Biomedical Research
Online ISSN : 1880-313X
Print ISSN : 0388-6107
ISSN-L : 0388-6107
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  • Akihiro YAMAUCHI, Takahiro TONE, Andreia de TOLEDO, Kyoko IGARASHI, ...
    Type: research-article
    2020 Volume 41 Issue 1 Pages 1-12
    Published: February 01, 2020
    Released: February 22, 2020
    JOURNALS FREE ACCESS

    Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, which ultimately leads to cirrhosis and hepatocellular carcinoma. We previously showed that human placental extract (hPE) was intramuscularly injected to ameliorates liver injury in a methionine- and choline-deficient (MCD) diet-induced NASH model. In the present study, we investigated the effects of hPE using dB/dB mice which exhibit obesity and insulin resistance and are thought to reproduce the pathological background of NASH. The MCD-diet induced liver atrophy accompanied by fibrosis around the liver sinusoids. hPE dose-dependently reduced the perivascular fibrosis. Moreover, αSMA-positive activated hepatic stellate cells increased in number in mice on the MCD diet, with this effect reversed by hPE treatment. hPE significantly decreased expression of Acta2, Col1a1, and Tgfb1 genes in hepatic stellate cells, and inhibited Smad phosphorylation. Moreover, hPE treatment increased the expression of the anti-oxidative genes Hmox1, Nqo1, Cat, and Sod1, and significantly enhanced nuclear factor erythroid 2-related factor 2 activity. Furthermore, hPE decreased the expression of Nox4 and attenuated the levels of intracellular reactive oxygen species. These results, along with our previous study, suggest that hPE effectively ameliorates liver fibrosis in NASH. This beneficial effect may, in part, be due to suppression of hepatic stellate cell activation.

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  • Hidetaka IMAGITA, Yasue NISHII, Naoto FUJITA, Taiko SUKEDZANE, Shinnos ...
    Type: research-article
    2020 Volume 41 Issue 1 Pages 13-22
    Published: February 01, 2020
    Released: February 22, 2020
    JOURNALS FREE ACCESS

    The number of patients with chronic obstructive pulmonary disease (COPD), a typical respiratory disorder, is rapidly increasing globally. The purpose of this study was to determine the effects of appropriate-intensity treadmill exercise on skeletal muscle and respiratory functions in a rat model of emphysema. Twenty-one Wistar rats were randomly divided into three groups: the sham (SH) group, pulmonary emphysema (PE) group, and emphysema + exercise (EX) group. Cigarette smoke solution and lipopolysaccharide were intratracheally administered for 4 weeks in the PE and EX groups. The rats in the EX group were made to run on treadmills in the latter 2 weeks of the experiment. Lung tissue was stained with anti-macrophage antibodies; the specific force (contractile force per unit cross-sectional area) of the diaphragm and hind-limb muscles was measured, and blood was analyzed for serum cytokine levels. Many macrophages were observed in the lung tissue of the PE group. In the EX group, the population of macrophages was smaller, and the specific force of the diaphragm and extensor digitorum longus muscles was higher than in the PE group. Moreover, the degree of inflammation in the pulmonary tissue was reduced in the EX group. These results suggest that adaptive exercise may improve not only respiratory and muscle functions but also inflammation of the pulmonary tissue associated with emphysema.

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  • Natsuki GOTO, Naoto FUJITA, Wataru NINO, Kazuyoshi HISATSUNE, Ryosuke ...
    Type: research-article
    2020 Volume 41 Issue 1 Pages 23-32
    Published: February 01, 2020
    Released: February 22, 2020
    JOURNALS FREE ACCESS

    Mild hyperbaric treatment prevents type 2 diabetes progression due to increased oxygen concentration and blood flow in skeletal muscle. However, it remains unknown whether this treatment is effective during all stages of type 2 diabetes. This study aimed to investigate the influences of hyperbaric treatment at 1.3 atmospheres absolute (ATA) on hemodynamic response in various stages of type 2 diabetes. Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as models of type 2 diabetes and healthy controls, respectively. Glucose levels were significantly higher in OLETF rats than in LETO rats at all ages. Glucose intolerance gradually increased with age in OLETF rats. Insulin levels in OLETF rats were significantly higher at 20-week-old, however, were significantly lower at 60-week-old than in LETO rats. Oxy-Hb, total Hb, and StO2 in skeletal muscle were increased during hyperbaric treatment in both rats. The hemodynamic changes were significantly higher in OLETF rats than LETO rats, and those changes were also pronounced at 8-week-old compared with other age in OLETF rats. These results suggest that hyperbaric treatment at 1.3 ATA acts on pathophysiological factors and the efficacy could be found only in the early stage of type 2 diabetes.

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  • Keishi HATA, TOMATSU Sayaka, Masaki TAKAHASHI, Akira SASAKI, Yui UMEK ...
    Type: research-article
    2020 Volume 41 Issue 1 Pages 33-42
    Published: February 01, 2020
    Released: February 22, 2020
    JOURNALS FREE ACCESS

    We investigated lipid metabolism in PXB-cells, which are human primary hepatocytes isolated from liver-humanized mice, and HepG2 and HuH-7 human hepatoma cell lines. Lipoprotein levels were higher in PXB-cells than in the 2 other cell lines, and PXB-cells mainly released triglycerides and cholesterol as very low density lipoprotein (VLDL), similar to actual liver tissue, whereas the major lipoprotein released from the 2 hepatoma cell lines was LDL. RT-PCR analysis demonstrated that the gene expression levels of apolipoprotein B100 (ApoB100), the apolipoprotein of VLDL/LDL, were similar in PXB-cells and HepG2 cells, while the overexpression of ApoC2, ApoC3, and ApoE, which are components of VLDL, but not LDL, was observed in PXBcells. A protein immunoassay revealed that ApoB100 levels secreted from PXB-cells and HuH-7 cells were similar; however, ApoC3 levels were higher in PXB-cells than in the two other cell lines. We also examined the anti-lipidemic activities of fenofibrate using this assay system. Fenofibrate suppressed lipoprotein production from PXB-cells in a dose-dependent manner mainly by activating the β-oxidation pathway. These results suggest that PXB-cells produce high levels of lipoproteins and are suitable for screening anti-lipidemic agents.

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  • Hikaru SUGIMOTO, Yasutaka MURAHASHI, Ryota CHIJIMATSU, Satoshi MIWA, F ...
    Type: research-article
    2020 Volume 41 Issue 1 Pages 43-51
    Published: February 01, 2020
    Released: February 22, 2020
    JOURNALS FREE ACCESS

    Synovial fibroblasts have attracted considerable attention in studies of joint diseases. Although mice are useful and powerful in in vitro and in vivo experiments, primary cultures of mouse synovial fibroblasts are notoriously difficult because the mouse synovial tissues are much smaller and cell cycle arrests can be induced more easily in murine cells than in human cells. Here, we report a precise protocol for the isolation and culture of fibroblasts from mouse adipose and fibrous knee joint synovia. In both adipose and fibrous synovial fibroblasts, proliferation was decreased in addition to a higher rate of cellular senescence under normoxic conditions (20% O2); however, it was maintained over 20 days with low cellular senescence under hypoxic conditions (3% O2). The marker gene expression in adipose and fibrous synovial fibroblasts was not markedly altered after a 3-week culture. Both cells displayed similar potencies for chondrogenic, osteogenic, and adipogenic differentiation, and responses to a proinflammatory cytokine. The present method provides a sufficient amount of mouse synovial fibroblasts for in vitro and in vivo experiments in joint biology and the pathophysiology of osteoarthritis and rheumatoid arthritis.

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  • Yuki KUCHITSU, Ryo NAGASHIO, Satoshi IGAWA, Seiichiro KUSUHARA, Benio ...
    Type: research-article
    2020 Volume 41 Issue 1 Pages 53-65
    Published: February 01, 2020
    Released: February 22, 2020
    JOURNALS FREE ACCESS

    Platinum-based adjuvant chemotherapy after complete resection has become a standard treatment for patients with stage II to IIIA non-small cell lung cancer; however, not all patients exhibit survival benefits. Therefore, the development of predictive biomarkers for selecting a subgroup of patients who may show improved survival after these treatments is important. Among the 42 proteins identified here using a proteomics analysis that were recognized by autoantibodies in pretreated sera from patients with lung adenocarcinoma who received platinum-based adjuvant chemotherapy, the tumor necrosis factor-receptor-associated protein 1 (TRAP1) was detected in patients with a short disease-free survival. TRAP1 expression was immunohistochemically analyzed in 64 patients with completely resected stage II and IIIA lung adenocarcinoma treated with platinum-based adjuvant chemotherapy. TRAP1 expression was significantly associated with higher p-TNM stage (P = 0.005) and lymph node metastasis (P = 0.017). Moreover, TRAP1 expression was significantly correlated with a shorter disease-free survival (P = 0.028). Furthermore, TRAP1-siRNA-treated LC-2/ad cells derived from lung adenocarcinoma exhibited significantly reduced proliferation and increased sensitivity to cisplatin. These results suggest that TRAP1 expression is a valuable biomarker for predicting the poor survival of platinum-based adjuvant chemotherapy in patients with resected lung adenocarcinoma.

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