肝線維化におけるペリオスチンの役割 : レニン・アンギオテンシン系とクロストーク

Periostin is a 90‑kDa extracellular matrix protein, which is secreted primarily from fibroblasts and is expressed in the lungs, kidneys and heart valves. Angiotensin II (AT‑II) serves pivotal roles in the pathogenesis of several diseases with accompanying fibrosis, including chronic liver diseases. AT‑II induces periostin expression by regulating transforming growth factor‑β1 (TGF‑β1)/Smad signaling during cardiac fibrosis. The aim of the present study was to investigate the interaction between AT‑II and periostin during liver fibrosis development. Fischer 344 rats were fed a choline‑deficient L‑amino‑acid (CDAA)‑defined diet for 12 weeks to simulate the development of steatohepatitis with liver fibrosis. Losartan, an AT‑II type I receptor blocker, was administered to inhibit the effect of AT‑II. The therapeutic effect of losartan on hepatic fibrosis development and on periostin expression was then evaluated. Several in vitro experiments were performed to examine the mechanisms underlying the interaction between AT‑II and periostin in activated hepatic stellate cells (Ac‑HSCs). Treatment with losartan suppressed the development of liver fibrosis induced by the CDAA diet, and reduced hepatic periostin expression. In addition, losartan treatment suppressed hepatic Ac‑HSC expansion and hepatic TGF‑β1 expression. In vitro analysis using LX2 HSC cells indicated that AT‑II can augment TGF‑β1 and collagen type I α1 mRNA expression via periostin expression, suggesting that the interaction between AT‑II and periostin may serve a role in liver fibrosis development. In conclusion, blockade of AT‑II‑induced periostin may suppress the progression of liver fibrosis development.博士（医学）・乙第1413号・平成30年3月15日Copyright: © Takeda et al. This is an open access article distributed under the terms of Creative Commons Attribution License(CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/

フルクトースの経口投与はラット脂肪性肝炎モデルにおいて腸管透過性亢進作用を介して肝線維化および肝発癌を悪化させる

Recent reports have revealed the impact of a western diet containing large amounts of fructose on the pathogenesis of non-alcoholic steatohepatitis (NASH). Fructose exacerbates hepatic inflammation in NASH by inducing increasing intestinal permeability. However, it is not clear whether fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH. The aim of this study was to investigate the effect of fructose intake on NASH in a rat model. A choline-deficient/L-amino acid diet was fed to F344 rats to induce NASH. Fructose was administrated to one group in the drinking water. The development of liver fibrosis and hepatocarcinogenesis were evaluated histologically. Oral fructose administration exacerbated liver fibrosis and increased the number of preneoplastic lesions positive for glutathione S-transferase placental form. Fructose-treated rats had significantly higher expression of hepatic genes related to toll-like receptor-signaling, suggesting that fructose consumption increased signaling in this pathway, leading to the progression of NASH. We confirmed that intestinal permeability was significantly higher in fructose-treated rats, as evidenced by a loss of intestinal tight junction proteins. Fructose exacerbated both liver fibrosis and hepatocarcinogenesis by increasing intestinal permeability. This observation strongly supports the role of endotoxin in the progression of NASH.博士（医学）・乙第1432号・令和元年9月27日Copyright © 2018 Impact Journals, LLCCopyright © Seki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The contrast media containing soft drinks for X-ray examination of the stomach

胃検診の受診者を増やし、検査を円滑に行う上で、造影剤である硫酸バリウム懸濁液の飲みにくさが障害の一つとなっている。これを改善する試みとして、懸濁液に市販の粉末清涼飲料を混入し検討したところ72.1％の人から通常のものよりも飲みやすいという回答を得た。今後、臨床的な検討を加えながら、さらに創意工夫していく必要がある。Barium sulfate suspensions are disliked to drink by many people. That is one of the obstacles to increse person who consult doctors and to have medical examinations smoothly. We mixed soft drinks into the suspensions to improve this problem. As a result they were popular among 72.1% people. We need to study about these suspensions further, adding the clinical matters

スルフォラファンの肝癌発育抑制効果および血管新生抑制効果に関する基礎的検討

Sulforaphane (SFN) exhibits inhibitory effects in different types of cancers. However, its inhibitory effect on liver cancer remains unknown. This study aimed to determine the therapeutic potential of SFN for the treatment of liver cancer and explore the functional mechanisms underlying the inhibitory effects of SFN. Water-Soluble Tetrazolium salt (WST-1) assay was performed to assess the in vitro effect of SFN on cell proliferation in the human liver cancer cell lines, HepG2 and Huh-7. The mRNA levels of Nrf2 target genes and cell cycle-related genes were determined using quantitative RT-PCR. For assessing the inhibitory effect of SFN in vivo, we injected immortalized liver cancer cells into BALB/c nude mice as a xenograft model. SFN was orally administrated daily after tumor inoculation and continued for thirty-five days until their sacrifices. Nrf2 activation, induced by SFN, was confirmed by mRNA upregulation of HO-1, MRP2, and NQO1 in both the cell lines. Significant inhibition of liver cancer cell proliferation by SFN was shown in vitro in a dose-dependent manner by the downregulation of CCND1, CCNB1, CDK1 and CDK2. In in vivo studies, the administration of SFN significantly reduced the subcutaneous tumor burdens at the end of experiments by suppressing tumor cell proliferation, confirmed by Ki67 immunohistochemical analysis. The mRNA levels of CCND1, CCNB1, CDK1 and CDK2 were also decreased in these SFNtreated xenograft tumors. Moreover, CD34 immunostaining elucidated that the intratumoral neovascularization was markedly attenuated in the SFN-treated xenograft tumors. SFN exerts inhibitory effect on human liver cancer cells with antiangiogenic activity. The earlier version of this study was presented at the meeting of AASLD Liver Learning on Oct 2017.博士（医学）・甲第707号・平成31年3月15日© The Author(s) 2018 Under License of Creative Commons Attribution 3.0 License https://creativecommons.org/licenses/by/3.0

Clinical application of the contrast media containing soft drinks for the X-ray examination of the stomach

胃X線検査の被験者を増やし、検査を円滑に行う上で造影剤である硫酸バリウム懸濁液の飲みにくさが障害の一つとなっている。これを改善する目的で、懸濁液に市販の粉末清涼飲料を混入したところ、64.2％の人が通常のものよりも飲みやすいと答えた。臨床上も造影剤の付着が悪くなったり、胃の蠕動を促進する等の問題は生じず、有用であると考えられた。Barium sulfate suspensions are disliked by many people. This is one of the obstacles to increase persons who consult doctors and to have medical examinations smoothly. We mixed soft drinks into the suspensions to improve this problem. As a result, they were popular among 64.2% people, there were not any clinical troubles that the suspensions did not stick to the mucous membrane of the stomach well, the peristalsis of the sotmach were promoted, and so on. These results suggest that the contrast media containing soft drinks is useful for the X-ray examinations of the stomach

Examination of density and mixing ratio of barium preparations, using an originally created phantom

胃Ⅹ線検査に造影剤として用いられる硫酸バリウム懸濁液の濃度を,簡便に,客観的に決定する目的で,歯科用アルギン酸塩印象材を用いて,コインの図柄を写しとったファントムを制作した｡これを使って二種類の硫酸バリウム製剤の適正濃度(PD)を調べた結果,BARITOP PとBARICON MEALを単体,若くは混合した場合には,おおよそ,PD(W/V%)=0.75C+165(ただし,CはBARICON MEALの混合比(%))となった｡また,BARICON MEALはコントラストが高く,精密検査に有利だと考えられ,BARITOP PとBARICON MEALを混合すると濃度の許容範囲が広がるため,通常の検査に都合がよいと考えられた｡更に,このファントムは簡便に作成することができ,しかも,硫酸バリウム懸濁 液との親和性も良いことから,硫酸バリウム製剤やⅩ線TV装置の評価,増感紙･フィルム系の評価等にも応用できると考えられた｡A phantom copied designs of coins was created with alginate dental impression material to establish a objective, simple and easy method for deciding density of barium sulfate suspensions which are used for stomach X-ray examination as contrast media. As a result of examining proper density (PD) of two kind of barium preparations with this phantom, in case of BARITOP P and BARICON MEAL, PD were almost shown by the next equation : PD(W/V%)=0.75C+165(C meant content of BARICON MEAL (%)). As BARICON MEAL resulted in hight contrast, it was thought to be suitable for a close examination. Mixture of BARITOP P and BARICON MEAL was thought to be suited to a routine examination becouse of wide permissible level of density. This phantom would be able to apply to the test of balium preparations, X-ray TV systems, screen/film systems and so on

肝線維化に対するファルネソイドX受容体アゴニストとジペプチジルペプチダーゼ-4阻害薬の併用効果

Aim: Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. Methods: Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro. Results: Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-β1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-β1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC. Conclusions: Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.博士（医学）・甲第737号・令和2年3月16日© 2019 The Japan Society of HepatologyThis is the peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1111/hepr.13385], which has been published in final form at [https://doi.org/10.1111/hepr.13385]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions