Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 43 , Issue 12
Showing 1-28 articles out of 28 articles from the selected issue
Review
  • Kazuaki Taguchi
    2020 Volume 43 Issue 12 Pages 1815-1822
    Published: December 01, 2020
    Released: December 01, 2020
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    Blood transport proteins are biogenic molecules with unique and interesting inherent characteristics that make up living organisms. As the utilization of their inherent characteristics can be a groundbreaking strategy to resolve and improve several clinical problems, attempts have been made to develop pharmaceutical and biomedical preparations based on blood transport proteins for the treatment and diagnosis of disorders. Among various blood transport proteins, we focus on the immense potential of hemoglobin and albumin to serve as carriers of biomedical gases (oxygen and carbon monoxide) and anticancer agents (low-molecular compounds and antisense oligodeoxynucleotides), respectively, for the development of innovative drug delivery systems (DDS) to treat intractable disorders and solid cancers. In this review, I introduce the pharmaceutical technology, strategies, and application of DDS carriers that have been designed on the basis of the structure and function of hemoglobin and albumin. In addition, the prospect of using hemoglobin and albumin as materials for DDS carriers is discussed.

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    Editor’s picks

    Hemoglobin and albumin are biogenic molecules with unique and interesting inherent characteristics. The utilization of their inherent characteristics makes it possible to develop innovative pharmaceutical and biomedical preparations for the treatment and diagnosis of intractable disorders that can be a groundbreaking strategy to resolve and improve several clinical problems. In this review, author introduces the pharmaceutical technology, strategies, and therapeutic application of drug delivery system carriers that have been designed on the basis of the structure and function of hemoglobin and albumin.

Regular Articles
  • Dongya Chai, Jiaqi Yuan, Xiang Zhu, Yueqin Zeng, Rongrong Yang, Yingji ...
    2020 Volume 43 Issue 12 Pages 1823-1830
    Published: December 01, 2020
    Released: December 01, 2020
    [Advance publication] Released: September 19, 2020
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    Our previous study demonstrated that the total saponins from Paris forristii (PCT3) had obvious inhibitory effect on the proliferation of adriamycin-resistant human breast adenocarcinoma cells (MCF-7/ADM), and this effect was significantly stronger than that in parental cells (MCF-7). This study was designed to test the reversal effect of PCT3 on MCF-7/ADM cells and to understand its mechanism of action. Results demonstrated that low cytotoxic concentrations of PCT3 (0.3, 1 and 3 µg/mL) reversed resistance of MCF-7/ADM cells to ADM, cisplatin (DDP) and 5-fluorouracil (5-FU), with reversal fold of 16.4, 19.5 and 31.7 for ADM, 1.6, 1.4 and 1.4 for DDP, 1.7, 1.8 and 5.6 for 5-FU, respectively. Moreover, PCT3 significantly increased the accumulation of ADM and Rhodamine 123 (Rh123) in MCF-7/ADM cells, suggesting that PCT3 may act by affecting the function of drug efflux pump P-glycoprotein (P-gp), which is encoded by MDR1 gene. Both MDR1 gene and P-gp protein expression was downregulated by PCT3 treatment. Further results demonstrated that p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathway was remarkably activated in MCF-7/ADM cells, inhibition of p38 or ERK attenuated P-gp expression. While, only the phosphorylation level of ERK was downregulated by PCT3, indicating that PCT3 sensitized P-gp overexpressed MCF-7/ADM cells to ADM via inhibition of ERK signaling pathway.

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  • Ririka Mukai, Kazuyo Shimada, Takaaki Suzuki, Satoshi Nakao, Mizuki Ta ...
    2020 Volume 43 Issue 12 Pages 1831-1838
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    Hemorrhoids are a common anorectal disease. Epidemiological studies on medication trends and risk factors using information from real-world databases are rare. Our objective was to analyze the relationship between hemorrhoid treatment prescription trends and several risk factors using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan and related medical information datasets. We calculated the standardized prescription ratio (SPR) based on the 2nd NDB Open Data Japan from 2015. The correlation coefficients between the SPR of antihemorrhoidals and those of “antispasmodics,” “antiarrhythmic agents,” “antidiarrheals, intestinal regulators,” “purgatives and clysters,” “hypnotics and sedatives, antianxietics,” “psychotropic agents,” and “opium alkaloids preparations” were 0.7474, 0.7366, 0.7184, 0.6501, 0.6320, 0.4571, and 0.4542, respectively. The correlation coefficient between the SPR of antihemorrhoidals and those of “average annual temperature,” “percentage of people who were smokers,” and “percentage of people who drank regularly” were −0.7204, 0.6002, and 0.3537, respectively. The results of cluster analysis revealed that Hokkaido and Tohoku regions tended to have low average annual temperature values and high percentage of people who were smokers and had comparatively high SPRs of “antispasmodics,” “antiarrhythmic agents,” “antidiarrheals, intestinal regulators,” “purgatives and clysters,” “hypnotics and sedatives, antianxietics,” “psychotropic agents,” and “opium alkaloids preparations.” Antihemorrhoidals are frequently used in Hokkaido and Tohoku, Japan; thus, it is important for these prefectural governments to focus on these factors when taking measures regarding health promotion.

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  • Fu-Sheng Zhang, Xuan Zhang, Qian-Yu Wang, Ya-Jie Pu, Chen-Hui Du, Xue- ...
    2020 Volume 43 Issue 12 Pages 1839-1846
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    Polygala tenuifolia Willd. is a traditional Chinese herbal medicine that is widely used in treating nervous system disorders. Triterpene saponins in P. tenuifolia (polygala saponins) have excellent biological activity. As a precursor for the synthesis of presenegin, oleanolic acid (OA) plays an important role in the biosynthesis of polygala saponins. However, the mechanism behind the biosynthesis of polygala saponins remains to be elucidated. In this study, we found that CYP716A249 (GenBank: ASB17946) oxidized the C-28 position of β-amyrin to produce OA. Using quantitative real-time PCR, we observed that CYP716A249 had the highest expression in the roots of 2-year-old P. tenuifolia, which provided a basis for the selection of samples for gene cloning. To identify the function of CYP716A249, the strain R-BE-20 was constructed by expressing β-amyrin synthase in yeast. Then, CYP716A249 was co-expressed with β-amyrin synthase to construct the strain R-BPE-20 by using the lithium acetate method. Finally, we detected β-amyrin and OA by ultra-HPLC-Q Exactive hybrid quadrupole-Orbitrap high-resolution accurate mass spectrometry and GC-MS. The results of this study provide insights into the biosynthesis pathway of polygala saponins.

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  • Yuanjin Chan, Wenjing Chen, Yanjie Chen, Zhongkuan Lv, Wenbin Wan, Yam ...
    2020 Volume 43 Issue 12 Pages 1847-1858
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    Alzheimer’s disease (AD) is a chronic neurodegeneration disease that is closely related to the abnormal tight junction scaffold proteins (TJ) proteins of the blood–brain barrier (BBB). Recently, Yi-Zhi-Fang-Dai Formula (YZFDF) had exerted a neuronal protective effect against amyloid peptide (Aβ) toxicity. Still, the therapeutic mechanism of YZFDF in restoring Aβ-induced injury of TJ proteins (ZO-1, Occludin, and Claudin-5) remains unclear. This study aimed to explore the underlying mechanism of YZFDF in alleviating the injury of TJ proteins. We examined the impacts of YZFDF on autophagy-related proteins and the histopathology of Aβ in the APP/PS1 double-transgenic male mice. We then performed the free intracellular calcium levels [Ca2+]i analysis and the cognitive behavior test of the AD model. Our results showed that YZFDF ameliorated the injury of TJ proteins by reducing the mRNA transcription and expression of the receptor for advanced glycation end-products (RAGE), the levels of [Ca2+]i, calmodulin-dependent protein kinase β (CaMKKβ), phosphorylated AMP-activated protein kinase (AMPK). Accordingly, YZFDF increased the expression of the phosphorylated mammalian targets of rapamycin (mTOR), leading to inhibition of autophagy (downregulated LC3 and upregulated P62). Moreover, the Aβ1–42 oligomers-induced alterations of autophagy in murine mouse brain capillary (bEnd.3) cells were blocked by RAGE small interfering RNA (siRNA). These results suggest that YZFDF restored TJ proteins’ injury by suppressing autophagy via RAGE signaling. Furthermore, YZFDF reduced the pathological precipitation of Aβ in the hippocampus, and improved cognitive behavior impairment of the AD model suggested that YZFDF might be a potential therapeutic candidate for treating AD through RAGE/CaMKKβ/AMPK/mTOR-regulated autophagy pathway.

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  • Ning Ding, Kohei Sano, Yoichi Shimizu, Hiroyuki Watanabe, Takeshi Nami ...
    2020 Volume 43 Issue 12 Pages 1859-1866
    Published: December 01, 2020
    Released: December 01, 2020
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    Surgery remains one of the main treatments of cancer and both precise pre- and intraoperative diagnoses are crucial in order to guide the operation. We consider that using an identical probe for both pre- and intra-operative diagnoses would bridge the gap between surgical planning and image-guided resection. Therefore, in this study, we developed gold nanorods (AuNRs) conjugated with radiolabeled anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and investigated their feasibility as novel HER2-targeted dual-imaging probes for both single photon emission computed tomography (SPECT) (preoperative diagnosis) and photoacoustic (PA) imaging (intraoperative diagnosis). To achieve the purpose, AuNRs conjugated with different amount of trastuzumab (Tra) were prepared, and Tra-AuNRs were labeled with indium-111. After the evaluation of binding affinity to HER2, cell binding assay and biodistribution studies were carried out for optimization. AuNRs with moderate trastuzumab conjugation (Tra2-AuNRs) were proposed as the novel probe and demonstrated significantly higher accumulation in NCI-N87 (HER2 high-expression) tumors than in SUIT2 (low-expression) tumors 96 h post-injection along with good affinity towards HER2. Thereafter, in vitro PA imaging and in vivo SPECT imaging studies were performed. In in vitro PA imaging, Tra2-AuNRs-treated N87 cells exhibited significant PA signal increase than SUIT2 cells. In in vivo SPECT, signal increase in N87 tumors was more notable than that in SUIT2 tumors. Herein, we report that the Tra2-AuNRs enabled HER2-specific imaging, suggesting the potential as a robust HER2-targeted SPECT and PA dual-imaging probe.

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  • Febby Nurdiya Ningsih, Tetsuya Okuyama, Shoko To, Yuto Nishidono, Tada ...
    2020 Volume 43 Issue 12 Pages 1867-1875
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    The rhizome of Cnidium officinale (Umbelliferae) (known as Senkyu in Japan; COR) has been used as a crude drug in Japanese Kampo formulas, such as Jumihaidokuto (to treat eczema and urticaria) and Kakkontokasenkyushin’i (to treat rhinitis). COR contains phthalides, which are thought to be potent principal constituents. Few studies have been reported about the comparison of anti-inflammatory activity of COR constituents. We aimed to identify the constituents in COR and compare their anti-inflammatory activity. COR was extracted with methanol and fractionated into ethyl acetate (EtOAc)-soluble, n-butanol-soluble, and water-soluble fractions. Primary cultured rat hepatocytes were used to assess anti-inflammatory activity by monitoring the interleukin (IL)-1β-induced production of nitric oxide (NO), an inflammatory mediator. The EtOAc-soluble fraction significantly suppressed NO production without showing cytotoxicity in IL-1β-treated hepatocytes, whereas the n-butanol-soluble fraction showed less potency, and the water-soluble fraction did not significantly affect the NO levels. Four constituents were isolated from the EtOAc-soluble fraction and identified as senkyunolide A, (3S)-butylphthalide, neocnidilide, and cnidilide. Among these phthalides and (Z)-ligustilide, senkyunolide A and (Z)-ligustilide efficiently suppressed NO production in hepatocytes, whereas the others showed less potency in the suppression of NO production. Furthermore, senkyunolide A decreased the levels of the inducible nitric oxide synthase (iNOS) protein and mRNA, as well as the levels of mRNAs encoding proinflammatory cytokines (e.g., tumor necrosis factor α) and chemokine C–C motif ligand 20. These results suggest that senkyunolide A may cause the anti-inflammatory and hepatoprotective effects of COR by suppressing the genes involved in inflammation.

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  • Akane Chiba, Nanami Kawabata, Masaru Yamaguchi, Shinji Tokonami, Ikuo ...
    2020 Volume 43 Issue 12 Pages 1876-1883
    Published: December 01, 2020
    Released: December 01, 2020
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    Ionizing radiation induces severe oxidative stress, resulting in individual death by acute radiation syndrome. The nuclear factor-erythroid-2-related factor 2 (Nrf2) plays an important role in the antioxidant response pathway. Recently, romiplostim (RP), an idiopathic thrombocytopenic purpura therapeutic drug, was reported to completely rescue mice exposed to lethal total-body irradiation (TBI). However, the details underlying the mechanism for reducing radiation damage remain largely unknown. To elucidate the involvement of the master redox regulator Nrf2 in the radio-mitigative efficacy of RP on TBI-induced oxidative stress, expression of Nrf2 target genes in hematopoietic tissues such as bone marrow, spleen, and lung from mice treated with RP for three consecutive days after 7 Gy of X-ray TBI was analyzed. RP promoted the recovery of bone marrow cells from day 10 and the significant up-regulation of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1 (Nqo1), glutamate–cysteine ligase catalytic subunit (Gclc) and glutamate–cysteine ligase modifier subunit (Gclm) was observed compared to the TBI mice. RP also promoted the recovery of splenic cells on day 18, and the significant up-regulation of Nqo1, Gclc and Gclm in spleen both on day 10 and 18 and Nqo1 and Gclm in lung on day 10 was observed compared to the TBI mice. The present study suggests that the radio-mitigative effects of RP indicates on the activation of Nrf2 target genes involved in redox regulation and the antioxidative function, especially Nqo1, Gclc and Gclm. It is indicating the importance of these genes in the maintenance of biological homeostasis in response to radiation-induced oxidative stress.

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  • Naofumi Uesato, Koji Inagaki, Naoki Miyagawa, Yoshihiro Kitagawa, Rein ...
    2020 Volume 43 Issue 12 Pages 1884-1892
    Published: December 01, 2020
    Released: December 01, 2020
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    Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.

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    Editor’s picks

    Bone damage in rheumatoid arthritis (RA) occurs in an early stage after disease onset, and osteoclasts play a pivotal role in its progression and subsequent irreversible structural destruction of joints. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Authors investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in an animal model of RA. In this article, Uesato et al. suggested that JTE-952 effectively prevents the progression of the structural destruction of joints, a major unmet clinical need for RA.

  • Xiaohuan Ding, Jing Lv, Jia Luan, Jun Zhang
    2020 Volume 43 Issue 12 Pages 1893-1898
    Published: December 01, 2020
    Released: December 01, 2020
    [Advance publication] Released: October 01, 2020
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    Over-expression of angiotensin II (Ang II) is an important reason for the development of chronic kidney disease. Calycosin is the active component of traditional Chinese medicine astragali radix. The present work aims to explore whether calycosin could affect the growth and apoptosis ability of the Ang II treated glomerular mesangial cells and the underlying mechanism. Human glomerular mesangial cells (GMCs) were cultured and treated by Ang II and 0, 0.1, 1, or 10 µM calycosin, and the viability and proliferation of the cells were determined by methyl thiazolyl tetrazolium (MTT) and 5-ethynil-2′-deoxyuridine (EdU) staining; moreover, the apoptosis of the cells was examined by flow cytometry assay; furthermore, the expression levels of extracellular signal-regulated kinase (ERK), p-ERK, anti-apoptotic factor Bcl-2, as well as pro-apoptotic factor Bax have been examined by Western blot (WB) methods; finally, the expression of autophagic markers in each group was examined by WB and immunocytochemistry methods. We found that Ang II increased viability and proliferation, meanwhile inhibited apoptosis of the GMCs; furthermore, 1 and 10 µM calycosin significantly inhibited the growth and promoted the apoptosis of the GMCs treated by Ang II; moreover, calycosin also inhibited ERK signaling in mesangial cells activated by Ang II treatment; Finally, calycosin could inhibit Ang II induced autophagy of GMCs in a dose-dependent manner. In conclusion, calycosin may alleviate Ang II-induced pro-proliferative and anti-apoptotic effects on glomerular mesangial cells at least partially via inhibiting autophagy and ERK signaling pathway, suggesting that calycosin may function as a potential alternative medication for the management of chronic kidney diseases.

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  • Gorrepotu Dani Susmitha, Kiho Miyazato, Keisuke Ogura, Satoru Yokoyama ...
    2020 Volume 43 Issue 12 Pages 1899-1905
    Published: December 01, 2020
    Released: December 01, 2020
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    Signal transducer and activator of transcription 3 (STAT3) is considered a potential target for cancer treatment because of its relationship with cellular transformation and tumor initiation and progression. In this study, we aimed to identify a new anti-cancer drug candidate from natural products by targeting STAT3 activity. Using STAT3-luciferase reporter cell line, we screened the chemical library of natural products and found that baicalein, a flavone isolated from the roots of Scutelleria baicalensis, strongly suppressed STAT3 activity in breast cancer cells. Baicalein inhibited STAT3 transcriptional activity and its phosphorylation, and further exhibited anti-proliferative effects in breast cancer cells. Moreover, baicalein suppressed the production of interleukin (IL)-6 and the metastatic potential of breast cancer cells both in vitro and in vivo. Collectively, our study suggests baicalein as an attractive phytochemical compound for reducing metastatic potential of breast cancer cells by regulating STAT3 activity.

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    Editor’s picks

    Signal transducer and activator of transcription 3 (STAT3) plays an essential role in a pro-carcinogenic inflammatory microenvironment, both at the initiation of malignant transformation and during cancer progression. In this study, Hayakawa and colleagues found that baicalein, a flavone isolated from the roots of Scutelleria baicalensis, inhibited STAT3 transcriptional activity and its phosphorylation, and further exhibited anti-proliferative effects in breast cancer cells. Moreover, baicalein suppressed the production of IL-6 and the metastatic potential of breast cancer cells both in vitro and in vivo. This study suggests baicalein as an attractive phytochemical compound for reducing metastatic potential of breast cancer cells by regulating STAT3 activity.

  • Ryota Goto, Ryo Inose, Yoshiki Kusama, Ayako Kawabe, Saki Ishii, Ai Eb ...
    2020 Volume 43 Issue 12 Pages 1906-1910
    Published: December 01, 2020
    Released: December 01, 2020
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    Patterns of the use of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents in Japan might be influenced by the launch of new anti-MRSA agents, the publication of relevant guidelines, and the increase in the number of generic medicines. However, as anti-MRSA agents are included in multiple anatomical therapeutic chemical classifications, such as glycopeptides and aminoglycosides, the trends of the use of individual anti-MRSA agents remain unclear. Here, we aimed to clarify the trends of anti-MRSA agent use in Japan from 2006 to 2015 based on sales data. Total anti-MRSA agent use was found to have significantly increased from 2006 to 2015 (Pfor trend = 0.027, r = 0.00022). Individual trends for vancomycin (VCM), daptomycin, and linezolid (LZD) use showed significant increases, while those for arbekacin (ABK) and teicoplanin (TEIC) showed decreases. In addition, oral LZD use significantly increased, while there was no significant change in intravenous LZD use. The ratio of oral LZD use to total LZD use increased from 25.5% in 2006 to 39.9% in 2015. Meanwhile, TEIC and ABK use decreased, while VCM use increased, following the launch of generic medicines. These results might reflect the status of guideline compliance, the launch of new anti-MRSA agents, and the decline in the sales promotion of the original medicines. It is extremely important to investigate trends for the use of not only different antibiotic groups but also individual antibiotics to develop and implement antimicrobial resistance countermeasures.

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  • Naho Minegaki, Tetsuo Koshizuka, Saeka Nishina, Hiroki Kondo, Keita Ta ...
    2020 Volume 43 Issue 12 Pages 1911-1916
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    Royal jelly (RJ) is known as an important functional foodstuff that promotes several health benefits and contains various bioactive substances, including major royal jelly proteins (MRJPs). Among the MRJPs, MRJP3 possesses both cell proliferation and wound healing effects. As the carboxyl domain of MRJP3 contains tandem penta-peptide repeat (TPR) sequences unique to MRJP3 among the MRJPs, we purified the TPRs as glutathione-S-transferase (GST)-fusion proteins and demonstrated their dose-dependent effects on THP-1 and Vero cell proliferation. The GST-TPR protein with 19 repeats (GST-TPR19) showed cell proliferative activity equivalent to MRJP3 and higher than GST-TPR6. GST-TPR19 also exhibited wound healing activity at a level similar to MRJP3. Digestion of GST-TPR19 with trypsin had no effect on its cell proliferative activity, suggesting that the main digested products; i.e., penta-peptides (Q-N-x-N-[K/R]), maintain the cell proliferative ability of MRJP3. In conclusion, the TPRs of MRJP3 are critical to the beneficial effect(s) of RJ.

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    Editor’s picks

    Royal jelly (RJ) is a well-known functional foodstuff derived from honey bees and contains various functional substances.  In this report, the authors focused on major royal jelly protein 3 (MRJP3), which is one of the major protein components in RJ, and found that MRJP3 possessed cell proliferation activities in cultured cell lines.  The activities were identified in the tandem penta-peptide repeats (TPRs) consisting of Q-N-x-N-[K/R] at its C-terminus of MRJP3.  As the cell proliferation activities remained even after treatment of TRPs with trypsin, it is plausible that the penta-peptide is the minimal functional unit.

  • Yukino Oya, Daisuke Watahiki, Mitsuki Matsunaga, Keiichi Hirono, Fukik ...
    2020 Volume 43 Issue 12 Pages 1917-1923
    Published: December 01, 2020
    Released: December 01, 2020
    [Advance publication] Released: October 02, 2020
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    Supplementary material

    This study was performed for a better understanding of the pharmacokinetics of sildenafil (SIL) and N-desmethyl sildenafil (DMS) in 13 children treated in the intensive care unit (ICU). Blood samples were taken periodically after the first oral administration of SIL (0.5 mg/kg). Plasma concentrations were analyzed by tandem LC/MS. Of the 13 patients, apparent peaks in the plasma concentration of SIL were observed in four patients, with the other nine patients showing reduced or delayed drug absorption of SIL. The maximum plasma concentrations of SIL after administration varied in range from 7.8 to 101.0 ng/mL. The parent drug-to-metabolite (SIL/DMS) ratios of the nine patients with reduced or delayed drug absorption of SIL were relatively lower than those in the four patients with rapid absorption of the drug. These observations suggested that the inter-individual variability of intestinal absorption and/or first-pass extraction of SIL was involved in the pharmacokinetic variability of the drug. Next, we evaluated the impact of changes in the gastrointestinal absorption rate on the pharmacokinetics of the drug. That is, SIL (2.5 mg/body) was administered at two different rates in the duodenum of rats. When SIL was administered for 10 min, the Cmax and bioavailability were 3.46 ± 1.65 µg/mL and 23.2 ± 11.1%, respectively. When SIL was administered for 60 min, the Cmax and bioavailability were 0.990 ± 0.352 µg/mL and 9.91 ± 3.79%, respectively. These findings suggest that the drug absorption rate was at least partly responsible for the pharmacokinetic variability of SIL in the ICU children.

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  • Ayaka Maki, Ying Lin, Michihiko Aoyama, Kenta Sato, Jian-Qing Gao, Hir ...
    2020 Volume 43 Issue 12 Pages 1924-1930
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    Nanoparticles are used in many fields and in everyday products. Silver nanoparticles are the most frequently used nanoparticles; for example, in food-related products, owing to their antibacterial activity. However, it has been pointed out that they might have unexpected biological effects, and evaluation of their effects is underway. Although there is a growing body of evidence that nanoparticles can also induce epigenetic changes, there is still little information on the underlying mechanisms. Here, we evaluated changes in DNA methylation induced by silver nanoparticles and attempted to elucidate the induction mechanism. Immunofluorescence staining analysis revealed that silver nanoparticles with a diameter of 10, 50, or 100 nm (nAg10, nAg50, and nAg100, respectively) decreased the content of methylated DNA in A549 alveolar epithelial cells. The level of DNA methyltransferase 1 (Dnmt1) protein, which is involved in maintaining methylation during DNA replication, was significantly decreased, whereas that of Dnmt3b, which is responsible for de novo DNA methylation, was significantly increased by nAg10 treatment. Co-treatment with nAg10 and cycloheximide, which inhibits translation by inhibiting the translocation step of protein synthesis, decreased the level of Dnmt1 in comparison with nAg10-treated A549 cells, indicating a post-translational effect of nAg10. Furthermore, pretreatment with the proteasome inhibitor lactacystin restored the levels of Dnmt1 protein and DNA methylation in nAg10-treated cells. Collectively, these results suggest that nAg10 induced DNA hypomethylation through a proteasome-mediated degradation of Dnmt1.

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    Editor’s picks

    In this study, Maki et al., evaluated changes in DNA methylation induced by silver nanoparticles and attempted to elucidate the induction mechanism. The results showed that silver nanoparticles with diameter of 10 nm (nAg10) induces DNA hypomethylation accompanied with a decrease in the level of Dnmt1 in A549 alveolar epithelial cells. We The authors also revealed that nAg10 promotes the degradation of Dnmt1 by the proteasome system. Collectively, these results suggest that nAg10 induced DNA hypomethylation through a proteasome-mediated degradation of Dnmt1. This paper provides basic evidence for the effect of silver nanoparticles on DNA methylation.

  • Koichi Kato, Tomoki Nakayoshi, Hiroki Inoue, Shuichi Fukuyoshi, Kimino ...
    2020 Volume 43 Issue 12 Pages 1931-1939
    Published: December 01, 2020
    Released: December 01, 2020
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    Androgen receptor (AR) has a key role in the development and progression of prostate cancer, and AR antagonists are used for its remedy. Recently, carborane derivatives, which are carbon-containing boron clusters have attracted attention as new AR ligands. Here we determined the force field parameters of 10-vertex and 12-vertex p-carborane to facilitate in silico drug design of boron clusters. Then, molecular dynamics (MD) simulations of complexes of AR-carborane derivatives were performed to evaluate the parameters and investigate the influences of carborane derivatives on the three-dimensional structure of AR. Energy profiles were obtained using quantum chemical calculations, and the force-field parameters were determined by curve fitting of the energy profiles. The results of MD simulations indicated that binding of the antagonist–BA341 changed some hydrogen-bond formations involved in the structure and location of helix 12. Those results were consistent with previously reported data. The determined parameters are also useful for refining the structure of the carborane-receptor complex obtained by docking simulations and development of new ligands with carborane cages not only for AR but also for various receptors.

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  • Shigeyoshi Honma, Iori Tani, Mayu Sakai, Iori Soma, Kohei Toriyabe, Ma ...
    2020 Volume 43 Issue 12 Pages 1940-1944
    Published: December 01, 2020
    Released: December 01, 2020
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    This study examined the effect of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) inhibitor, on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO led to a significant increase in the fibrotic area of obstructed kidneys, which was attenuated by NAC (84.8 mg/kg/d) in the drinking water. Renal expression of type III collagen and tumor necrosis factor (TNF)-α mRNAs was elevated in UUO mice and inhibited by NAC. Extracellular signal-regulated kinase (ERK1/2) phosphorylation was significantly elevated by UUO, and NAC significantly attenuated the elevation. UUO inhibited the activity of glutathione peroxidase, while NAC restored its activity. Together, the results of this study suggest that renal interstitial fibrosis induced by UUO was ameliorated by NAC via several mechanisms including increased glutathione peroxidase activity, reduced phosphorylation of ERK1/2, and reduced expression of TNF-α and type III collagen mRNAs.

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Notes
  • Takeshi Yamamoto, Yuka Nagata, Shusaku Hayashi, Makoto Kadowaki
    2020 Volume 43 Issue 12 Pages 1945-1949
    Published: December 01, 2020
    Released: December 01, 2020
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    Supplementary material

    Isoflavones have many biological activities and are major bioactive components of kakkonto, a traditional Japanese herbal medicine. We previously reported that the combined therapy of oral immune therapy (OIT) and kakkonto downregulates the mRNA expression of Cyp26b1, a major retinoic acid (RA)-degrading enzyme, in the colon of food allergy mice and thereby ameliorates allergic symptoms. In this study, we evaluated the effects of various isoflavones on Cyp26b1 expression in primary cultured lamina propria (LP) cells isolated from the mouse colon. The mRNA expression of Cyp26b1 was extremely downregulated by all isoflavones tested in the LP cells except for puerarin. In particular, genistein and genistin markedly suppressed Cyp26b1 mRNA expression without affecting RA-synthesizing enzyme expression. Moreover, to evaluate the effects of isoflavones on allergic reactions, genistein and genistin were administered to ovalbumin (OVA)-induced food allergy mice. Oral administration of genistin suppressed the development of allergic symptoms. These results raise the possibility that isoflavones elevated the level of RA in the colon by inhibiting RA degradation and then the high concentration of RA in the colon might exert immunosuppressive and antiallergic effects on food allergy mice.

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  • Masato Mashimo, Marina Fujii, Natsumi Sakagawa, Yoshika Fukuda, Rika I ...
    2020 Volume 43 Issue 12 Pages 1950-1953
    Published: December 01, 2020
    Released: December 01, 2020
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    B cells express muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively). Following immunization with ovalbumin, serum immunoglobulin G (IgG) and interleukin (IL)-6 levels were lower in M1 and M5 mAChR double-deficient mice and higher in α7 nAChR-deficient mice than in wild-type mice. This suggests mAChRs participate in the cytokine production involved in B cell differentiation into plasma cells, which induces immunoglobulin class switching from IgM to IgG. However, because these results were obtained with conventional knockout mice, in which all cells in the body were affected, the specific roles of these receptors expressed in B cells remains unclear. In the present study, Daudi B lymphoblast cells were used to investigate the specific roles of mAChRs and nAChR in B cells. Stimulating Daudi cells using Pansorbin cells (heat-killed, formalin-fixed Staphylococcus aureus coated with protein A) upregulated expression of M1–M4 mAChRs and the α4 nAChR subunit. Under these conditions, mAChRs, but not nAChRs, mediated immunoglobulin class switching to IgG. This effect was blocked by scopolamine, a non-selective mAChR antagonist, and 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a Gq/11-coupled M1, M3, M5 antagonist. In addition, IL-6 secretion was further enhanced following mAChR activation. Thus, Gq/11-coupled mAChRs expressed in B cells thus appear to contribute to IL-6 production and B cell maturation into IgG-producing plasma cells.

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  • Shimako Tanaka, Shinya Uchida, Mai Sotoyama, Yasuharu Kashiwagura, Nor ...
    2020 Volume 43 Issue 12 Pages 1954-1959
    Published: December 01, 2020
    Released: December 01, 2020
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    The taste of medicines can significantly affect patient adherence. Pediatric patients often cannot take powder medicines because of their unpleasant taste. Therefore, patients’ parents and health care professionals, including pharmacists, often combine medicines with food or beverages to make them easier for pediatric patients to consume because this can reduce their unpleasant taste. The purpose of this study was to evaluate the palatability of powder formulations of azithromycin and carbocysteine and explore their combination with food or beverages to improve palatability for pediatric patients. We quantitatively evaluated the palatability of powder formulations by performing the gustatory sensation test using the visual analog scale score. The gustatory sensation tests were performed on 16 healthy adult volunteers (age 23.0 ± 2.6 years) and indicated that some food and beverages improved the palatability of the powder formulations of azithromycin and carbocysteine. The results of this study indicate that ice cream improves the palatability of azithromycin, while yogurt improves the palatability of carbocysteine. Moreover, the subjects recommended these same combinations for pediatric patients. This study suggests that some foods and beverages improve the palatability of powder formulations, thereby decreasing the possibility that pediatric patients will refuse medications because of their unpleasant taste.

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  • Yu Norikoshi, Tokunori Ikeda, Kodai Sasahara, Mariko Hamada, Erika Tor ...
    2020 Volume 43 Issue 12 Pages 1960-1965
    Published: December 01, 2020
    Released: December 01, 2020
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    The novel anti-influenza virus agent baloxavir marboxil is a selective inhibitor of an influenza cap-dependent endonuclease. Although a single oral dose in tablet form of baloxavir marboxil is expected to improve drug compliance and rapidly reduce viral titers for pediatric patients with influenza, there is a concern that baloxavir marboxil-resistant influenza A variants could be generated. In this study, we investigated the frequency of prescription and pharmacy revisits for baloxavir marboxil at an outpatient clinic compared with that of neuraminidase inhibitors in pediatric patients with influenza. A total of 475 pediatric patients who were infected with the influenza virus visited the pharmacy between December 2019 and March 2020. Baloxavir marboxil (n = 149), oseltamivir (n = 161) and laninamivir (n = 162) were mainly prescribed and only a few patients were treated with peramivir (n = 2) or zanamivir (n = 1). Baloxavir marboxil-, oseltamivir- and laninamivir-treated pediatric patients were enrolled, and a log-rank test showed that the revisits of pediatric patients who were taking baloxavir marboxil was lower than those for oseltamivir (p < 0.001). Moreover, Cox proportional hazards models also revealed that baloxavir marboxil decreased the risk of revisits in comparison to oseltamivir (hazard ratio 0.28, 95% confidence interval 0.11–0.70, p = 0.006), while no difference was found between laninamivir and baloxavir marboxil. Although there is a need to acquire appropriate and relevant information concerning resistant viruses, our results suggest that baloxavir marboxil may be a useful drug for treating pediatric patients with influenza infections.

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  • Masahiro Ishii, Ayako Senju, Ami Oguro, Masayuki Shimono, Shunsuke Ara ...
    2020 Volume 43 Issue 12 Pages 1966-1968
    Published: December 01, 2020
    Released: December 01, 2020
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    Estradiol has an important role in the brain, such as in neuronal development and protection, but estradiol levels in the human brain have not been well investigated. In this study, we measured the estradiol concentration in the cerebrospinal fluid (CSF) of infants to reveal the relationships between the estradiol concentrations in the serum and the CSF and further determined exosomal microRNAs in serum. Estradiol in the CSF was strongly correlated with serum estradiol and moderately correlated with miR-126-5p in the serum exosomes. This report is the first to determine the estradiol concentration in CSF from infants and showed that the levels of miR-126-5p as well as serum estradiol can be candidates to predict brain estrogen status.

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  • Yoshitaka Saito, Kazuki Uchiyama, Tatsuhiko Sakamoto, Kojiro Yamazaki, ...
    2020 Volume 43 Issue 12 Pages 1969-1974
    Published: December 01, 2020
    Released: December 01, 2020
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    We previously reported that successive pharmaceutical care by oncology pharmacy specialists contributes to quality outpatient chemotherapy. However, there are a few reports regarding such care during immune checkpoint inhibitors (ICIs) treatment, despite increasing patients being treated with ICIs and the profile of immune-related adverse events being quite different from that of the adverse effects of cytotoxic agents. We retrospectively evaluated the effectiveness of continuous pharmaceutical care in outpatient ICI treatment, focusing especially on the period of providing pharmaceutical recommendations. The adoption rate, efficacy, and period of pharmaceutical interventions, such as prescription questions and pharmaceutical recommendations, were evaluated. A total of 3597 ICI administrations (366 patients) were evaluated. We performed 2625 face-to-face medication counseling. A total of 282 prescription questions and 147 pharmaceutical recommendations were conducted. Approximately 70% of the questions were regarding ordering of laboratory examination, and 86.5% of these questions were adopted. Pharmaceutical recommendations were categorized into medication recommendations (81.1%), examination recommendations (10.8%), and recommendation of expert consultation (8.1%). The adoption rate of pharmaceutical recommendations was 96.0, and 70% of the medication recommendations attenuated the symptoms. Finally, the provision rate of pharmaceutical recommendations was significantly higher in the first 3 months after ICI treatment initiation. We found that pharmaceutical care contributes to an improved quality of outpatient ICI treatment, and face-to-face pharmaceutical counseling up to 3 months after ICI treatment initiation is the most important.

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  • Haruna Tamano, Junichi Togo, Yuichi Sato, Aoi Shioya, Munekazu Tempaku ...
    2020 Volume 43 Issue 12 Pages 1975-1978
    Published: December 01, 2020
    Released: December 01, 2020
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    The pathological significance of amyloid-β1–42 (Aβ1–42) dynamics is poorly understood in the brain extracellular compartment. Here we test which of the concentration or the retention is critical for Aβ1–42 toxicity after injection of equal dose into dentate granule cell layer of freely moving rats. The toxicity of Aβ1–42 (25 µM) was compared between injections at the rate of 0.25 µL/min for 4 min (fast injection) and 0.025 µL/min for 40 min (slow injection). Dentate gyrus long-term potentiation (LTP) was affected 1 and 2 h after the fast injection, but not 4 h. In contrast, LTP was affected even 72 h after the slow injection. Aβ1–42 staining 5 min after finish of the slow injection was more intense in the dentate granule cell layer than of the fast injection. The present study indicates that the retention of Aβ1–42 in the extracellular fluid is correlated with neuronal Aβ1–42 uptake and plays a key role in Aβ1–42 neurotoxicity. In the extracellular fluid of the dentate gyrus, the retention period of Aβ1–42 is much more critical for Aβ1–42 toxicity than Aβ1–42 concentration. It is likely that Aβ1–42 toxicity is accelerated by the disturbance of Aβ1–42 metabolism in the dentate gyrus.

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  • Naoko Tanaka-Totoribe, Muneaki Hidaka, Shuji Gamoh, Atsuko Yokota, Eis ...
    2020 Volume 43 Issue 12 Pages 1979-1982
    Published: December 01, 2020
    Released: December 01, 2020
    [Advance publication] Released: September 30, 2020
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    Sarpogrelate, a selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, inhibits 5-HT-induced platelet aggregation and vasoconstriction. It improves ischemic symptoms in patients with arteriosclerosis obliterans. M-1 is a major metabolite of sarpogrelate, and has been reported to show a higher affinity for the 5-HT2A receptor on platelets than sarpogrelate. However, the effects of M-1 on 5-HT-induced constrictive response in human blood vessels have not been investigated. The internal thoracic artery (ITA) is the key conduit for coronary artery bypass grafting (CABG). 5-HT has been implicated as playing an important role in the pathogenesis of vasospasm. Thus, in the present study, the effects of M-1 on 5-HT-induced vasoconstriction were examined in isolated human endothelium denuded ITA. M-1 inhibited 5-HT-induced vasoconstriction in a concentration-dependent manner. At the highest concentration, M-1 almost completely inhibited the 5-HT-induced vasoconstriction. Expression of 5-HT2A and 5-HT1B receptor proteins in the membrane fraction of ITA smooth muscle cells was confirmed by Western blot analysis. Individually, supramaximal concentrations of sarpogrelate and SB224289, a selective 5-HT1B receptor antagonist, only partially inhibited the 5-HT-induced vasoconstriction. However, simultaneous pretreatment with both these antagonists almost completely inhibited the 5-HT-induced vasoconstriction. The inhibitory effect of M-1 pretreatment mimicked the inhibitory effect of simultaneous pretreatment with sarpogrelate and SB224289. These results suggest that M-1 has antagonistic effects not only on the 5-HT2A receptor but also on the 5-HT1B receptor in human ITA smooth muscle cells. M-1 may be useful as a lead compound for the development of drugs for the treatment of 5-HT-induced vasospasms in CABG.

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  • Sayuki Iwahashi, Kazuya Tokumura, Gyujin Park, Shinsuke Ochiai, Yasuka ...
    2020 Volume 43 Issue 12 Pages 1983-1986
    Published: December 01, 2020
    Released: December 01, 2020
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    The mechanistic/mammalian target of rapamycin complex-1 (mTORC1) integrates multiple signaling pathways and regulates various cellular processes. Tuberous sclerosis complex 1 (Tsc1) and complex 2 (Tsc2) are critical negative regulators of mTORC1. Mouse genetic studies, including ours, have revealed that inactivation of mTORC1 in undifferentiated mesenchymal cells and chondrocytes leads to severe skeletal abnormalities, indicating a pivotal role for mTORC1 in skeletogenesis. Here, we show that hyperactivation of mTORC1 influences skeletal development through its expression in undifferentiated mesenchymal cells at the embryonic stage. Inactivation of Tsc1 in undifferentiated mesenchymal cells by paired-related homeobox 1 (Prx1)-Cre-mediated recombination led to skeletal abnormalities in appendicular skeletons. In contrast, Tsc1 deletion in chondrocytes using collagen type II α1 (Col2a1)-Cre or in osteoprogenitors using Osterix (Osx)-Cre did not result in skeletal defects in either appendicular or axial skeletons. These findings indicate that Tsc complex-mediated chronic overactivation of mTORC1 influences skeletal development at the embryonic stage through its expression in undifferentiated mesenchymal cells but not in chondrocytes or osteoprogenitors.

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  • Takayuki Matsumoto, Keisuke Takayanagi, Mihoka Kojima, Kumiko Taguchi, ...
    2020 Volume 43 Issue 12 Pages 1987-1992
    Published: December 01, 2020
    Released: December 01, 2020
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    Extracellular nucleotides play an important role in the regulation of vascular function, and an abnormal vascular function is an important participant in the development and progression of diabetic vascular complications. The purpose of this study was to determine whether contractile responses induced by extracellular nucleotides and a dinucleotide, uridine adenosine tetraphosphate (Up4A), in femoral arteries would be altered at the chronic stage of type 2 diabetes. We determined the changes in contractile reactivity induced by ATP, uridine triphosphate (UTP), uridine diphosphate (UDP), and Up4A in the femoral arteries of Otsuka Long–Evans Tokushima Fatty (OLETF) rats (aged male type 2 diabetic rats) and, Long–Evans Tokushima Otsuka (LETO) rats (controls for OLETF rats). ATP-induced contractions were greater in OLETF rats than in LETO rats. UTP-induced contractions were lower in OLETF rats than in LETO rats. UDP- and Up4A-induced contractions were similar between OLETF and LETO rats. The femoral artery contractile changes induced by the extracellular nucleotides and dinucleotide were similar when nitric oxide synthase was inhibited. These results suggest that the extent of femoral artery contractile reactivity to nucleotides/dinucleotides differs during long-term duration of type 2 diabetes.

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  • Iyuki Namekata, Ryosuke Odaka, Shogo Hamaguchi, Hikaru Tanaka
    2020 Volume 43 Issue 12 Pages 1993-1996
    Published: December 01, 2020
    Released: December 01, 2020
    [Advance publication] Released: October 06, 2020
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    The effect of KB-R7943, an inhibitor of the plasmalemmal Na+–Ca2+ exchanger, on mitochondrial Ca2+ transporters was examined with membrane-permeabilized cardiomyocyte-derived H9c2 cells expressing the fluorescent Ca2+ indicator, yellow cameleon 3.1, in the mitochondria. KB-R7943, as well as ruthenium red, inhibited the rise in mitochondrial Ca2+ on increasing the extramitochondrial Ca2+ concentration from 0 nM to 300 nM. CGP-37157, but not KB-R7943, inhibited the decline in mitochondrial Ca2+on return to Ca2+ free extramitochondrial solution. These results indicated that KB-R7943 has inhibitory effects on the mitochondrial Ca2+ uniporter, but not on the mitochondrial Na+–Ca2+ exchanger.

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