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Background and aim Elimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti-HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti-hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti-HBV activity of GGA. Methods We used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV-infected hepatocyte models. After GGA treatment, HBV-related antigen was measured by chemiluminescent immunoassay. HBV-related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real-time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors. Results After GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV-infected hepatocyte models. HBV-related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV-related antigen secretion. Conclusions Geranylgeranylacetone treatment reduces HBV-related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti-HBV effects in combination with other therapies.

Since the discovery of the senescence-associated secretory phenotype, the role of senescent hepatic stellate cells (HSCs) in hepatocellular carcinoma (HCC) development has gained increasing attention. Similar to cytokines, extracellular vesicles (EVs) are essential for intercellular communication. However, the function of EVs derived from senescent HSCs in HCC progression has not been extensively studied. The aims of the present study were to characterize the EVs derived from senescent HSCs and determine their role in the tumor microenvironment. Cellular senescence was induced in human hepatic stellate cells (HHSteCs) with various concentrations of etoposide. Induction was confirmed using EdU staining and 53BP1 and p21 immunostaining. EVs were isolated by ultracentrifugation and analyzed by nanoparticle tracking analysis. Multiplex immunoassays were used to compare the levels of growth factors secreted from hepatoma cell lines and macrophage cells pretreated with EVs derived from senescent HHSteCs (senescent EVs) with those pretreated with EVs derived from normal cultured HHSteCs (normal EVs). Treatment with 25 μM etoposide for 3 days was the most effective at inducing senescence in HHSteCs. This finding was confirmed by induction of irreversible cell-cycle arrest, upregulation of 53BP1 and p21 expression, and increased SA-β-gal staining. Senescent HHSteCs released increased quantities of EV particles compared with normally cultured HHSteCs. Multiplex analysis revealed that there was no difference between hepatoma cell lines treated with normal EVs and those treated with senescent EVs in growth factor secretion. In contrast, the secretion of epidermal growth factor (EGF) was increased by macrophage cells treated with senescent EVs compared with those treated with normal EVs. Furthermore, senescent EVs did not affect the viability of hepatoma cells but increased the viability of hepatoma cells co-cultured with macrophage cells. In conclusion, the release of EVs from senescent HSCs was higher compared with normal HSCs. Furthermore, senescent EVs promoted HCC development by upregulating EGF secretion from macrophages., Biomedical Reports, 12(4), pp.163-170; 2020

Exosomal microRNAs (miRNAs) have been investigated as potential novel biomarkers, and miR-122 and miR-21 were shown to be important in hepatocellular carcinoma (HCC). We analyzed the importance of serum exosomal miRNA expression levels in HCC patients that underwent transarterial chemoembolization (TACE). Seventy-five HCC patients who underwent TACE as the initial treatment in Nagasaki University Hospital were enrolled. Exosomal miRNAs were isolated from serum samples collected before and after TACE. Exosomal miR-122 expression levels significantly decreased after TACE (P=0.012), while the exosomal miR-21 expression levels did not significantly change. The expression levels of exosomal miR-122 before TACE were shown to correlate significantly with aspartate aminotransferase (r=0.31, P=0.004) and alanine aminotransferase (r=0.33, P=0.003) levels, tumor diameter (r=0.29, P=0.010) and Child-Pugh score (r=-0.28, P=0.013). The median survival time for all patients was 47 months, and neither of the investigated exosomal miRNAs were shown to be independent factors associated with the disease-specific survival. According to the median relative expression of miR-122 after TACE/before TACE (miR-122 ratio) in liver cirrhosis patients (n=57), the patients with a higher miR-122 ratio had significantly longer disease-specific survival, compared with that of the patients with the lower miR-122 ratio (P=0.0461). Multivariate Cox proportional hazards regression analysis of clinical parameters revealed that a lower exosomal miR-122 ratio (HR 2.720; 95% confidence interval, 1.035-8.022; P=0.042) is associated with the disease-specific survival. Taken together, our results demonstrate that the exosomal miR-122 level alterations may represent a predictive biomarker in HCC patients with liver cirrhosis treated with TACE., Oncology Letters, 16(3), pp.3267-3273; 2018

Gut microbiota has been associated with liver cirrhosis and, possibly, hepatic encephalopathy. However, only a few studies have examined the link between mucosa-associated microbiota (MAM) and minimal hepatic encephalopathy (MHE). Our aim was to investigate this relationship. Twenty-four patients with cirrhosis underwent colon biopsies at our institution, between January 2014 and April 2015. Patterns of microbial colonization were examined using 16S rRNA gene sequences. MHE was diagnosed using the Neuropsychological Test. Ten (41.7%) of the 24 patients were diagnosed as having MHE. There was no significant difference in the diversity of gut microbiota by sampling locations between those with and without MHE. However, the diversity of the gut microbiota and the proportion of the genus Bacteroides decreased as a function of declining liver function. We divided patients into those with the highest proportion of the genus Bacteroides (Bacteroides-dominant group; n = 9) and into a Bacteroides non-dominant group (n = 15). In the Bacteroides-dominant group, only 1 patient (11.1%) was diagnosed as having MHE, with the incidence rate of MHE being significantly lower in the Bacteroides-dominant group than in the non-dominant group (p = 0.019). The Child–Pugh score (p = 0.05) and use of proton-pump inhibitors (p = 0.015) were negatively correlated to the proportion of Bacteroides. Furthermore, the proportion of the family Clostridiaceae was significantly higher in the Bacteroides-dominant group than in the non-dominant group (p = 0.078). The decrease in microbial diversity and genus Bacteroides in MAM is a risk factor for MHE in patients with liver cirrhosis.

Background and aims A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD. Methods Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed. Results Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine- adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes. Conclusions The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans., PLOS ONE, 12(3), e0170591; 2017

Over 30 years have passed since co-infection with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) was first documented in hemophilia patients in Japan. In such cases, the leading cause of mortality is reportedly HCV-associated end-stage liver disease. However, the current characteristics of hemophilia patients co-infected with HIV/HCV are unknown. The aim of the present study was to reveal the current characteristics, notably HCV geno-prevalence and liver function, among hemophilia patients co-infected with HIV/HCV in Japan. Current characteristics were evaluated using cross-sectional retrospective data of 44 hemophilia patients positive for anti-HCV and anti-HIV antibodies who underwent screening of liver dysfunction. A total of 56.8% of hemophilia patients co-infected with HIV/HCV were positive for HCV RNA. The most common HCV genotypes were 1a, 1b and 3a. Liver cirrhosis was diagnosed in 26.3% patients negative for HCV RNA and 60.0% patients positive for HCV RNA. Decompensated liver cirrhosis was diagnosed in 33.3% HCV RNA-positive patients and none of the HCV RNA-negative patients. The rate of liver cirrhosis was greater for HCV genotype 3a compared with other genotypes. Overall, the current primary HCV RNA genotypes among hemophilia patients co-infected with HIV/HCV are 1a, 1b and 3a. Over 50% of HIV/HCV co-infected hemophilia patients positive for HCV RNA were diagnosed with liver cirrhosis and some were diagnosed with decompensated liver cirrhosis., Experimental and Therapeutic Medicine, 15(2), pp.2148-2155; 2018

歴史的語用論は,実質語が機能語へと変化する「文法化」現象を語用論的効力によるものと説明する。この立場から現代語の「ノダ」文の用法を見れば,その意味機能は準体助詞「ノ」の意味変化に帰するものではなく,同様の機能を有する中古の「用言連体形+指定助動詞」構文,いわゆる「連体+なり」構文に遡って考察すべきである。本稿は「ノダ」文の各構成要素を先行研究の成果を援用して歴史的にたどり,それぞれの変化による「連体+なり」構文の形式および用法の上代から平安初期に至るまでの変遷を見た。「ノダ」の原型を古代に探る予備調査としての研究ノートである。, 論文(Article)

Helen S. Oatey(2000)の提唱する「ラポール維持管理のストラテジー」は,ラポール(親愛感情)を維持することがポライトネスであるとして,5つの「ポライトネスの領域」によってラポール維持管理がなされるという。そこに挙げられているストラテジーの一つとして「格下げ表現downgraders(緩衝表現とも言う)」がある。このストラテジーが言語普遍的なものであるなら日本語にも適用されるはずである。そこで本稿は「格下げ表現」の7つの項目について日本語の実際例を検討し,「格下げ表現」の認定とその理由を考察した。結果として7つのうち「ポライトネス表示」はポライトネスの定義による相対的なものであること,「おだて」はより広義に捉えるべきであるということ,「控えめ表現」と「緩衝表現」のいずれにもまたがるような日本語表現があるということなどが知見された。

本稿はClaudia Caffi & Richard W. Jannyの"Toward a pragmatics of emotive communication" (Journal of Pragmatics Volume 22 (1994))を抄訳し,そこで提案されている装置の日本語への適用を考察したものである。彼らは人の感情を扱った心理学および言語学上の膨大な研究には概念や用語の面で統一性が少なく,一致した理論,分析手法を見出すのは困難であるとして,過去数十年にわたる心理学および言語学における研究を整理した。そして心理学での主たる概念を「評価evaluation/潜在能力potency/活動activity」の3つに分類し,それぞれの概念に通じる言語学のカテゴリーを6つに分類した上,言語学が扱えるものは「外的に表された言語・非言語事象から話者の内的状態を推測すること」と限定して,それぞれのカテゴリーに含まれる言語事象を「情意表現装置」と名づけ具体例を示した。さらにそうした装置が応用されうる分析アプローチ,およびマクロレベルでの情意装置を,情意コミュニケーションの統合的アプローチ発展への資とするべく提示した。

「顰蹙を買う」や「影響を与える」のような「語結合」は慣用句と一般的語結合との中間に位置するものとして「機能動詞結合」と呼ばれる。その中には語結合全体の意味として,その構成動詞が他動詞であっても他動性を持たないものがある。「AヲBスル」という構文をとる機能動詞結合について言えば,その他動陛は,構成素としての名詞と動詞の性質によって決まる。すなわち(1)「動作主体Xが対象YニAヲBスル」の構文をとるものは他動性が強い。(2)「Yニ」をとらないものは動作主体X自身の意図的行為を表すものが多いが,Aに否定的評価を持つもの,あるいは心理作用を表す名詞がくる場合は他動性は弱い。(3)Aが動作主体自身の所有あるいは動作主体に属する場合は「再帰構文」となり,他動性は弱い。

これまでの研究において「のだ」は「認識モダリティ」を表すという説が一般的であった。しかし,泉子・K・メイナード(2000)は「のだ」には「情意」を表す機能があることを指摘しており,彼女の言う「情意」とはモダリティの側面からいえば「発話・伝達モダリティ」に属するものである。なぜ「のだ」に二つのモダリティが認められるのであろうか。本稿はこのようなモダリティの食い違いは「のだ」に二種の機能があることに原因すると見て,「主観的論理の「のだ」」と「情意の「のだ」」があることを示す。そして,とりわけ後者が話し手の発話伝達における心的態度を直接的に表現するものとして,その語用論的機能を観察する。

Protein denaturalization in the aqueous solution of surfactant was discussed by measuring the degree of the inhibition of invertase activity. Evaluation of the human skin-roughness was performed by the dropping method and the immersion method. A strong correlation was observed between the inhibition o invertase activity by surfactants and the skin-roughness. This screening method is an excellently valuable selecting mild surfactans for skin.