Biomedical Research
Online ISSN : 1880-313X
Print ISSN : 0388-6107
Volume 39 , Issue 3
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  • Syota SEINO, Takeru KIMOTO, Hidemi YOSHIDA, Kunikazu TANJI, Tomoh MATS ...
    2018 Volume 39 Issue 3 Pages 105-115
    Published: June 01, 2018
    Released: June 12, 2018
    JOURNALS FREE ACCESS

    Accumulation and oligomerization of amyloid-beta (Aβ) peptides have been known to be a potent cause of neurodegenerative diseases such as Alzheimer’s disease (AD). To expand the possibilities of preventing AD, we investigated the effects of resveratrol dimers, gnetin C and ε-viniferin, on Aβ 1–42 (Aβ42) production and the reduced cell viability observed after Aβ42 treatment (monomers, 10 μM) in cultured SH-SY5Y human neuroblastoma cells. Among them, addition of gnetin C (20 μM) into the media reduced Aβ42 production most efficiently. Gnetin C suppressed the expression of β-site amyloid precursor protein-cleaving enzyme-1 (BACE1, β-secretase). Furthermore, gnetin C ameliorated the Aβ42-reduced cell viability most significantly. Concomitantly, gnetin C reduced intracellular Aβ oligomers (ca. 15 and 130 kDa) and elevated both levels of intracellular and extracellular Aβ monomers. Under the treatment with or without Aβ42, gnetin C upregulated the expression of matrix metalloproteinase-14 (MMP-14) which is assumed to be an Aβ-decomposing enzyme. Gnetin C may thereby prevent Aβ toxicity by suppressing BACE1 and enhancing MMP-14, together with reducing both internalization and oligomerization of exogenous Aβ monomers. The use of gnetin C may lead to the prevention of Aβ-mediated diseases, particularly AD.

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  • Satoshi TSUZUKI, Yusaku KIMOTO, Shinhye LEE, Tatsuya SUGAWARA, Yuki MA ...
    2018 Volume 39 Issue 3 Pages 117-129
    Published: June 01, 2018
    Released: June 12, 2018
    JOURNALS FREE ACCESS

    Class B scavenger receptors, scavenger receptor B1 (SR-B1) and cluster of differentiation 36 (CD36), are broadly expressed cell-surface proteins and are believed to serve as multifaceted players in lipid and lipoprotein metabolism in mammals. Because of its ability to recognise distinct odour-active volatile compounds and its presence in murine olfactory epithelium, CD36 has recently emerged as a participant in the detection of odorants within the nasal cavity. However, there have been no attempts to assess whether SR-B1 has such a role. In this study, we performed a cell-free in-vitro assay utilising a peptide mimic of the receptor, and demonstrated that SR-B1 could recognise aliphatic aldehydes (e.g., tetradecanal), a distinct class of volatile odorants, as potential ligands. By reverse transcription-polymerase chain reaction and western immunoblot analyses, we detected the expression of SR-B1 mRNA and protein, respectively, in mouse olfactory tissue. Finally, we immunohistochemically mapped the distribution of SR-B1 in the surface layer of olfactory epithelium in vivo, which is the first line of odorant detection. These findings uncover a novel role for SR-B1 as a contributor to the capture of specific odorants in the nasal cavity of mammals.

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  • Junkichi KANDA, Nobuo IZUMO, Megumi FURUKAWA, Taketoshi SHIMAKURA, Nor ...
    2018 Volume 39 Issue 3 Pages 131-139
    Published: June 01, 2018
    Released: June 12, 2018
    JOURNALS FREE ACCESS

    Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.

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  • Takuji MACHIDA, Mikiko YUTANI, Akihiro GOTO, Saaya NISHIMURA, Ayaka KA ...
    2018 Volume 39 Issue 3 Pages 141-148
    Published: June 01, 2018
    Released: June 12, 2018
    JOURNALS FREE ACCESS

    Elevated mechanical stress applied to vascular walls is well known to modulate vascular remodeling and plays a part in the pathogenesis of atherosclerosis. On the other hand, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has been shown to protect against several types of cardiovascular diseases including atherosclerosis and hypertension. The aim of this study was to clarify the effect of pulsatile pressure stress and DHA on angiotensin II-induced proliferation and migration in A7r5 vascular smooth muscle cells (VSMCs). Pulsatile pressure of between 80 and 160 mmHg was repeatedly applied to VSMCs at a frequency of 4 cycles per min using an apparatus that we developed. Cell proliferation and migration were evaluated using a live cell movie analyzer. Application of pulsatile pressure stress for 24 h significantly increased cell proliferation. Angiotensin II also significantly increased cell proliferation in the presence or absence of pressure stress. DHA significantly inhibited angiotensin II-induced cell proliferation regardless of the pressure load. Angiotensin II significantly induced cell migration regardless of the pulsatile pressure load. Pulsatile pressure stress alone slightly, but not significantly, induced cell migration. DHA inhibited angiotensin II-induced VSMC proliferation and migration under abnormal pressure conditions. Pressure stress tended to induce extracellular signal-regulated kinase (ERK) phosphorylation in the absence of angiotensin II, whereas it significantly induced ERK phosphorylation in the presence of angiotensin II. However, the pressure-induced ERK phosphorylation was not observed in the DHA-treated VSMCs. Our findings may contribute to the understanding of the beneficial effect of DHA on various cardiovascular disorders.

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  • Teruyuki HIGA, Hana TAKAHASHI, Sayomi HIGA-NAKAMINE, Mikio SUZUKI, Hid ...
    2018 Volume 39 Issue 3 Pages 149-158
    Published: June 01, 2018
    Released: June 12, 2018
    JOURNALS FREE ACCESS

    Gonadotropin-releasing hormone (GnRH) is secreted from hypothalamic neurons (GnRH neurons) and stimulates anterior pituitary gonadotrophs to synthesize and secrete gonadotropins. In addition to gonadotrophs, GnRH neurons also express GnRH receptors, and the autocrine action of GnRH is reportedly involved in the regulation of functions of GnRH neurons. There is accumulating evidence that extracellular signal-regulated kinase (ERK), one of mitogen-activated protein kinases (MAPKs), is activated by GnRH and involved in various effects of GnRH in GnRH neurons. In the present study, we performed microarray analysis to examine the types of genes whose expression was regulated by GnRH in immortalized mouse GnRH neurons (GT1-7 cells). We found that 257 genes among 55,681 genes examined were up-regulated after 30-min treatment of GT1-7 cells with GnRH. These up-regulated genes included four dual-specificity MAPK phosphatases (DUSPs), DUSP1, DUSP2, DUSP5, and DUSP6. Reverse transcription-polymerase chain reaction analysis confirmed that the mRNA levels of DUSP5 and DUSP6 were robustly increased within 30 min. U0126, an inhibitor of ERK activation, completely inhibited the increases in the mRNA levels of DUSP5 and DUSP6. Immunoblotting analysis revealed that ERK activation peaked at 5 min and declined steeply at 60 min, whereas DUSP5 and DUSP6 proteins were increased from 60 min. It was notable that down-regulation of DUSP6 augmented GnRH-induced ERK activation approximately 1.7-fold at 60 min. These results suggested that the up-regulation of DUSP6 regulates the duration of ERK activation at least in part.

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  • Keiichi HATAKEYAMA, Takeshi NAGASHIMA, Kenichi URAKAMI, Keiichi OHSHIM ...
    2018 Volume 39 Issue 3 Pages 159-167
    Published: June 01, 2018
    Released: June 12, 2018
    JOURNALS FREE ACCESS

    Tumor mutational burden (TMB) is an emerging characteristic in cancer and has been associated with microsatellite instability, defective DNA replication/repair, and response to PD-1 and PD-L1 blockade immunotherapy. When estimating TMB, targeted panel sequencing is performed using a few hundred genes; however, a comparison of TMB results obtained with this platform and with whole exome sequencing (WES) has not been performed for various cancer types. In the present study, we compared TMB results using the above two platforms in 2,908 solid tumors that were obtained from Japanese patients. For next-generation sequencing, we used fresh-frozen tissue specimens. The Ion Proton System was employed to detect somatic mutations in the coding genome and to sequence an available cancer panel that targeted 409 genes. We then selected 2,040 samples with sufficient tumor cellularity for TMB analysis. In tumors with TMB-high (TMB ≥ 20 mutations/Mb), TMB derived from WES correlated well with the estimated TMB (eTMB) based on panel sequencing, whereas TMB in the remaining tumors showed a weak correlation. In particular, eTMB was overestimated in tumors with low-frequency mutations, resulting in the accumulation of EGFR mutations not being discriminated as a feature of lung cancer with low-frequency mutations. The eTMB in tumors harboring POLE mutations and microsatellite instability was not overestimated, suggesting that panel sequencing could accurately estimate TMB in tumors with high-frequency mutations such as hypermutator tumors. These results may provide helpful information for interpreting TMB results based on clinical sequencing using a targeted gene panel.

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