    Sugammadex 4 mg·kg-1 is recommended for reversal from rocuronium-induced deep neuromuscular block. However, there is limited data regarding the dose-response of sugammadex required for reversal from deep neuromuscular block in pediatric patients. The aim of this study was to determine the reversibility of rocuronium-induced deep neuromuscular block with sugammadex in infants and children. Seventy-five children (48 infants and 27 children, mean (SD) age: 11.6 (6.7)) were enrolled in this study. After induction of anesthesia and administration of 0.6 mg·kg-1 rocuronium, neuromuscular block was acceleromyographically evaluated by observing contractions of the adductor pollicis muscle to ulnar nerve train-of-four (TOF) stimulation. Subsequently, the intensity of rocuronium-induced block was determined every 6 min using post-tetanic count (PTC) stimulation during sevoflurane and remifentanil anesthesia. When the first response to the PTC stimulus was detected, either 1, 2 or 4 mg·kg-1 sugammadex was administered and the time required for facilitated recovery to a TOF ratio of 0.9 following each dose was compared. The time [mean (SD)] from the administration of 1 mg·kg-1 sugammadex until recovery to a TOF ratio of 0.9 was significantly longer [129.1 (83.5) s, P<0.001] than that with 2 mg·kg-1 and 4 mg·kg-1 sugammadex [70.3 (26.7) s and 68.2 (34.5) s, respectively]. Incomplete reversal was seen in 3 patients in the 1 mg·kg-1 group. The results suggested that a 4 mg·kg-1 sugammadex dose is recommended for reversal from rocuronium-induced deep neuromuscular block even in infants and children.

  • Jingping Lu, Jinjun Shan, Ning Liu, Yao Ding, Pei Wang
    論文ID: b19-00053
    発行日: 2019年
    [早期公開] 公開日: 2019/08/07
    ジャーナル フリー 早期公開

    To examine the effect of tanshinone IIA on Angiotensin II (Ang II)-induced proliferation and autophagy in vascular smooth muscle cells (VSMCs) and the related mechanism. VSMCs were treated with Ang II with or without tanshinone IIA (1 μg/ml, 5 μg/ml and 10 μg/ml), and the proliferation, apoptosis in cells with different treatment were examined by MTT and flow cytometry methods. Moreover, the expression of autophagy related proteins and MAPK signaling molecules were examined by RT-qPCR and WB methods. Ang II induced significantly increase in the proliferation and autophagy of VSMCs, and the MAPK signaling was activated. Tanshinone IIA can attenuate Ang II-induced effects via down-regulating the MAPK signaling pathway. Tanshinone IIA can inhibit Ang II-induced proliferation and autophagy of VSMCs via regulating the MAPK signaling pathway.

  • Keita Hirai, Toshihiro Shirai, Yuuka Rachi, Sekiko Uehara, Megumi Ueda ...
    論文ID: b19-00476
    発行日: 2019年
    [早期公開] 公開日: 2019/08/06
    ジャーナル フリー 早期公開

    Genetic variations in glucocorticoid-induced transcript 1 (GLCCI1) have been associated with the response to corticosteroid treatment. However, the associations of GLCCI1 polymorphisms or gene expression with the prognosis of asthma and pathophysiological factors related to steroid insensitivity remain unclear. We sought to investigate the associations of GLCCI1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and histone deacetylase 2 (HDAC2) mRNA expression levels and the GLCCI1 rs37973 polymorphism with asthma severity and future exacerbation in patients with asthma. Subjects included 25 patients with severe asthma and 127 patients with nonsevere asthma. mRNA expression levels in peripheral blood mononuclear cells were measured and evaluated as predictors of severe asthma using receiver operating characteristic (ROC) analysis. The hazard ratios of the mRNA expression levels for time to first exacerbation in the 1-year follow-up period were calculated. GLCCI1, Nrf2, and HDAC2 mRNA expression levels were significantly lower in patients with severe asthma than in patients with nonsevere asthma and could predict severe asthma with an area under the ROC curve of 0.68, 0.71, and 0.65, respectively. In contrast, no relationship was found between the GLCCI1 rs37973 polymorphism and severe asthma. The hazard ratios for asthma exacerbation in patients with low GLCCI1, Nrf2, and HDAC2 mRNA expression levels were 3.24 (95% confidence interval, 1.42–7.40), 3.13 (1.37–7.16), and 2.98 (1.22–7.25), respectively. Patients with severe asthma could be distinguished by lower GLCCI1, Nrf2, and HDAC2 mRNA levels in peripheral blood cells, and all of these gene signatures could predict future asthma exacerbations.

  • Jian Chen, Xiaofei Huang, Cheng Tao, Ting Xiao, Xinping Li, Qiang Zeng ...
    論文ID: b19-00391
    発行日: 2019年
    [早期公開] 公開日: 2019/08/03
    ジャーナル フリー 早期公開

    Lung cancer is the most common cause of cancer death, approximately 85% of which are non-small cell lung cancer (NSCLC). Here we found that artemether (ART), a natural derivative of artemisinin, significantly inhibits the proliferation of NSCLC cells in a dose- and time-dependent manner. We also demonstrated that high concentration of ART induces apoptosis in NSCLC cells through down-regulating the level of anti-apoptotic protein B-cell lymphoma-2 (Bcl-2), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2). While low concentration of ART inhibits the mRNA level of cell cycle related genes including cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 6 (CDK6), cyclin A2, cyclin B1 and cyclin D1, leading to cell cycle arrest in NSCLC cells. Moreover, we confirmed that low concentration of ART induces DNA double-stranded breaks (DSBs), as well as promoting cellular senescence in NSCLC cells by up-regulating the mRNA and protein level of p16. Taken together, ART represents a promising new anti-NSCLC drug candidate that could attenuate progression of NSCLC cells in a p53-independent manner through inducing apoptosis, cell cycle arrest and promoting cellular senescence.

  • Xiabin Ren, Juan Liu, Li Hu, Quan Liu, Dehui Wang, Xianhui Ning
    論文ID: b19-00315
    発行日: 2019年
    [早期公開] 公開日: 2019/07/30
    ジャーナル フリー 早期公開

    Caffeic acid phenethyl ester (CAPE), an active polyphenolic component of honeybee propolis, has been demonstrated to have many medicinal properties. However, the antitumor effect and mechanism of CAPE on laryngeal carcinoma cells have not been examined. In this study, we treated HEp2 cells with various concentration of CAPE, and the results showed that CAPE can reduce the viability of HEp2 cells with IC50 values of 23.8 ± 0.7 μM for 72 h. Meanwhile, CAPE significantly inhibited activation of Stat3 in a concentration dependent manner in HEp2 cells and regulated the expression and transcription of Plk1. AG490, a specific Stat3 inhibitor, not only inhibited the activation and expression of Stat3, but also inhibited the expression of Plk1 in HEp2 cells, so Stat3 was probably involved in the regulation of Plk1 in HEp2 cells. In addition, treatment of CAPE leaded to a blockage of cell cycle in S phase in HEp2 cells. Therefore, CAPE inhibited the proliferation of HEp2 Cells probably by regulating Stat3/Plk1 pathway and inducing S phase arrest.

  • Kaori Ito, Takahiro Hayashi, Yoko Inaguma, Tomohiko Terazawa, Maiko An ...
    論文ID: b19-00184
    発行日: 2019年
    [早期公開] 公開日: 2019/07/25
    ジャーナル フリー 早期公開

    Patients with myelodysplastic syndrome (MDS) often require blood transfusion and anticancer therapy; however, elderly patients are intolerant to the associated side effects of anticancer therapy. Because L-leucine can be used to treat Diamond–Blackfan anemia, which is caused by defects in ribosomal protein (RP) genes, resulting in increased in vivo hemoglobin synthesis, it is possible that some MDS patients who have aberrations in their RP genes could also be effectively treated with L-leucine. In the present study, we investigated the effects of L-leucine on hematopoietic function (reticulocyte count), red blood cell count, and hemoglobin level in MDS patients. We administered L-leucine (1.8 g, twice daily, 3 days/week) with oral vitamin B6 supplements to a final cohort of eight MDS patients for 15 (interquartile range: 11–18) weeks. We assessed the patients at 10 ± 2 weeks after therapy initiation. Only the absolute reticulocyte count was affected, improving in 6/8 (75%) patients. The median absolute reticulocyte count was 3.5 × 104 (range: 2.7-6.4 × 104) cells/μL, an increase of 0.5 × 104 (range: 0.2–0.7× 104) cells/μL. At 10 weeks, there was only one case of an improved hemoglobin level. Non-hematological adverse events of grade 3 were observed one raised triglycerides. These data suggest that L-leucine has little effect on MDS. However It may contribute to the recovery of hematopoietic function, futher study be desired.

  • Xiaoping Hu, Wanli Jiang, Zhiwei Wang, Luocheng Li, Zhipeng Hu
    論文ID: b18-01012
    発行日: 2019年
    [早期公開] 公開日: 2019/07/02
    ジャーナル フリー 早期公開

    Aortic dissection (AD) diseases are characterized by degeneration of the aortic media. Oxidative stress plays a crucial role in the development of AD. NADPH oxidase 1 deficiency reduces the incidence of aortic dissection induced by angiotensin II, but its mechanism remains to be further elucidated. The expression of Fibulin-5 is decreased in patients with AD, but its upstream mechanism is still unclear. This study was to clarify the relationship between NOX1 and Fibulin-5 in the AD. Results showed that the expressions of NOX1 and Fibulin-5 were increased and decreased in the AD, respectively. Next, by employing gain- and loss-of-function approaches in vitro, NOX1 negatively regulated Fibulin-5 in the vascular smooth muscle cells. Moreover, the blunted activity of NOX1 with VAS2870 could upregulate the expression of Fibulin-5. These findings indicate NOX1 is a negative modulator of Fibulin-5 in the AD.

  • Ki Mo Kim, A-Rang Im, Se Kyu Park, Hyoung Seok Shin, Sung-wook Chae
    論文ID: b19-00222
    発行日: 2019年
    [早期公開] 公開日: 2019/07/02
    ジャーナル フリー 早期公開

    Ultraviolet B (UVB) radiation changes several photoaging pathway in the body, thereby prompting skin injury. Besides, chronic ultraviolet B (UVB) radiation leads to photoaging, sustained immunosuppression, and photocarcinogenesis. We investigated the protective effect of Timosaponin AIII (TA-III), a naturally occurring steroidal saponin separated from Anemarrhena asphodeloides, against UVB-induced invasive properties of human epidermal keratinocytes (HEKs) and human dermal fibroblasts (HDF). No cytotoxicity was observed up to 50 nM concentration of TA-III. Similarly, TA-III inhibited UVB-induced cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9) transcription level and protein expression in a dose-dependent manner at non-cytotoxic dose. Further, TA-III decreased UVB-induced invasion in primary skin cells. Additionally, TA-III suppressed UVB-stimulates mitogen-activated protein kinase signaling (MAPK), activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) activation, thereby preventing the overexpression of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) in human epidermal keratinocytes cells. Furthermore, TA-III prevented UVB-mediated formation of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxo-dG) and activation of DNA repair enzymes and, cell cycle arrest genes like as proliferating cell nuclear antigen (PCNA), structural maintenance of chromosomes protein 1 (SMC1). This results support understanding into the molecular action of TA-III, which can useful for developing photoprotective agents.

  • Kai Zhang, Lei Yao
    論文ID: b19-00380
    発行日: 2019年
    [早期公開] 公開日: 2019/06/29
    ジャーナル フリー 早期公開

    Cedrol has been reported to be effective in reducing anxiety of male mice. The limited application of females in animal models of anxiety makes it difficult to systematically investigate new drug substitutes with potential anxiolytic activity. In the present study, we investigated the behavioral response of female ICR mice to cedrol after intraperitoneal (i.p.) administration using the elevated plus maze (EPM) and the light-dark box (LDB) test, followed by determination of neurochemical changes in brain. The data suggested that cedrol at dose of 1200-1600 mg∙kg-1 exhibited anxiolytic activity on the female mice, as reflected by greater percentage of entries into the open arms and time spent in the open arms in the EPM, and greater transitions between chambers and percentage of time spent in the light chamber in the LDB. Cedrol increased the level of 5-hydroxytryptamine (5-HT), decreased the level of dopamine (DA), reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and increased the ratio of 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, compared with the control group, indicative of an anxiolytic-like effect on female mice via the 5-HTnergic or DAnergic pathways.

  • Yuki Kai, Momoko Motegi, Yuta Suzuki, Yui Harada, Hiroto Takeuchi, Ris ...
    論文ID: b19-00404
    発行日: 2019年
    [早期公開] 公開日: 2019/06/25
    ジャーナル フリー 早期公開

    Recently, we demonstrated that Rac1 upregulation is involved in augmented bronchial smooth muscle (BSM) contractions of antigen-challenged mice. However, change in GPCR-induced Rac1 activation remains unknown in BSMs of repeatedly antigen-challenged (Chal.) mice. We here examined carbachol (CCh)-induced Rac1 activation in BSMs of Chal. mice. Gene expression levels of both Rac1 and Rac-guanine nucleotide exchange factors (GEFs), such as Tiam1 and Trio, were increased in BSMs of Chal. mice. Furthermore, CCh-induced Rac1 activation was inhibited by pretreatment with Rac1-GEF inhibitor NSC23766 and Rac1 inhibitor EHT1864 in BSMs of sensitized-control (S.C.) and Chal. mice. Compared with S.C. mice, CCh-induced Rac1 activation was increased in BSMs of Chal. mice. In conclusion, we reported that increased CCh-induced Rac1 activation via Tiam1 and Trio upregulation, in addition to upregulate Rac1, may be involved in increased CCh-induced BSM contractions in Chal. mice.

  • Yiping Zhu, Liangrui Zhong, Jianzhong Peng, Qiang Yuan, Aie Xu
    論文ID: b19-00319
    発行日: 2019年
    [早期公開] 公開日: 2019/06/19
    ジャーナル フリー 早期公開

    Vitiligo is a commom disease of skin. Its pathogenesis is complex, resulting in the incapacity to find a targeted cure. Baicalin, which is isolated from Scutellariae radix, has been known to exhibit a number of pharmacological effects on autoimmune diseases. In this study, we explored the effects of baicalin on the recovery of vitiligo stimulated by monophenylketone in mice. We observed that Baicalin slowed down the progression of depigmentation, decreased the incidence of depigmentation, and reduced the area of depigmentation. Moreover, reflectance confocal microscopy (RCM) shown that Baicalin increased the epidermal melanocytes in depigmented skin. Baicalin decreased CD8+ T cell infiltration in mice skin, and decreased the expression of CXCL10 and CXCR3. Baicalin significantly decreased the levels of serum cytokine (IL-6, TNF-α, IFN-γ, and IL-13). Collectively, these data suggest that Baicalin play an important role in the occurrence and development of vitiligo.

  • Dan-Hong Wei, Jiu-Ling Deng, Rong-Zhen Shi, Li Ma, Jia-Man Shen, Rober ...
    論文ID: b19-00159
    発行日: 2019年
    [早期公開] 公開日: 2019/06/14
    ジャーナル フリー 早期公開

    Endothelial cell injury and apoptosis induced by oxidative stress serve important roles in many vascular diseases. The repair of endothelial cell vascular injury relies on the function of local endothelial progenitor cells (EPCs). Our previous study indicated that epimedin C, a major flavonoid derived from Herba epimedii (yin yang huo), could promote vascularization by inducing endothelial-like differentiation of mesenchymal stem cells C3H/10T1/2 both in vivo and in vitro. In view of the significant cardiovascular protective effects of Herba epimedii, we detected a protective effect of epimedin C on H2O2-induced peroxidation injury in human umbilical vein endothelial cells (HUVECs) and the role of EPC in this process. The results show that epimedin C increased the expression of the stem cell marker, CD34 and PROM1, and subsequently enhanced the expression and function of vascular endothelial growth factor and MMP-2 in local vascular endothelial cells. In conclusion, epimedin C protects H2O2-induced peroxidation injury by enhancing the function of endothelial progenitor HUVEC populations.

  • Zhongpu Chen, Xiaodong Pan, Zulong Sheng, Gaoliang Yan, Long Chen, Gen ...
    論文ID: b19-00196
    発行日: 2019年
    [早期公開] 公開日: 2019/06/14
    ジャーナル フリー 早期公開

    Atherosclerosis (AS) is a chronic inflammatory disease threatening human health, and vascular smooth muscle cells (VSMCs) are involved in AS processes. Baicalin is a flavonoid compound, which has anti-atherosclerotic effect. The aim of our study was to explore the molecular mechanism of baicalin on AS. The expression of miR-126-5p was measured in peripheral blood of AS patients and healthy control. We found miR-126-5p expression was decreased in AS. Then, high-mobility group box 1 (HMGB1) was verified as a target of miR-126-5p and its expression was increased in AS. Similarly, miR-126-5p and HMGB1 expression was downregulated and upregulated in oxidized low-density lipoprotein treated VSMCs (ox-LDL-VSMCs), respectively. Furthermore, baicalin upregulated miR-126-5p and downregulated HMGB1 expression. Functionally, baicalin significantly inhibited ox-LDL-VSMCs proliferation and migration, and miR-126-5p targets HMGB1 to enhance the inhibition induced by baicalin. Taken together, baicalin is able to prevent AS, which suppressed the proliferation and migration of ox-LDL-VSMCs through upregulating miR-126-5p by targeting HMGB1. These findings suggested that baicalin is an effective drug to alleviate AS, and miR-126-5p is a novel therapeutic target for AS.

  • Jun Ho Kim, Jin Hyup Lee, Young Jun Kim
    論文ID: b15-00585
    発行日: 2016年
    [早期公開] 公開日: 2015/11/06
    ジャーナル フリー 早期公開
    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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