低用量アスピリンによる十二指腸輪状潰瘍の一例

京都府立医科大学附属北部医療センター　消化器内科京都府立医科大学消化器内科学Department of Gastroenterology and Hepatology, North Medical Center, Kyoto Prefectural University of MedicineDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine症例は74歳男性。主訴は腹痛と嘔吐。造影CTにて十二指腸下行脚の壁肥厚と狭窄を認め、上部消化管内視鏡検査では同部位に輪状潰瘍及び高度狭窄を認めた。冠動脈疾患と脳梗塞の既往から低用量アスピリン(LDA)を内服していたためLDA潰瘍と診断した。薬物治療としてボノプラザンの投与を開始し、十二指腸狭窄に対してバルーン拡張術を施行したところ、輪状潰瘍は治癒し現在も再発を認めていない。(著者抄録

アニサキス症による好酸球性肉芽腫を合併した早期胃癌の一例

京都府立医科大学附属北部医療センター　消化器内科京都府立医科大学　消化器内科京都府立医科大学附属北部医療センター　外科Department of Gastroenterology, North Medical Center,Kyoto Prefectural University of MedicineMolecular Gastro enterology and Hepatology, Kyoto Prefectural University of MedicineDepartment of Surgery, North Medical Center,Kyoto Prefectural University of Medicine症例は80代、男性。市民検診での胃透視で前庭部に異常所見を指摘され、精査加療目的に当院受診となった。上部消化管内視鏡検査では胃幽門部に30mm大の3型腫瘍を認めた。生検結果はadenocarcinoma tub2-porであった。胸腹部造影CT検査では所属リンパ節腫大・遠隔転移は認めず、術前診断:cT2N0M0 cStage Iとして手術加療を行った。最終病理診断はadenocarcinoma(por1>tub2>tub1)pT1b(SM2 0.7mm)Ly0V1aN0であり、腫瘍直下の筋層内に2mmの壊死を伴う肉芽腫を認めた。肉芽腫内には好酸球浸潤を認め、遺伝子解析の結果Anisakis simplexが検出された。その後術後経過良好で、現在再発なく、当院外科外来で経過観察されている。(著者抄録

Heme Positively Regulates the Expression of β-Globin at the Locus Control Region via the Transcriptional Factor Bach1 in Erythroid Cells

The transcription factor Bach1 hetero-dimerizes with small Maf proteins, to repress Maf recognition element (MARE) -dependent gene expression. The repressor activity of Bach1 is inhibited by the direct binding of heme. To the investigate involvement of Bach1 in the heme-dependent regulation of the expression of the β-globin gene, mouse erythroleukemia (MEL) cells were cultured with succinylacetone (SA), a specific inhibitor of heme biosynthesis, and the level of β-globin mRNA was examined. A marked decrease of β-globin mRNAin SA-treated cells was observed, and was reversed by the addition of hemin. An iron chelator, desferrioxamine, also lowered the level of β-globin mRNA. The heme-dependent expression of β-globin is a transcriptional event since the expression of the human β-globin gene promoter-reporter gene containing the micro-locus control region (μLCR) was inhibited when human erythroleukemia K562 cells and MEL cells were cultured with SA. Hemin treatment restored the decrease in promoter activity caused by SA. The control of the μLCR-β-globin promoter reporter gene by heme was dependent on DNase I-hypersensitive site 2 which contains MARE. Transient expression of Bach1 suppressed the μLCR activity, and this repressor activity was cancelled by treatment with hemin. The expression of a mutated Bach1 lacking heme-binding sites led to a loss in the heme-responsiveness of the μLCR. The MARE-binding activity of Bach1 in K562 and MEL cells increased upon SA-treatment, and the increase was diminished by the treatment with hemin. Furthermore, during erythroid differentiation of MEL cells, the MARE-binding activity of Bach1 decreased while simultaneously, the NF-E2 activity increased. Wepropose that heme positively regulates the β-globin gene expression by blocking the interaction of Bach1 with the MAREin the LCR in erythoid cells

Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1

Heme controls expression of genes involved in the synthesis of globins and heme. The mammalian transcription factor Bach1 functions as a repressor of the Maf recognition element (MARE) by forming antagonizing hetero-oligomers with the small Maf family proteins. We show here that heme binds specifically to Bach1 and regulates its DNA-binding activity. Deletion studies demonstrated that a heme-binding region of Bach1 is confined within its C-terminal region that possesses four dipeptide cysteine–proline (CP) motifs. Mutations in all of the CP motifs of Bach1 abolished its interaction with heme. The DNA-binding activity of Bach1 as a MafK hetero-oligomer was markedly inhibited by heme in gel mobility shift assays. The repressor activity of Bach1 was lost upon addition of hemin in transfected cells. These results suggest that increased levels of heme inactivate the repressor Bach1, resulting in induction of a host of genes with MAREs

Honokiol Acts as a Potent Anti-Fibrotic Agent in the Liver through Inhibition of TGF-β1/SMAD Signaling and Autophagy in Hepatic Stellate Cells

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-β (TGF-β1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-β1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-β1/SMAD signaling and autophagy in HSCs

FIB-4 Index and Diabetes Mellitus Are Associated with Chronic Kidney Disease in Japanese Patients with Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). The aim of this retrospective study was to determine the risk factors for progression of CKD in patients with biopsy-proven NAFLD including patatin-like phospholipase domain containing 3 (PNPLA3) polymorphism. A total of 344 patients with biopsy-proven NAFLD were enrolled consecutively in this study. Multivariate analysis identified males (odds ratio (OR) 5.46), age (per 1 year, OR 1.07), and FIB-4 index (≥1.30, OR 3.85) as factors associated with CKD. Of the 154 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min, 30 had a deterioration in CKD stage and 15 developed CKD after 3 years. Multivariate analysis identified diabetes mellitus (OR 2.44) as a risk factor for deterioration in CKD stage, while diabetes mellitus (OR 21.54) and baseline eGFR (per 1 mL/min OR 0.88) were risk factors for development of CKD. PNPLA3 did not affect the change in eGFR. In NAFLD patients, a high FIB-4 index was associated with CKD to increases in the index linked to reductions in eGFR. In order to prevent development of CKD, an appropriate therapy focusing on renal function is needed for NAFLD patients, especially those with diabetes

Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study's clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH-HCC treatment and prevention, and the GR-MIG6 axis is a newly defined target that can be activated by HNK and related compounds