mayuko_nutri_pathol/published_papers/52504366 Tomoyo Hara Hiroki Yamagami Ryoko Uemoto Akiko Sekine Yousuke Kaneko Kohsuke Miyataka Taiki Hori Mayuko Ichimura-Shimizu Masafumi Funamoto Takeshi Harada Tomoyuki Yuasa Shingen Nakamura Itsuro Endo Ken-Ichi Matsuoka Yutaka Kawano Koichi Tsuneyama Yasumasa Ikeda Ken-Ichi Aihara Pemafibrate Ameliorates Steatotic Liver Disease Regardless of Endothelial Dysfunction in Mice. Endothelial dysfunction contributes to the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD). Pemafibrate has been shown to ameliorate MASLD in basic and clinical studies, but it is unclear whether it is also effective in the status of endothelial dysfunction. An MASLD animal model was induced in male wild-type (WT) and endothelial nitric oxide synthase (eNOS)-deficient (eNOSKO) mice by feeding them a high-fat/cholesterol/cholate diet, and they were administered either a vehicle or pemafibrate at 0.17 mg/kg/day for 10 weeks. Although pemafibrate treatment did not change plasma lipid profiles in either WT or eNOSKO mice, pemafibrate reduced plasma AST levels in both WT and eNOSKO mice compared to the levels in the vehicle-treated mice. Histopathological analysis of the liver showed that MASLD was improved in the pemafibrate-treated groups in both WT and eNOSKO mice. Compared to vehicle treatment, pemafibrate treatment significantly reduced the expression levels of hepatic NADPH oxidase subunit genes, M1 macrophages, inflammatory-cytokine-related genes and profibrotic genes in both WT and eNOSKO mice, along with reduction in hepatic oxidative stress assessed by dihydroethidium staining and 4-hydroxynonenal protein levels. Thus, pemafibrate ameliorated MASLD with reduction in oxidative stress and inflammation even in vascular endothelial dysfunction. Antioxidants (Basel, Switzerland) 14 7 null null 20250720 10.3390/antiox14070891 40722995 mayuko_nutri_pathol/published_papers/49950403 Junji Chida Mayuko Ichimura-Shimizu Batzaya Batchuluun Khurelbaatar Bolorchimeg Koichi Tsuneyama Suehiro Sakaguchi Anti-prion Antibody Ameliorates Metabolic Dysfunction-associated Steatohepatitis in Mice Elsevier BV Cellular and Molecular Gastroenterology and Hepatology 2352-345X 101499 101499 20250300 10.1016/j.jcmgh.2025.101499 mayuko_nutri_pathol/published_papers/52443766 Orgil Jargalsaikhan Wenhua Shao Mayuko Ichimura-Shimizu Soichiro Ishimaru Takaaki Koma Masako Nomaguchi Battogtokh Chimeddorj Khongorzul Batchuluun Ganzorig Batbaatar Gankhuu Gankhuyag Saruul Gerelchuluun Minoru Irahara Masashi Akaike Koichi Tsuneyama Analysis of 69 Hepatocellular Carcinoma Cases from the National Center for Pathology in Mongolia : A Comprehensive Study of Samples Collected Nationwide. The high rate of chronic hepatitis, including hepatitis B, C and D, in Mongolia creates a large health burden of advanced liver disease. This includes liver failure and the highest incidence rate of hepatocellular carcinoma (HCC) worldwide. In the present study, we histopathologically examined 69 recent cases of HCC from the Mongolian National Center for Pathology, which collects specimens from across the country. The background liver histology of HCC exhibited a bimodal distribution, with one peak corresponding to advanced liver fibrosis and another to mild liver fibrosis. The fibrosis severity negatively correlated with age. Additionally, the frequency of poorly differentiated tumors was significantly higher in the HCC with early stage of fibrosis. A comparison of the pathological characteristics of HCC in urban and rural areas showed that poorly differentiated tumors were highly prevalent in urban areas. The characteristics of HCC in Mongolia are different from those in other countries, suggesting that the causes of liver disease are not only related to viruses but also other factors that depend on the region. This study will provide insight into what research is needed next for liver cancer control in Mongolia. J. Med. Invest. 72 : 47-53, February, 2025. The journal of medical investigation : JMI 72 1.2 47 53 20250000 10.2152/jmi.72.47 40268455 mayuko_nutri_pathol/published_papers/48537736 Masahiro Umemura Akira Honda Maho Yamashita Takeshi Chida Hidenao Noritake Kenta Yamamoto Takashi Honda Mayuko Ichimura-Shimizu Koichi Tsuneyama Teruo Miyazaki Nobuhito Kurono Patrick S C Leung M Eric Gershwin Takafumi Suda Kazuhito Kawata High-fat diet modulates bile acid composition and gut microbiota, affecting severe cholangitis and cirrhotic change in murine primary biliary cholangitis. Increasing evidence suggests that, in addition to a loss of tolerance, bile acid (BA) modulates the natural history of primary biliary cholangitis (PBC). We focused on the impacts of dietary changes on the immunopathology of PBC, along with alterations in BA composition and gut microbiota. In this study, we have taken advantage of our unique PBC model, a Cyp2c70/Cyp2a12 double knockout (DKO), which includes a human-like BA composition, and develops progressive cholangitis following immunization with the PDC-E2 mimic, 2-octynoic acid (2OA). We compared the effects of a ten-week high-fat diet (HFD) (60 % kcal from fat) and a normal diet (ND) on 2OA-treated DKO mice. Importantly, we report that 2OA-treated DKO mice fed HFD had significantly exacerbated cholangitis, leading to cirrhosis, with increased hepatic expression of Th1 cytokines/chemokines and hepatic fibrotic markers. Serum lithocholic acid (LCA) levels and the ratio of chenodeoxycholic acid (CDCA)-derived BAs to cholic acid-derived BAs were significantly increased by HFD. This was also associated with downregulated expression of key regulators of BA synthesis, including Cyp8b1, Cyp3a11, and Sult2a1. In addition, there were increases in the relative abundances of Acetatifactor and Lactococcus and decreases in Desulfovibrio and Lachnospiraceae_NK4A136_group, which corresponded to the abundances of CDCA and LCA. In conclusion, HFD and HFD-induced alterations in the gut microbiota modulate BA composition and nuclear receptor activation, leading to cirrhotic change in this murine PBC model. These findings have significant implications for understanding the progression of human PBC. Journal of autoimmunity 148 103287 103287 20240720 10.1016/j.jaut.2024.103287 39033687 mayuko_nutri_pathol/published_papers/47256394 Shun Takano Koudai Kani Kaichi Kasai Naoya Igarashi Miyuna Kato Kana Goto Yudai Matsuura Mayuko Ichimura-Shimizu Shiro Watanabe Koichi Tsuneyama Yukihiro Furusawa Yoshinori Nagai Antibiotic effects on gut microbiota modulate diet-induced metabolic dysfunction-associated steatohepatitis development in C57BL/6 mice. The potential involvement of the gut microbiota in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis has garnered increasing attention. In this study, we elucidated the link between high-fat/cholesterol/cholate-based (iHFC)#2 diet-induced MASH progression and gut microbiota in C57BL/6 mice using antibiotic treatments. Treatment with vancomycin (VCM), which targets gram-positive bacteria, exacerbated the progression of liver damage, steatosis, and fibrosis in iHFC#2-fed C57BL/6 mice. The expression levels of inflammation- and fibrosis-related genes in the liver significantly increased after VCM treatment for 8 weeks. F4/80+ macrophage abundance increased in the livers of VCM-treated mice. These changes were rarely observed in the iHFC#2-fed C57BL/6 mice treated with metronidazole, which targets anaerobic bacteria. A16S rRNA sequence analysis revealed a significant decrease in α-diversity in VCM-treated mice compared with that in placebo-treated mice, with Bacteroidetes and Firmicutes significantly decreased, while Proteobacteria and Verrucomicrobia increased markedly. Finally, VCM treatment dramatically altered the level and balance of bile acid (BA) composition in iHFC#2-fed C57BL/6 mice. Thus, the VCM-mediated exacerbation of MASH progression depends on the interaction between the gut microbiota, BA metabolism, and inflammatory responses in the livers of iHFC#2-fed C57BL/6 mice. Genes to cells : devoted to molecular & cellular mechanisms null null 20240612 10.1111/gtc.13134 38864277 mayuko_nutri_pathol/published_papers/46548742 Katsuhisa Omagari Juna Ishida Konomi Murata Ryoko Araki Mizuki Yogo Bungo Shirouchi Kazuhito Suruga Nobuko Sera Kazunori Koba Mayuko Ichimura-Shimizu Koichi Tsuneyama The Effect of Barley Bran Polyphenol-Rich Extracts on the Development of Nonalcoholic Steatohepatitis in Sprague–Dawley Rats Fed a High-Fat and High-Cholesterol Diet Oxidative stress and inflammation play a central role in the progression of nonalcoholic steatohepatitis (NASH), which can lead to liver cirrhosis. Barley bran has potential bioactivities due to its high content of functional substances, such as anthocyanins, with anti-inflammatory and anti-oxidative properties. Here, we investigated whether barley bran polyphenol-rich extracts (BP) can prevent NASH in Sprague–Dawley rats fed a high-fat and high-cholesterol diet including 1.25% or 2.5% cholesterol for 9 weeks. In the rat model of NASH with advanced hepatic fibrosis, BP prevented NASH development by ameliorating the histopathological findings of lobular inflammation. The BP also tended to attenuate serum aspartate aminotransferase level in this model. In the rat model of NASH with mild-to-moderate hepatic fibrosis, BP tended to attenuate the serum levels of transaminases. BP-dose-dependent effects were revealed for several parameters, including monocyte chemoattractant protein-1, transforming growth factor-β, and manganese superoxide dismutase gene expressions in the liver. These results suggest that BP may prevent NASH development or progression, presumably due to its anti-inflammatory and anti-oxidative properties. MDPI AG Livers 2673-4389 4 2 193 208 20240424 10.3390/livers4020015 mayuko_nutri_pathol/published_papers/46769697 Naoya Igarashi Kaichi Kasai Yuki Tada Koudai Kani Miyuna Kato Shun Takano Kana Goto Yudai Matsuura Mayuko Ichimura-Shimizu Shiro Watanabe Koichi Tsuneyama Yukihiro Furusawa Yoshinori Nagai Impacts of liver macrophages, gut microbiota, and bile acid metabolism on the differences in iHFC diet-induced MASH progression between TSNO and TSOD mice. BACKGROUND: Tsumura-Suzuki non-obese (TSNO) mice exhibit a severe form of metabolic dysfunction-associated steatohepatitis (MASH) with advanced liver fibrosis upon feeding a high-fat/cholesterol/cholate-based (iHFC) diet. Another ddY strain, Tsumura-Suzuki diabetes obese (TSOD) mice, are impaired in the progression of iHFC diet-induced MASH. AIM: To elucidate the underlying mechanisms contributing to the differences in MASH progression between TSNO and TSOD mice. METHODS: We analyzed differences in the immune system, gut microbiota, and bile acid metabolism in TSNO and TSOD mice fed with a normal diet (ND) or an iHFC diet. RESULTS: TSOD mice had more anti-inflammatory macrophages in the liver than TSNO mice under ND feeding, and were impaired in the iHFC diet-induced accumulation of fibrosis-associated macrophages and formation of histological hepatic crown-like structures in the liver. The gut microbiota of TSOD mice also exhibited a distinct community composition with lower diversity and higher abundance of Akkermansia muciniphila compared with that in TSNO mice. Finally, TSOD mice had lower levels of bile acids linked to intestinal barrier disruption under iHFC feeding. CONCLUSIONS: The dynamics of liver macrophage subsets, and the compositions of the gut microbiota and bile acids at steady state and post-onset of MASH, had major impacts on MASH development. Inflammation research : official journal of the European Histamine Research Society ... [et al.] null null 20240415 10.1007/s00011-024-01884-7 38619583 mayuko_nutri_pathol/published_papers/46205305 Mayuko Ichimura-Shimizu Khuleshwari Kurrey Misaki Miyata Takuya Dezawa Koichi Tsuneyama Masami Kojima Emerging Insights into the Role of BDNF on Health and Disease in Periphery Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to be associated with functional deficit and disease development in the brain, suggesting that BDNF is a crucial molecule for brain health. Interestingly, BDNF is also expressed in the hypothalamus in appetite and energy metabolism. Previous reports demonstrated that BDNF knockout mice exhibited overeating and obesity phenotypes remarkably. Therefore, we could raise a hypothesis that the loss of function of BDNF may be associated with metabolic syndrome and peripheral diseases. In this review, we describe our recent finding that BDNF knockout mice develop metabolic dysfunction-associated steatohepatitis and recent reports demonstrating the role of one of the BDNF receptors, TrkB-T1, in some peripheral organ functions and diseases, and would provide an insight into the role of BDNF beyond the brain. MDPI AG Biomolecules 2218-273X 14 4 444 444 20240405 10.3390/biom14040444 mayuko_nutri_pathol/published_papers/48537737 Honoka Tsunematsu Masaki Imanishi Yuka Uemura Yoshiya Higaki Miyu Morisaki Akari Katsura Licht Miyamoto Masafumi Funamoto Mayuko Ichimura-Shimizu Yuya Horinouchi Yasumasa Ikeda Koichi Tsuneyama Koichiro Tsuchiya Indigo Leaves-Induced Pulmonary Arterial Remodeling without Right Ventricular Hypertrophy in Rats. Indigo naturalis (IN), derived from the leaves of the indigo plant, is a traditional Chinese medicine that has historically been used for its anti-inflammatory properties in the treatment of various diseases, including ulcerative colitis (UC). However, long-term use of IN in UC patients is incontrovertibly associated with the onset of pulmonary arterial hypertension (PAH). To investigate the mechanisms by which IN induces PAH, we focused on the raw material of IN, indigo leaves (IL). Only the condition of long-term chronic (6 months) and high-dose (containing 5% IL in the control diet) administration of IL induced medial thickening in the pulmonary arteries without right ventricular hypertrophy in our rat model. IL administration for a month did not induce pulmonary arterial remodeling but increased endothelin-1 (ET-1) expression levels within endothelial cell (EC) layers in the lungs. Gene Expression Omnibus analysis showed that ET-1 is a key regulator of PAH and that the IL component indican and its metabolite IS induced ET-1 mRNA expression via reactive oxygen species-dependent mechanism. We identified the roles of indican and IS in ET-1 expression in ECs, which were linked to pulmonary arterial remodeling in an animal model. Biological & pharmaceutical bulletin 47 7 1350 1359 20240000 10.1248/bpb.b24-00289 39085074 mayuko_nutri_pathol/published_papers/44307285 Saya Matsuzaki Eiji Hase Hiroki Takanari Yuri Hayashi Yusaku Hayashi Haruto Oshikata Takeo Minamikawa Satoko Kimura Mayuko Ichimura-Shimizu Takeshi Yasui Masafumi Harada Koichi Tsuneyama Quantification of collagen fiber properties in alcoholic liver fibrosis using polarization-resolved second harmonic generation microscopy. Liver fibrosis is assessed mainly by conventional staining or second harmonic generation (SHG) microscopy, which can only provide collagen content in fibrotic area. We propose to use polarization-resolved SHG (PR-SHG) microscopy to quantify liver fibrosis in terms of collagen fiber orientation and crystallization. Liver samples obtained from autopsy cases with fibrosis stage of F0-F4 were evaluated with an SHG microscope, and 12 consecutive PR-SHG images were acquired while changing the polarization azimuth angle of the irradiated laser from 0° to 165° in 15° increments using polarizer. The fiber orientation angle (φ) and degree (ϱ) of collagen were estimated from the images. The SHG-positive area increased as the fibrosis stage progressed, which was well consistent with Sirius Red staining. The value of φ was random regardless of fibrosis stage. The mean value of ϱ (ϱ-mean), which represents collagen fiber crystallinity, varied more as fibrosis progressed to stage F3, and converged to a significantly higher value in F4 than in other stages. Spatial dispersion of ϱ (ϱ-entropy) also showed increased variation in the stage F3 and decreased variation in the stage F4. It was shown that PR-SHG could provide new information on the properties of collagen fibers in human liver fibrosis. Scientific reports 13 1 22100 22100 20231213 10.1038/s41598-023-48887-8 38092851 mayuko_nutri_pathol/published_papers/43743000 Mayuko Ichimura-Shimizu Masami Kojima Shingo Suzuki Misaki Miyata Yui Osaki Konomi Matsui Toshiyuki Mizui Koichi Tsuneyama Brain-derived neurotrophic factor knock-out mice develop non-alcoholic steatohepatitis. While brain-derived neurotrophic factor (BDNF), which is a growth factor associated with cognitive improvement and the alleviation of depression symptoms, is known to regulate food intake and body weight, the role of BDNF in peripheral disease is not fully understood. Here, we show that reduced BDNF expression is associated with weight gain and the chronic liver disease non-alcoholic steatohepatitis (NASH). At 10 months of age, BDNF-heterozygous (BDNF+/- ) mice developed symptoms of NASH: centrilobular/perivenular steatosis, lobular inflammation with infiltration of neutrophils, ballooning hepatocytes, and fibrosis of the liver. Obesity and higher serum levels of glucose and insulin - major pathologic features in human NASH - were dramatic. Dying adipocytes were surrounded by macrophages in visceral fat, suggesting that chronic inflammation occurs in peripheral organs. RNA sequencing (RNA-seq) studies of the liver revealed that the most significantly enriched Gene Ontology term involved fatty acid metabolic processes and the modulation of neutrophil aggregation, pathologies that well characterise NASH. Gene expression analysis by RNA-seq also support the notion that BDNF+/- mice are under oxidative stress, as indicated by alterations in the expression of the cytochrome P450 family and a reduction in glutathione S-transferase p, an antioxidant enzyme. Histopathologic phenotypes of NASH were also observed in a knock-in mouse (BDNF+/pro ), in which the precursor BDNF is inefficiently converted into the mature form of BDNF. Lastly, as BDNF reduction causes overeating and subsequent obesity, a food restriction study was conducted in BDNF+/pro mice. Pair-fed BDNF+/pro mice developed hepatocellular damage and showed infiltration of inflammatory cells, including neutrophils in the liver, despite having body weights and blood parameters that were comparable to those of controls. This is the first report demonstrating that reduced BDNF expression plays a role in the pathogenic mechanism of NASH, which is a hepatic manifestation of metabolic syndrome. © 2023 The Pathological Society of Great Britain and Ireland. The Journal of pathology null null 20231002 10.1002/path.6204 37781961 mayuko_nutri_pathol/published_papers/44312875 Nana Makiuchi Shun Takano Yuki Tada Kaichi Kasai Naoya Igarashi Koudai Kani Miyuna Kato Kana Goto Yudai Matsuura Mayuko Ichimura-Shimizu Yukihiro Furusawa Koichi Tsuneyama Yoshinori Nagai Dynamics of Liver Macrophage Subsets in a Novel Mouse Model of Non-Alcoholic Steatohepatitis Using C57BL/6 Mice. Macrophages are critical for the development of non-alcoholic steatohepatitis (NASH). Our previous findings in TSNO mouse livers showed that an iHFC (high-fat/cholesterol/cholate) diet induced liver fibrosis similar to human NASH and led to the accumulation of distinct subsets of macrophage: CD11c+/Ly6C- and CD11c-/Ly6C+ cells. CD11c+/Ly6C- cells were associated with the promotion of advanced liver fibrosis in NASH. On the other hand, CD11c-/Ly6C+ cells exhibited an anti-inflammatory effect and were involved in tissue remodeling processes. This study aimed to elucidate whether an iHFC diet with reduced cholic acid (iHFC#2 diet) induces NASH in C57BL/6 mice and examine the macrophage subsets accumulating in the liver. Histological and quantitative real-time PCR analyses revealed that the iHFC#2 diet promoted inflammation and fibrosis indicative of NASH in the livers of C57BL/6 mice. Cell numbers of Kupffer cells decreased and recruited macrophages were accumulated in the livers of iHFC#2 diet-fed C57BL/6 mice. Notably, the iHFC#2 diet resulted in the accumulation of three macrophage subsets in the livers of C57BL/6 mice: CD11c+/Ly6C-, CD11c-/Ly6C+, and CD11c+/Ly6C+ cells. However, CD11c+/Ly6C+ cells were not distinct populations in the iHFC-fed TSNO mice. Thus, differences in cholic acid content and mouse strain affect the macrophage subsets that accumulate in the liver. Biomedicines 11 10 null null 20230928 10.3390/biomedicines11102659 37893033 mayuko_nutri_pathol/published_papers/42596662 Takumi Kakimoto Masato Hosokawa Mayuko Ichimura-Shimizu Hirohisa Ogawa Yuko Miyakami Satoshi Sumida Koichi Tsuneyama Accumulation of α-synuclein in hepatocytes in nonalcoholic steatohepatitis and its usefulness in pathological diagnosis. BACKGROUNDS: Nonalcoholic steatohepatitis (NASH) is characterized by fat deposition, inflammation, and hepatocellular damage. The diagnosis of NASH is confirmed pathologically, and hepatocyte ballooning is an important finding for definite diagnosis. Recently, α-synuclein deposition in multiple organs was reported in Parkinson's disease. Since it was reported that α-synuclein is taken up by hepatocytes via connexin 32, the expression of α-synuclein in the liver in NASH is of interest. The accumulation of α-synuclein in the liver in NASH was investigated. Immunostaining for p62, ubiquitin, and α-synuclein was performed, and the usefulness of immunostaining in pathological diagnosis was examined. METHODS: Liver biopsy tissue specimens from 20 patients were evaluated. Several antibodies against α-synuclein, as well as antibodies against connexin 32, p62, and ubiquitin were used for immunohistochemical analyses. Staining results were evaluated by several pathologists with varying experience, and the diagnostic accuracy of ballooning was compared. RESULTS: Polyclonal α-synuclein antibody, not the monoclonal antibody, reacted with eosinophilic aggregates in ballooning cells. Expression of connexin 32 in degenerating cells was also demonstrated. Antibodies against p62 and ubiquitin also reacted with some of the ballooning cells. In the pathologists' evaluations, the highest interobserver agreement was obtained with hematoxylin and eosin (H&E)-stained slides, followed by slides immunostained for p62 and α-synuclein, and there were cases with different results between H&E staining and immunostaining CONCLUSION: These results indicate the incorporation of degenerated α-synuclein into ballooning cells, suggesting the involvement of α-synuclein in the pathogenesis of NASH. The combination of immunostaining including polyclonal α-synuclein may contribute to improving the diagnosis of NASH. Pathology, research and practice 247 154525 154525 20230700 10.1016/j.prp.2023.154525 37209576 mayuko_nutri_pathol/published_papers/43126985 Wenhua Shao Mayuko Ichimura-Shimizu Hirohisa Ogawa Shengjian Jin Mitsuko Sutoh Satoko Nakamura Miki Onodera Hirosuke Tawara Shunji Toyohara Ryoji Hokao Yasusei Kudo Takeshi Oya Koichi Tsuneyama Establishment of repeated liver biopsy technique in experimental mice. Biopsy is a commonly used method for determining pathological diagnoses by directly using human tissues and cells. Biopsies are widely used to determine disease progression and treatment efficacy. Although organs and tissues are usually obtained by sacrifice during animal experiments, it is theoretically possible to use the same biopsy techniques in humans. In the present study, we examined the feasibility of performing four repeated liver biopsies in a spontaneous metabolic syndrome mouse model. Even though a small number of mice died accidently, most mice were able to undergo four liver biopsies without significant adverse events. We also performed three liver biopsies in mouse liver tumor carcinogen models at 4, 8, and 12 weeks of age. In addition to the sample collected at 16 weeks of age during sacrifice, we successfully collected four liver samples from the same mice at different stages of disease progression. The application of this liver biopsy technique might make it possible for direct evaluation of pathological conditions in the same individual over time, thereby reducing the number of experimental animals. Heliyon 9 6 e16978 null 20230600 10.1016/j.heliyon.2023.e16978 37484353 mayuko_nutri_pathol/published_papers/42208321 Koudai Kani Kaichi Kasai Yuki Tada Riko Ishibashi Shun Takano Naoya Igarashi Mayuko Ichimura-Shimizu Koichi Tsuneyama Yukihiro Furusawa Yoshinori Nagai The innate immune receptor RP105 promotes metabolic syndrome by altering gut microbiota composition and intestinal barrier function Biochemical and Biophysical Research Communications null null 20230400 10.1016/j.bbrc.2023.04.068 mayuko_nutri_pathol/published_papers/42642676 Maho Yamashita Akira Honda Shin Shimoyama Masahiro Umemura Kazuyoshi Ohta Takeshi Chida Hidenao Noritake Nobuhito Kurono Mayuko Ichimura-Shimizu Koichi Tsuneyama Teruo Miyazaki Atsushi Tanaka Patrick S C Leung M Eric Gershwin Takafumi Suda Kazuhito Kawata Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis. Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC. Journal of autoimmunity 136 103027 103027 20230328 10.1016/j.jaut.2023.103027 36996700 mayuko_nutri_pathol/published_papers/42051287 Minoru Matsumoto Takuya Ohmura Yuto Hanibuchi Mayuko Ichimura-Shimizu Yasuyo Saijo Hirohisa Ogawa Ryuichiro Miyazawa Junko Morimoto Koichi Tsuneyama Mitsuru Matsumoto Takeshi Oya AIRE illuminates the feature of medullary thymic epithelial cells in thymic carcinoma. Despite the clear distinction between cortical (cTECs) and medullary thymic epithelial cells (mTECs) in physiology, the cell of origin of thymic carcinomas (TCs) and other thymic epithelial tumors remained enigmatic. We addressed this issue by focusing on AIRE, an mTEC-specific transcriptional regulator that is required for immunological self-tolerance. We found that a large proportion of TCs expressed AIRE with typical nuclear dot morphology by immunohistochemistry. AIRE expression in TCs was supported by the RNA-seq data in the TCGA-THYM database. Furthermore, our bioinformatics approach to the recent single-cell RNA-seq data on human thymi has revealed that TCs hold molecular characteristics of multiple mTEC subpopulations. In contrast, TCs lacked the gene signatures for cTECs. We propose that TCs are tumors derived from mTECs. Cancer medicine 12 8 9843 9848 20230313 10.1002/cam4.5777 36912123 mayuko_nutri_pathol/published_papers/42607681 Kaichi Kasai Naoya Igarashi Yuki Tada Koudai Kani Shun Takano Tsutomu Yanagibashi Fumitake Usui-Kawanishi Shiho Fujisaka Shiro Watanabe Mayuko Ichimura-Shimizu Kiyoshi Takatsu Kazuyuki Tobe Koichi Tsuneyama Yukihiro Furusawa Yoshinori Nagai Impact of Vancomycin Treatment and Gut Microbiota on Bile Acid Metabolism and the Development of Non-Alcoholic Steatohepatitis in Mice. The potential roles of the gut microbiota in the pathogenesis of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis (NASH), have attracted increased interest. We have investigated the links between gut microbiota and NASH development in Tsumura-Suzuki non-obese mice fed a high-fat/cholesterol/cholate-based (iHFC) diet that exhibit advanced liver fibrosis using antibiotic treatments. The administration of vancomycin, which targets Gram-positive organisms, exacerbated the progression of liver damage, steatohepatitis, and fibrosis in iHFC-fed mice, but not in mice fed a normal diet. F4/80+-recruited macrophages were more abundant in the liver of vancomycin-treated iHFC-fed mice. The infiltration of CD11c+-recruited macrophages into the liver, forming hepatic crown-like structures, was enhanced by vancomycin treatment. The co-localization of this macrophage subset with collagen was greatly augmented in the liver of vancomycin-treated iHFC-fed mice. These changes were rarely seen with the administration of metronidazole, which targets anaerobic organisms, in iHFC-fed mice. Finally, the vancomycin treatment dramatically modulated the level and composition of bile acid in iHFC-fed mice. Thus, our data demonstrate that changes in inflammation and fibrosis in the liver by the iHFC diet can be modified by antibiotic-induced changes in gut microbiota and shed light on their roles in the pathogenesis of advanced liver fibrosis. International journal of molecular sciences 24 4 null null 20230217 10.3390/ijms24044050 36835461 mayuko_nutri_pathol/published_papers/46771741 Shinichiro Yamada Yuji Morine Tetsuya Ikemoto Yu Saito Katsuki Miyazaki Mayuko Shimizu Koichi Tsuneyama Mitsuo Shimada Inhibitory effect of non-alcoholic steatohepatitis on colon cancer liver metastasis. BACKGROUND: The incidence of non-alcoholic steatohepatitis (NASH) is dramatically increasing, but the effect of NASH on colon cancer liver metastasis (CLM) is controversial. The aim of this study was to investigate the impact and mechanism of action of NASH on CLM using a western diet (WD)-fed mouse model. METHODS: Six-week-old male C57BL/6 J mice were used. They were divided into the WD group and control group with normal diet. MC38 colon cancer cells were injected into the spleen at 2, 6, 8 and 16 weeks, and mice were killed at 2 weeks after injection to evaluate hepatic steatosis, fibrosis, metastasis and mRNA/protein expression in the liver. RESULTS: Only mice fed a WD for 16 weeks showed hepatic fibrosis. These mice showed significantly higher alanine aminotransferase and total cholesterol levels compared with the control group (p < 0.05). The WD group showed significantly lower tumor number and smaller tumor diameter (p < 0.05). In the WD group, expression of SAA1, IL6, STAT3 and MMP9 mRNA in the liver was significantly lower than in the control group (p < 0.05). Serum amyloid A1 protein expression was also lower in the WD group. CONCLUSIONS: The WD-fed NASH mouse model showed an inhibitory effect on CLM. Suppressed interleukin-6/signal transducer and activator of transcription 3 signaling and serum amyloid A/matrix metalloproteinase 9 expression may affect this phenomenon. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 49 2 410 415 20230200 10.1016/j.ejso.2022.11.002 36371329 mayuko_nutri_pathol/published_papers/46548740 Katsuhisa Omagari Ayumi Maruta Natsuki Yayama Yuki Yoshida Kyoko Okamoto Bungo Shirouchi Shouhei Takeuchi Kazuhito Suruga Kazunori Koba Mayuko Ichimura-Shimizu Koichi Tsuneyama The Effects of Overnight Fasting Duration on Glucose and Lipid Metabolism in a Sprague-Dawley Rat Model of Nonalcoholic Steatohepatitis with Advanced Fibrosis. Nonalcoholic steatohepatitis (NASH) can progress to hepatic fibrosis, and is associated with cardiovascular and liver-related mortality. To understand the pathogenesis of NASH, reliable animal models of the disease are useful. In animal studies, the animals are usually fasted overnight before biospecimens are taken, but little is known about the effects of fasting. Here, we investigated the impact of overnight fasting for approximately 9 to 17 h on glucose and lipid metabolism in a Sprague-Dawley (SD) rat model of diet-induced moderate and advanced NASH in comparison to normal SD rats. Our results revealed that in the moderate NASH model rats, the fasting duration did not affect glucose and lipid metabolism, the histopathological findings, or the hepatic mRNA expression levels of genes related to lipid metabolism, cholesterol metabolism, inflammation, fibrosis, and oxidative stress. In contrast, in the normal rats, significant fasting time-dependent reductions were observed in the epididymal fat pad weight and the hepatic mRNA expression levels of adipose differentiation-related protein and heme oxygenase-1. Moreover, in the advanced NASH model rats, a significant fasting time-dependent reduction and increase were observed in the serum insulin level and mRNA expression level of alpha-smooth muscle actin, respectively. Our present results suggest that the influence of the overnight fasting duration differs among the healthy condition, moderate NASH, and advanced NASH statuses. Further studies are needed in humans to determine the appropriate overnight fasting duration for the accurate evaluation of glucose and lipid metabolism in NASH patients. Journal of nutritional science and vitaminology 69 5 357 369 20230000 10.3177/jnsv.69.357 37940576 mayuko_nutri_pathol/published_papers/42596666 Shinichiro Yamada Yuji Morine Satoru Imura Tetsuya Ikemoto Yu Saito Mayuko Shimizu Koichi Tsuneyama Mitsue Nishiyama Shiori Ishizawa Mitsuo Shimada Effect of daikenchuto (TU-100) on carcinogenesis in non-alcoholic steatohepatitis. BACKGROUND: Non-alcoholic steatohepatitis (NASH) is associated with a higher risk of hepatocellular carcinoma (HCC), and the importance of the gut?liver axis has been recognized in NASH-associated HCC. We investigated the effect of TU-100 on the intestinal microbiome and hepatocarcinogenesis in a NASH model. METHODS: Seven-week-old Tsumura Suzuki obese diabetes mice, a model that shows the spontaneous onset of NASH and HCC, were used. They were divided into a TU-100 treated group and a control group. Mice were sacrificed at 24 and 48 weeks to evaluate hepatic steatosis, fibrosis, carcinogenesis, cytokine expression, and microbiome abundance. RESULTS: At 24 weeks, the TU-100 group showed significantly lower expression of IL6, IL1B, and ACTA2 mRNA in the liver (P?<?0.05). At 48 weeks, the TU-100 group showed significantly lower levels of serum alanine aminotransferase. The TU-100 group also showed a lower rate of NASH than the control group (28% vs 72%?;?P?=?0.1). Tumor diameter was significantly smaller in the TU-100 group compared with that in the control group (P?<?0.05). Regarding the intestinal microbiome, the genera Blautia and Ruminococcus were increased in the TU-100 group (P?<?0.05), whereas Dorea and Erysipelotrichaceae were decreased in the TU-100 group (P?<?0.05). CONCLUSIONS: TU-100 regulates the intestinal microbiome and may suppress subsequent hepatocarcinogenesis in the NASH model. J. Med. Invest. 70 : 66-73, February, 2023. The journal of medical investigation : JMI 70 1.2 66 73 20230000 10.2152/jmi.70.66 37164745 mayuko_nutri_pathol/published_papers/42311485 Satoshi Sumida Mayuko Ichimura-Shimizu Yuko Miyakami Takumi Kakimoto Tomoko Kobayashi Yasuyo Saijo Minoru Matsumoto Hirohisa Ogawa Takeshi Oya Yoshimi Bando Hisanori Uehara Shu Taira Mitsuo Shimada Koichi Tsuneyama Histological and immunohistochemical analysis of epithelial cells in epidermoid cysts in intrapancreatic accessory spleen. BACKGROUND: Epidermoid cysts in intrapancreatic accessory spleen (ECIPAS) are a rare lesion. Its pathogenesis, including the origin of cystic epithelium, is not well established. We aimed to elucidate new aspects of the pathological features of ECIPAS to clarify its pathogenesis. METHODS: Six cases of ECIPAS were included in this study. As well as histopathological analysis, to elucidate the features and nature of cystic epithelial cells, immunohistochemical analysis including Pbx1 and Tlx1 and imaging mass spectrometry was performed. RESULTS: Histologically, the cysts were covered by either monolayered or multilayered epithelium. Immunohistochemistry revealed that the epithelial cells in multilayered epithelium exhibited different attributes between the basal and superficial layers. Few epithelial cells had abundant clear cytoplasm and were immunohistochemically positive for adipophilin, suggesting lipid-excreting function. The intracystic fluid contained cholesterol clefts and foamy macrophages, and imaging mass spectrometry revealed the accumulation of lipids. Immunohistochemical analysis indicated that the epithelial cells were positive for Pbx1 in some cases. CONCLUSION: Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023. The journal of medical investigation : JMI 70 1.2 251 259 20230000 10.2152/jmi.70.251 37164730 mayuko_nutri_pathol/published_papers/40726817 Ryosuke Nagatomo Haruki Kaneko Shihori Kamatsuki Mayuko Ichimura-Shimizu Naozumi Ishimaru Koichi Tsuneyama Koichi Inoue Short-chain fatty acids profiling in biological samples from a mouse model of Sjögren's syndrome based on derivatized LC-MS/MS assay. An analytical platform is required to characterize the short-chain fatty acids (SCFAs) in a mouse model of pathological immune conditions. Therefore, liquid chromatography tandem mass spectrometry combined with 2-picolylamine derivatization and a comprehensive study of SCFAs distribution based on serum, saliva, feces, liver, and brain from a mouse model of Sjögren's syndrome (SS) is performed. The design of experiments is used to achieve efficient 2-picolylamine derivatization, and optimize the reaction conditions. Twelve SCFAs are derivatized, and separated on a reversed-phase C18 column. All SCFAs show high linearity (r2 > 0.995) and intra/inter-day accuracy values from 71.6% to 115.6% (precision < 13.7%). This method was used to determine SCFAs concentrations in the serum, saliva, feces, liver, and brain of an SS model mice, and isobutyric acid, valeric acid, isovaleric acid, and 2-methylbutyric acid in liver from SS were significantly different compared with control group. Moreover, the preliminary evaluation of propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid in saliva is conducted based on the respective SS stages and are correlated with these histological scores. This analytical platform for the widely SCFAs profiling in several tissues can be a clue for studying unclear immune pathophysiology. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1210 123432 123432 20221101 10.1016/j.jchromb.2022.123432 36063699 mayuko_nutri_pathol/published_papers/42607680 Yuki Tada Kaichi Kasai Nana Makiuchi Naoya Igarashi Koudai Kani Shun Takano Hiroe Honda Tsutomu Yanagibashi Yasuharu Watanabe Fumitake Usui-Kawanishi Yukihiro Furusawa Mayuko Ichimura-Shimizu Yoshiaki Tabuchi Kiyoshi Takatsu Koichi Tsuneyama Yoshinori Nagai Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis. Macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is unclear which macrophage subsets are critically involved in the development of inflammation and fibrosis in NASH. In TSNO mice fed a high-fat/cholesterol/cholate-based diet, which exhibit advanced liver fibrosis that mimics human NASH, we found that Kupffer cells (KCs) were less abundant and recruited macrophages were more abundant, forming hepatic crown-like structures (hCLS) in the liver. The recruited macrophages comprised two subsets: CD11c+/Ly6C- and CD11c-/Ly6C+ cells. CD11c+ cells were present in a mesh-like pattern around the lipid droplets, constituting the hCLS. In addition, CD11c+ cells colocalized with collagen fibers, suggesting that this subset of recruited macrophages might promote advanced liver fibrosis. In contrast, Ly6C+ cells were present in doughnut-like inflammatory lesions, with a lipid droplet in the center. Finally, RNA sequence analysis indicates that CD11c+/Ly6C- cells promote liver fibrosis and hepatic stellate cell (HSC) activation, whereas CD11c-/Ly6C+ cells are a macrophage subset that play an anti-inflammatory role and promote tissue repair in NASH. Taken together, our data revealed changes in liver macrophage subsets during the development of NASH and shed light on the roles of the recruited macrophages in the pathogenesis of advanced fibrosis in NASH. International journal of molecular sciences 23 21 null null 20221031 10.3390/ijms232113251 36362037 mayuko_nutri_pathol/published_papers/40726851 Wenhua Shao Orgil Jargalsaikhan Mayuko Ichimura-Shimizu Qinyi Cai Hirohisa Ogawa Yuko Miyakami Kengo Atsumi Mitsuru Tomita Mitsuko Sutoh Shunji Toyohara Ryoji Hokao Yasusei Kudo Takeshi Oya Koichi Tsuneyama Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice. Male Tsumura-Suzuki Obese Diabetes (TSOD) mice, a spontaneous metabolic syndrome model, develop non-alcoholic steatohepatitis and liver tumors by feeding on a standard mouse diet. Nearly 70% of liver tumors express glutamine synthetase (GS), a marker of hepatocellular carcinoma. In contrast, approximately 30% are GS-negative without prominent nuclear or structural atypia. In this study, we examined the characteristics of the GS-negative tumors of TSOD mice. Twenty male TSOD mice were sacrificed at 40 weeks and a total of 21 tumors were analyzed by HE staining and immunostaining of GS, liver fatty acid-binding protein (L-FABP), serum amyloid A (SAA), and beta-catenin. With immunostaining for GS, six (29%) tumors were negative. Based on the histological and immunohistological characteristics, six GS-negative tumors were classified into several subtypes of human hepatocellular adenoma (HCA). One large tumor showed generally similar findings to inflammatory HCA, but contained small atypical foci with GS staining and partial nuclear beta-catenin expression suggesting malignant transformation. GS-negative tumors of TSOD mice contained features similar to various subtypes of HCA. Different HCA subtypes occurring in the same liver have been reported in humans; however, the diversity of patient backgrounds limits the ability to conduct a detailed, multifaceted analysis. TSOD mice may share similar mechanisms of HCA development as in humans. It is timely to review the pathogenesis of HCA from both genetic and environmental perspectives, and it is expected that TSOD mice will make further contributions in this regard. International journal of molecular sciences 23 19 null null 20221007 10.3390/ijms231911923 36233225 mayuko_nutri_pathol/published_papers/40726854 Mayuko Ichimura-Shimizu Shiro Watanabe Yuka Kashirajima Ami Nagatomo Hitomi Wada Koichi Tsuneyama Katsuhisa Omagari Dietary Cholic Acid Exacerbates Liver Fibrosis in NASH Model of Sprague-Dawley Rats Fed a High-Fat and High-Cholesterol Diet. BACKGROUND: Recently, we established a novel rodent model of nonalcoholic steatohepatitis (NASH) with advanced fibrosis induced by a high-fat and high-cholesterol (HFC) diet containing cholic acid (CA), which is known to cause hepatotoxicity. The present study aimed to elucidate the direct impact of dietary CA on the progression of NASH induced by feeding the HFC diet. METHODS: Nine-week-old male Sprague-Dawley rats were randomly assigned to receive a normal, HFC, or CA-supplemented (0.1%, 0.5% or 2.0%, w/w) HFC diet for 9 weeks. RESULTS: Histopathological assessment revealed that the supplementation of CA dose-dependently aggravated hepatic steatosis, inflammation, and fibrosis, reaching stage 4 cirrhosis in the 2.0% CA diet group. In contrast, the rats that were fed the HFC diet without any added CA developed mild steatosis and inflammation without fibrosis. The hepatic cholesterol content and mRNA expression involved in inflammatory response and fibrogenesis was higher in a CA dose-dependent manner. The hepatic chenodeoxycholic acid levels were higher in 2.0% CA diet group than in the control, although hepatic levels of total bile acid and CA did not increase dose-dependently with CA intake. CONCLUSION: Adding CA to the HFC diet altered bile acid metabolism and inflammatory response and triggered the development of fibrosis in the rat liver. International journal of molecular sciences 23 16 null null 20220817 10.3390/ijms23169268 36012527 mayuko_nutri_pathol/published_papers/40726844 Hirohisa Ogawa Masahiko Azuma Aya Umeno Mayuko Shimizu Kazutoshi Murotomi Yasukazu Yoshida Yasuhiko Nishioka Koichi Tsuneyama Singlet oxygen -derived nerve growth factor exacerbates airway hyperresponsiveness in a mouse model of asthma with mixed inflammation. BACKGROUND: Refractory asthma, which is caused by several factors including neutrophil infiltration is a serious complication of bronchial asthma. We previously reported that nerve growth factor (NGF) is involved in AHR. NGF-derived induction of hyperalgesia is dependent on neutrophils; however, this relationship remains unclear in respiratory disease. In this study, we examined the roles of neutrophils and NGF in refractory asthma. METHODS: Using intranasal house dust mite sensitization, we established a mouse model of asthma with mixed inflammation (Mix-in). AHR, NGF production and hyperinnervation of the lungs were examined with or without different inhibitory treatments. The levels of the singlet oxygen markers, 10- and 12-(Z,E)-hydroxyoctadecadienoic acids (HODE) in the lungs, were measured by liquid chromatography-tandem mass spectrometry. An in vitro experiment was also performed to evaluate the direct effect of singlet oxygen on NGF production. RESULTS: NGF production and hyperinnervation were higher in Mix-in mice than in conventional eosinophilic-asthmatic mice and were positively correlated with AHR. Asthmatic parameters were inhibited by NGF neutralizing Abs and myeloperoxidase (MPO) inhibition. The 10- and 12-(Z,E)-HODEs levels were increased in the lungs and were positively correlated with MPO activity and NGF production. NGF was produced by bronchial epithelial cells in vitro upon stimulation with singlet oxygen. CONCLUSIONS: Our findings suggest that neutrophil MPO-derived singlet oxygen induces increased NGF production, leading to AHR and 10- and 12-(Z,E)-HODEs production. These findings may help to develop new therapies targeting this mechanism and to establish a new biomarker for non-type 2 and refractory asthma. Allergology international : official journal of the Japanese Society of Allergology 71 3 395 404 20220700 10.1016/j.alit.2022.02.005 35346582 mayuko_nutri_pathol/published_papers/42362503 Mayuko Ichimura-Shimizu Soichiro Ishimaru Christine Yee Yan Wai Takeo Minamikawa Takaaki Tsunematsu Aiko Endo Takumi Kojima Minoru Matsumoto Tomoko Kobayashi Satoshi Sumida Takumi Kakimoto Yuko Miyakami Hirohisa Ogawa Takeshi Oya Koichi Tsuneyama Establishment of an Epicutaneously Sensitized Murine Model of Shellfish Allergy and Evaluation of Skin Condition by Raman Microscopy Applied Sciences (Switzerland) 2076-3417 12 7 null null 20220400 10.3390/app12073566 2-s2.0-85128213235 mayuko_nutri_pathol/published_papers/37820900 Katsuki Miyazaki Yu Saito Mayuko Ichimura-Shimizu Satoru Imura Tetsuya Ikemoto Shinichiro Yamada Kazunori Tokuda Yuji Morine Koichi Tsuneyama Mitsuo Shimada Defective endoplasmic reticulum stress response via X box-binding protein 1 is a major cause of poor liver regeneration after partial hepatectomy in mice with non-alcoholic steatohepatitis. BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Poor regeneration after hepatectomy in NAFLD is well recognized, but the mechanism is unclear. Endoplasmic reticulum (ER) stress plays an important role in the development of NAFLD. Here, we show that an impaired ER stress response contributes to poor liver regeneration in partially hepatectomized mice. METHODS: Non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) was induced in mice using our patented feed and 70% partial hepatectomy (PH) was performed. Mice were sacrificed 0, 4, 8, 24, or 48 hours, or 7 days after PH, and liver regeneration and the mRNA expression of ER stress markers were assessed. RESULTS: NAFLD activity score was calculated as 4-6 points for NAFL and 7 points for NASH. NASH was characterized by inflammation and high ER stress marker expression before PH. After PH, NASH mice showed poorer liver regeneration than controls. High expression of proinflammatory cytokine genes was present in NASH mice 4 hours after PH. Xbp1-s mRNA expression was high in control and NAFL mice after PH, but no higher in NASH mice. CONCLUSIONS: Dysfunction of the ER stress response might be a cause of poor liver regeneration in NASH. Journal of hepato-biliary-pancreatic sciences null null 20220324 10.1002/jhbp.1142 35325502 mayuko_nutri_pathol/published_papers/40072818 Takeo Minamikawa Eiji Hase Mayuko Ichimura-Shimizu Yuki Morimoto Akihiro Suzuki Takeshi Yasui Satoko Nakamura Akemi Tsutsui Koichi Takaguchi Koichi Tsuneyama Assessment of Ultra-Early-Stage Liver Fibrosis in Human Non-Alcoholic Fatty Liver Disease by Second-Harmonic Generation Microscopy {MDPI} {AG} International Journal of Molecular Sciences 1422-0067 23 6 3357 3357 20220320 10.3390/ijms23063357 2-s2.0-85126575411 mayuko_nutri_pathol/published_papers/40726846 Katsuhisa Omagari Miku Uchida Yumeno Tagawa Mizuki Yogo Kae Inagaki Ryoko Hongo Shouhei Takeuchi Kazuhito Suruga Kazunori Koba Mayuko Ichimura-Shimizu Koichi Tsuneyama Influence of Fasting Time on Serum and Hepatic Lipid Profiles in a Sprague-Dawley Rat Model of Nonalcoholic Steatohepatitis. Nonalcoholic steatohepatitis (NASH) is associated with several cardiovascular risk factors, including atherogenic dyslipidemia. Recently, fasting prior to lipid profile evaluation has been thought to be unnecessary for most individuals. We investigated the impact of fasting for up to 9 h on the serum and hepatic lipid profiles in Sprague-Dawley (SD) rats of dietary-induced NASH model in comparison to SD rats fed a normal diet. In both groups, fasting affected the serum and hepatic triglyceride (TG), serum free fatty acid (FFA) and leptin levels, histopathologically assessed hepatocyte ballooning, and hepatic mRNA expression levels of several genes related to lipid metabolism. In contrast, the serum adiponectin and aminotransferase levels, serum and hepatic total cholesterol contents, and liver histopathological findings of hepatic steatosis, lobular inflammation and fibrosis were not influenced by fasting. A significant fasting time-dependent reduction was seen in the serum TG level only in the normal SD rats group. Regarding the hepatic TG level, a significant fasting time-dependent increase was seen only in the NASH model rat group. A significant fasting time-dependent reduction was also seen in the serum FFA level only in the NASH model rat group. Our present results indicate that excessive fasting can be avoided before blood or hepatic tissue sampling for the evaluation of several parameters in non-NASH and/or NASH model rats. Further investigations are needed in humans to determine whether excessive fasting before blood or hepatic tissue sampling can be avoided in both healthy individuals and NASH patients. Journal of nutritional science and vitaminology 68 5 409 419 20220000 10.3177/jnsv.68.409 36310075 mayuko_nutri_pathol/published_papers/37664390 Naohiro Nakamura Katsunori Yoshida Rinako Tsuda Miki Murata Takashi Yamaguchi Kanehiko Suwa Mayuko Ichimura Koichi Tsuneyama Koichi Matsuzaki Toshiaki Nakano Junko Hirohara Toshihito Seki Kazuichi Okazaki M Eric Gershwin Makoto Naganuma Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients. INTRODUCTION: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-β/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. METHODS AND RESULTS: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. CONCLUSION: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC. Frontiers in bioscience (Landmark edition) 26 12 1480 1492 20211230 10.52586/5042 34994163 mayuko_nutri_pathol/published_papers/37641243 Mayuko Ichimura-Shimizu Takeshi Kageyama Takeshi Oya Hirohisa Ogawa Minoru Matsumoto Satoshi Sumida Takumi Kakimoto Yuko Miyakami Ryosuke Nagatomo Koichi Inoue Chunmei Cheng Koichi Tsuneyama Verification of the Impact of Blood Glucose Level on Liver Carcinogenesis and the Efficacy of a Dietary Intervention in a Spontaneous Metabolic Syndrome Model. Metabolic syndrome (MS) is a risk factor for type 2 diabetes mellitus, vascular inflammation, atherosclerosis, and renal, liver, and heart diseases. Non-alcoholic steatohepatitis (NASH) is a progressive representative liver disease and may lead to the irreversible calamities of cirrhosis and hepatocellular carcinoma. Metabolic disorders such as hyperglycemia have been broadly reported to be related to hepatocarcinogenesis in NASH; however, direct evidence of a link between hyperglycemia and carcinogenesis is still lacking. Tsumura Suzuki Obese Diabetic (TSOD) mice spontaneously develop metabolic syndrome, including obesity, insulin resistance, and NASH-like liver phenotype, and eventually develop hepatocellular carcinomas. TSOD mice provide a spontaneous human MS-like model, even with significant individual variations. In this study, we monitored mice in terms of their changes in blood glucose levels, body weights, and pancreatic and liver lesions over time. As a result, liver carcinogenesis was delayed in non-hyperglycemic TSOD mice compared to hyperglycemic mice. Moreover, at the termination point of 40 weeks, liver tumors appeared in 18 of 24 (75%) hyperglycemic TSOD mice; in contrast, they only appeared in 5 of 24 (20.8%) non-hyperglycemic mice. Next, we investigated three kinds of oligosaccharide that could lower blood glucose levels in hyperglycemic TSOD mice. We monitored the levels of blood and urinary glucose and assessed pancreatic lesions among the experimental groups. As expected, significantly lower levels of blood and urinary glucose and smaller deletions of Langerhans cells were found in TSOD mice fed with milk-derived oligosaccharides (galactooligosaccharides and lactosucrose). At the age of 24 weeks, mild steatohepatitis was found in the liver but there was no evidence of liver carcinogenesis. Steatosis in the liver was alleviated in the milk-derived oligosaccharide-administered group. Taken together, suppressing the increase in blood glucose level from a young age prevented susceptible individuals from diabetes and the onset of NAFLD/NASH, as well as carcinogenesis. Milk-derived oligosaccharides showed a lowering effect on blood glucose levels, which may be expected to prevent liver carcinogenesis. International journal of molecular sciences 22 23 null null 20211127 10.3390/ijms222312844 34884650 mayuko_nutri_pathol/published_papers/37534736 Mayuko Ichimura-Shimizu Yosuke Tsuchiyama Yuki Morimoto Minoru Matsumoto Tomoko Kobayashi Satoshi Sumida Takumi Kakimoto Takeshi Oya Hirohisa Ogawa Michiko Yamashita Satoru Matsuda Katsuhisa Omagari Shu Taira Koichi Tsuneyama A novel mouse model of non-alcoholic steatohepatitis suggests that liver fibrosis initiates around lipid-laden macrophages. Various cells such as macrophages and hepatic stellate cells interact in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), but the mechanism remains unclear. We employed a high fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis and investigate the pathogenesis of fibrosis. Two mouse strains differing in susceptibility to obesity, the susceptible strain C57BL/6J (B6) and the relatively resistant strain A/J, developed hepatic histological features of NASH including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis after 9 weeks of HFCC diet feeding. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in B6 mice. A/J mice fed the HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light visualized the Maltese cross, namely cholesterol crystals within the aggregated macrophages. Moreover, fibrosis developed in a ring-shape from the periphery of the aggregated macrophages, i.e., the starting point of fibrosis could be visualized histologically. Furthermore, matrix assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine (P-18:1 (11Z)/18:0) and phosphatidylethanolamine (18:0/20:2 (11Z, 14Z)), in aggregated macrophages in adjacent to the fibrotic lesions. In conclusion, the present HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis. The American journal of pathology null null 20211025 10.1016/j.ajpath.2021.10.002 34710382 mayuko_nutri_pathol/published_papers/34956721 Tomoko Kobayashi Mayuko Ichimura-Shimizu Takeshi Oya Hirohisa Ogawa Minoru Matsumoto Yuki Morimoto Satoshi Sumida Takumi Kakimoto Michiko Yamashita Mitsuko Sutoh Shunji Toyohara Ryoji Hokao Chunmei Cheng Koichi Tsuneyama Neonatal streptozotocin treatment rapidly causes different subtype of hepatocellular carcinoma without persistent hyperglycemia in 4CS mice fed on a normal diet. Although diabetes mellitus (DM) is a well-known risk factor for hepatocellular carcinoma (HCC), the underlying mechanisms have not yet to be defined. We previously reported that DIAR mice fed with standard murine diet developed type 1 diabetes and HCC at age of 16 weeks old with a neonatal streptozotocin treatment (n-STZ). Because DIAR mice did not manifest obesity nor develop steatohepatitis, hyperglycemia with streptozotocin trigger or streptozotocin alone might turn on the hepato-carcinogenesis. An insulin-recruitment to DIAR-nSTZ mice showed an increased frequency of HCC during the first 12 weeks of age, although the diabetic indications notably improved. To elucidate the role of hyperglycemia in hepato-carcinogenesis, we performed a head-to-head comparative study by using 4CS mice and DIAR mice with n-STZ treatment. Newborn 4CS mice and DIAR mice were divided into STZ treated group and control group. The blood glucose levels of DIAR-nSTZ mice increased at age of eight weeks, while that of 4CS-nSTZ mice were maintained in the normal range. At eight weeks old, three out of five DIAR-nSTZ mice (60%) and one out of ten 4CS-nSTZ mice (10%) developed multiple liver tumors. At age of 12 weeks old, all eight of DIAR-nSTZ mice (100%) and two of 10 4CS-nSTZ mice (20%) developed multiple liver tumors. At 16 weeks old, all animals of DIAR-nSTZ and 4CS-nSTZ mice occurred liver tumors. DIAR-nSTZ showed hyperglycemia and HCC, and 4CS-nSTZ developed HCC without hyperglycemia. These results were interpreted that the onset of HCC maybe not related to the presence or absence of hyperglycemia but nSTZ treatment. On the other hand, since the carcinogenesis of 4CS-nSTZ is delayed compared to DIAR-nSTZ, hyperglycemia may play a role in the progression of carcinogenesis. Histologically, the liver tumor appeared irregularly trabecular arrangements of hepatocytes with various degrees of nuclear atypia. By immunohistochemical analyses, all liver tumors showed positive staining of glutamine synthetase (GS), an established human HCC marker. The expression pattern of GS was divided into a strong diffuse pattern and weak patchy pattern, respectively. The liver tumor showing the weak GS-patchy pattern expressed biliary/stem markers, EpCAM, and SALL4, partially. Because 4CS-nSTZ mice did not show any metabolic complications such as gaining body weight or high blood glucose level, it is a unique animal model with a simple condition to investigate hepatic carcinogenesis by excluding other factors. Pathology, research and practice 225 153559 153559 20210721 10.1016/j.prp.2021.153559 34325313 mayuko_nutri_pathol/published_papers/34949354 Yuki Morimoto Takeshi Oya Mayuko Ichimura-Shimizu Minoru Matsumoto Hirohisa Ogawa Tomoko Kobayashi Satoshi Sumida Takumi Kakimoto Michiko Yamashita Chunmei Cheng Koichi Tsuneyama Applying Probe Electrospray Ionization Mass Spectrometry to Cytological Diagnosis: A Preliminary Study by Using Cultured Lung Cancer Cells. OBJECTIVES: Cytology and histology are 2 indispensable diagnostic tools for cancer diagnosis, which are rapidly increasing in importance with aging populations. We applied mass spectrometry (MS) as a rapid approach for swiftly acquiring nonmorphological information of interested cells. Conventional MS, which primarily rely on promoting ionization by pre-applying a matrix to cells, has the drawback of time-consuming both on data acquisition and analysis. As an emerging method, probe electrospray ionization-MS (PESI-MS) with a dedicated probe is capable to pierce sample and measure specimen in small amounts, either liquid or solid, without the requirement for sample pretreatment. Furthermore, PESI-MS is timesaving compared to the conventional MS. Herein, we investigated the capability of PESI-MS to characterize the cell types derived from the respiratory tract of human tissues. STUDY DESIGN: PESI-MS analyses with DPiMS-2020 were performed on various type of cultured cells including 5 lung squamous cell carcinomas, 5 lung adenocarcinomas, 5 small-cell carcinomas, 4 malignant mesotheliomas, and 2 normal controls. RESULTS: Several characteristic peaks were detected at around m/z 200 and 800 that were common in all samples. As expected, partial least squares-discriminant analysis of PESI-MS data distinguished the cancer cell types from normal control cells. Moreover, distinct clusters divided squamous cell carcinoma from adenocarcinoma. CONCLUSION: PESI-MS presented a promising potential as a novel diagnostic modality for swiftly acquiring specific cytological information. Acta cytologica 1 10 20210607 10.1159/000516639 34098551 mayuko_nutri_pathol/published_papers/37534739 Katsuhisa Omagari Chiaki Koba Asuka Nagata Linh Chi Thi Ngo Mayu Yamasaki Ayumi Fukuda Masahiro Yuasa Kazuhito Suruga Nobutada Inada Mayuko Ichimura-Shimizu Koichi Tsuneyama Olive leaf powder prevents nonalcoholic steatohepatitis in Sprague–Dawley rats fed a high-fat and high-cholesterol diet Clinical Nutrition Open Science 2667-2685 37 47 59 20210600 10.1016/j.nutos.2021.04.002 2-s2.0-85105746604 mayuko_nutri_pathol/published_papers/34609027 Mayuko Ichimura-Shimizu Katsuhisa Omagari Michiko Yamashita Koichi Tsuneyama Development of a novel mouse model of diet-induced nonalcoholic steatohepatitis-related progressive bridging fibrosis. Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis. Existing mouse models of NASH rarely develop diet-induced severe fibrosis. We aimed to establish a dietary model of NASH with rapid progression to fibrosis. Six-week-old male Tsumura-Suzuki obese diabetes (TSOD) mice (a model of spontaneous metabolic syndrome) and corresponding control Tsumura-Suzuki nonobese (TSNO) mice were fed a novel diet high in fat, cholesterol, and cholate (iHFC). Histologic steatohepatitis, including steatosis, inflammation, and fibrosis, were observed in both TSNO and TSOD iHFC diet-fed mice at 20 weeks of age. As compared with TSOD mice, TSNO mice developed much more severe fibrosis and reached stage 3 of bridging fibrosis within 14 weeks under the iHFC diet feeding. Perivenular/perisinusoidal pattern of fibrosis in TSNO mice resembled human NASH. Our model of NASH with advanced fibrosis by simple diet offers many advantages useful in studying the mechanism of liver fibrosis and preclinical drug testing. Bioscience, biotechnology, and biochemistry null null 20201211 10.1093/bbb/zbaa107 33620426 mayuko_nutri_pathol/published_papers/34382846 Takeo Minamikawa Mayuko Ichimura-Shimizu Hiroki Takanari Yuki Morimoto Ryosuke Shiomi Hiroki Tanioka Eiji Hase Takeshi Yasui Koichi Tsuneyama Molecular imaging analysis of microvesicular and macrovesicular lipid droplets in non-alcoholic fatty liver disease by Raman microscopy. Predominant evidence of non-alcoholic fatty liver disease (NAFLD) is the accumulation of excess lipids in the liver. A small group with NAFLD may have a more serious condition named non-alcoholic steatohepatitis (NASH). However, there is a lack of investigation of the accumulated lipids with spatial and molecular information. Raman microscopy has the potential to characterise molecular species and structures of lipids based on molecular vibration and can achieve high spatial resolution at the organelle level. In this study, we aim to demonstrate the feasibility of Raman microscopy for the investigation of NAFLD based on the molecular features of accumulated lipids. By applying the Raman microscopy to the liver of the NASH model mice, we succeeded in visualising the distribution of lipid droplets (LDs) in hepatocytes. The detailed analysis of Raman spectra revealed the difference of molecular structural features of the LDs, such as the degree of saturation of lipids in the LDs. We also found that the inhomogeneous distribution of cholesterol in the LDs depending on the histology of lipid accumulation. We visualised and characterised the lipids of NASH model mice by Raman microscopy at organelle level. Our findings demonstrated that the Raman imaging analysis was feasible to characterise the NAFLD in terms of the molecular species and structures of lipids. Scientific reports 10 1 18548 18548 20201029 10.1038/s41598-020-75604-6 33122711 mayuko_nutri_pathol/published_papers/37650359 Katsuhisa Omagari Masako Suzuta Asami Taniguchi Risa Kumamoto Yuko Koyama Ayumi Fukuda Kazuhito Suruga Mayuko Ichimura-Shimizu Koichi Tsuneyama A non-obese, diet-induced animal model of nonalcoholic steatohepatitis in Wistar/ST rats compared to Sprague-Dawley rats Clinical Nutrition Experimental 2352-9393 30 1 14 20200400 10.1016/j.yclnex.2020.03.001 2-s2.0-85082200359 mayuko_nutri_pathol/published_papers/25334841 Mayuko Ichimura Miki Masuzumi Miku Kawase Mika Sakaki Shizuka Tamaru Yasuo Nagata Kazunari Tanaka Kazuhito Suruga Koichi Tsuneyama Satoru Matsuda Katsuhisa Omagari A diet-induced Sprague-Dawley rat model of nonalcoholic steatohepatitis-related cirrhosis JOURNAL OF NUTRITIONAL BIOCHEMISTRY 1873-4847 40 62 69 20170200 10.1016/j.jnutbio.2016.10.007 27863346 mayuko_nutri_pathol/misc/52514668 梅村昌宏 本多彰 山下真帆 千田剛士 則武秀尚 山本健太 本多隆 清水真祐子 常山幸一 川田一仁 高脂肪食による胆汁酸組成と腸内微生物叢の変化は原発性胆汁性胆管炎の胆管炎所見の悪化と肝線維化進展を誘導する 日本消化器病学会雑誌(Web) 1349-7693 121 null null 20240000 mayuko_nutri_pathol/misc/52422174 宮崎克己 齋藤裕 清水真祐子 森根裕二 池本哲也 山田眞一郎 常山幸一 島田光生 小胞体ストレス応答に着目した非アルコール性脂肪肝炎の肝切除後肝再生/肝不全に関する研究 肝臓 0451-4203 65 5 null null 20240000 mayuko_nutri_pathol/misc/37559835 菊池健太郎 松本光太郎 高井敦子 清水真祐子 守時由起 常山幸一 原眞純 宮川浩 Gastrointestinal microbiome and non-alcoholic steatohepatitis. 非アルコール性脂肪肝炎(NASH)と腸内細菌 月刊糖尿病・内分泌代謝科 2435-1946 53 3 null null 20210000 mayuko_nutri_pathol/misc/34124157 常山 幸一 林 祐里 清水 真祐子 高成 広起 日下 寛貴 長谷 栄治 南川 丈夫 安井 武史 線維化の詳細な評価を可能にする新たなモダリティ SHG顕微鏡 日本法医病理学会 法医病理 1341-5395 25 2 82 82 20200100 mayuko_nutri_pathol/misc/27566077 市村 真祐子 尾矢 剛志 小川 博久 大曲 勝久 常山 幸一 非アルコール性脂肪肝炎モデルマウスにおける肝線維化発症とコレステロール貪食マクロファージの関連 (一社)日本病理学会 日本病理学会会誌 0300-9181 108 1 328 328 20190400 mayuko_nutri_pathol/misc/25334809 常山 幸一 市村 真祐子 免疫チェックポイント阻害薬による肝障害を来した4例の病理学的特徴 (一社)日本肝臓学会 肝臓 1881-3593 60 Suppl.1 A331 A331 20190400 mayuko_nutri_pathol/misc/25334796 小川 博久 吾妻 雅彦 市村 真祐子 松本 穣 尾矢 剛志 西岡 安彦 常山 幸一 気管支喘息における好中球性酸化ストレスと神経成長因子(NGF)産生増加の役割 (一社)日本病理学会 日本病理学会会誌 0300-9181 108 1 353 353 20190400 mayuko_nutri_pathol/misc/25334803 長友 涼介 福田 敦子 市村 真祐子 赤津 裕康 常山 幸一 井之上 浩一 2-ピコリルアミン誘導体化UHPLC-ESI-MS/MS法を用いた短鎖脂肪酸のマウス臓器分布解析 (公社)日本薬学会 日本薬学会年会要旨集 0918-9823 139 2 245 245 20190300 mayuko_nutri_pathol/misc/25334812 常山 幸一 市村 真祐子 尾矢 剛志 松本 穣 西辻 和親 小川 博久 肝臓病理所見のとり方とその解釈 疾患モデル動物が教えてくれること 日本法医病理学会 法医病理 1341-5395 24 2 105 105 20181200 mayuko_nutri_pathol/misc/25013206 松本光太郎 綱島弘道 安田一朗 市村真祐子 常山幸一 守時由起 大曲勝久 原眞純 宮川浩 菊池健太郎 fructooligosaccharidesによるNASH発症抑制効果 アルコールと医学生物学 36 27-28 null 20180420 mayuko_nutri_pathol/misc/25334830 市村 真祐子 大曲 勝久 常山 幸一 TSODおよびTSNOマウスにおける高脂肪・コレステロール食の長期摂取による肝臓への影響 (一社)日本病理学会 日本病理学会会誌 0300-9181 107 1 368 368 20180400 mayuko_nutri_pathol/misc/27983651 Ayumi Sugitani Mayuko Ichimura Shu Taira Hirohisa Ogawa Takaaki Tsunematsu Koichi Tsuneyama Analysis of fibrogenic roles of liver infiltrating macrophages in a novel Non-alcoholic steato-hepatitis (NASH) rat model with liver cirrhosis HEPATOLOGY 1527-3350 66 1099A 1100A 20171000 mayuko_nutri_pathol/misc/25013128 市村真祐子 常山幸一 守時由起 松本光太郎 綱島弘道 大曲勝久 菊池健太郎 異なる非アルコール性脂肪肝炎モデル間におけるフラクトオリゴ糖による肝脂肪化抑制機序の違い (一社)日本肝臓学会 肝臓 0451-4203 58 Supplement 1 A395 A395 20170420 mayuko_nutri_pathol/misc/25013104 菊池健太郎 常山幸一 市村真祐子 守時由起 松本光太郎 綱島弘道 大曲勝久 安田一朗 原眞純 宮川浩 monosodium glutamate投与によるNASHモデルマウスに対するフラクトオリゴ糖の効果 肝臓 0451-4203 58 Supplement 1 A388 null 20170420 mayuko_nutri_pathol/misc/35577826 市村 真祐子 Animal models of NASH induced by high-fat plus high-cholesterol diet コレステロール添加高脂肪飼料を用いたNASH病態モデル動物の開発 奈良女子大学家政学会 家政学研究 = Research journal of living science 0286-7036 62 1 57 61 20151000 mayuko_nutri_pathol/misc/25334774 松本 光太郎 菊池 健太郎 綱島 弘道 常山 幸一 市村 真祐子 守時 由起 大曲 勝久 宮川 浩 安田 一朗 NASHモデルマウスの腸内環境の解析 (一社)日本肝臓学会 肝臓 0451-4203 56 Suppl.2 A753 A753 20150900 mayuko_nutri_pathol/misc/25334756 TSUNASHIMA HIROMICHI 綱島弘道 KIKUCHI KENTARO 菊池健太郎 TSUNEYAMA KOICHI 常山幸一 KANEKO RENA 金子麗奈 ICHIMURA MAYUKO 市村真祐子 MORITOKI YUKI 守時由起 HARA MASUMI 原眞純 OMAGARI KATSUHISA 大曲勝久 MIYAKAWA HIROSHI 宮川浩 YASUDA ICHIRO 安田一朗 NASHにおけるIgAの病態的意義の検討 肝臓 0451-4203 56 Supplement 1 A546 null 20150420 mayuko_nutri_pathol/presentations/43840088 高野 峻 清水 真祐子 常山 幸一 長井 良憲 抗生剤投与による腸内細菌叢変化がNASHの発症・病態に与える影響の解析 (一社)日本肝臓学会 肝臓 20230400 mayuko_nutri_pathol/presentations/43840086 五十嵐 直哉 清水 真祐子 常山 幸一 長井 良憲 肝臓構成細胞に着目した非アルコール性脂肪性肝炎進展の差異に関する研究 (一社)日本肝臓学会 肝臓 20230400 mayuko_nutri_pathol/presentations/48119070 長友 涼介 金子 東暉 清水 真祐子 石丸 直澄 常山 幸一 井之上 浩一 誘導体化LC-MS/MS法を用いたシェーグレン症候群モデルマウス組織中短鎖脂肪酸プロファイル (一社)日本医用マススペクトル学会 JSBMS Letters 20220800 mayuko_nutri_pathol/presentations/43840093 葛西 海智 常山 幸一 清水 真祐子 長井 良憲 NASH線維化亢進モデルマウス"3-Fマウス"における腸内細菌叢及び胆汁酸組成の変化 (一社)日本肝臓学会 肝臓 20220400 mayuko_nutri_pathol/presentations/40711745 立花 尚太郎 小川 博久 清水 真祐子 常山 幸一 慢性気管支喘息の気道リモデリングにおけるリゾホスファチジン酸受容体の役割 (一社)日本病理学会 日本病理学会会誌 20220300 mayuko_nutri_pathol/presentations/40711743 中原 穂乃佳 清水 真祐子 小川 博久 常山 幸一 渡部 あすか NASHモデルマウスにおけるベルベリンによる肝線維化抑制効果の検討 (一社)日本病理学会 日本病理学会会誌 20220300 mayuko_nutri_pathol/presentations/40711741 石丸 漱一郎 清水 真祐子 小川 博久 常山 幸一 経皮感作食物アレルギーモデル動物の皮膚の評価におけるラマン散乱顕微鏡の応用 (一社)日本病理学会 日本病理学会会誌 20220300 mayuko_nutri_pathol/presentations/39855780 松本 穣 西條 康代 清水 真祐子 小川 博久 常山 幸一 松本 満 尾矢 剛志 胸腺癌におけるAIRE発現と胸腺髄質上皮細胞との類似性 (一社)日本病理学会 日本病理学会会誌 20220300 mayuko_nutri_pathol/presentations/40711752 リゾフォスファチジン酸は慢性気管支喘息の気道リモデリング形成に関与する(Lysophosphatidic acid is involved in the formation of airway remodeling in chronic bronchial asthma) (一社)日本病理学会 日本病理学会会誌 20211000 mayuko_nutri_pathol/presentations/40711750 柿本 拓海 清水 真祐子 小川 博久 常山 幸一 非アルコール性脂肪性肝炎の診断におけるα-synuclein免疫組織化学染色の有用性 (一社)日本病理学会 日本病理学会会誌 20211000 mayuko_nutri_pathol/presentations/37534740 西田 憲生 清水 真祐子 吾妻 雅彦 常山 幸一 赤池 雅史 オンラインPBLチュートリアルの実施から見えてきた課題 (一社)日本医学教育学会 医学教育 20210700 mayuko_nutri_pathol/presentations/37534742 長友 涼介 清水 真祐子 常山 幸一 石丸 直澄 井之上 浩一 誘導体化LC-MS/MSによる網羅的短鎖脂肪酸解析 モデルマウス病態への応用 (一社)日本医用マススペクトル学会 JSBMS Letters 20210600 mayuko_nutri_pathol/presentations/37534745 南川 丈夫 清水 真祐子 常山 幸一 肝臓研究のfrontline ラマン散乱分光法を用いた非アルコール性脂肪性肝疾患の分子構造イメージング解析 (一社)日本肝臓学会 肝臓 20210400 mayuko_nutri_pathol/presentations/35016115 宮崎 克己 齋藤 裕 清水 真祐子 森根 裕二 居村 暁 池本 哲也 山田 眞一郎 徳田 和憲 沖川 昌平 山下 祥子 常山 幸一 島田 光生 非アルコール性脂肪性肝疾患(NAFLD)における肝切除後肝再生機能不全に関する研究 小胞体ストレス応答不全の観点より (一社)日本外科学会 日本外科学会定期学術集会抄録集 20210400 mayuko_nutri_pathol/presentations/37534751 福岡 敦子 長友 涼介 清水 真祐子 石丸 直澄 常山 幸一 井之上 浩一 2-ピコリルアミン誘導体化UHPLC-ESI-MS/MSによる短鎖脂肪酸の分析法の開発 マウス唾液への応用 (公社)日本薬学会 日本薬学会年会要旨集 20210300 mayuko_nutri_pathol/presentations/37534749 小川 博久 木内 華由 清水 真祐子 常山 幸一 喘息モデルにおける脳由来神経栄養因子(BDNF)の産生とその役割 (一社)日本病理学会 日本病理学会会誌 20210300 mayuko_nutri_pathol/presentations/37534747 清水 真祐子 遠藤 亜衣子 石丸 漱一郎 小島 拓海 小川 博久 常山 幸一 モデル動物における食物アレルギーの経皮感作条件の検討 (一社)日本病理学会 日本病理学会会誌 20210300 mayuko_nutri_pathol/presentations/35031614 住田 智志 清水 真祐子 西條 康代 松本 穣 小川 博久 尾矢 剛志 坂東 良美 上原 久典 常山 幸一 膵内副脾発生類表皮嚢胞の発生機序・組織学的特徴に関する検討 (一社)日本病理学会 日本病理学会会誌 20210300 mayuko_nutri_pathol/presentations/37534755 諏訪 兼彦 山口 隆志 吉田 勝紀 村田 美樹 清水 真祐子 常山 幸一 関 寿人 岡崎 和一 非アルコール性脂肪肝炎患者のリン酸化Smadによる肝発癌のリスク評価 (一社)日本肝臓学会 肝臓 20200900 mayuko_nutri_pathol/presentations/37534754 清水 真祐子 富永 俊弼 常山 幸一 NASH線維化の定量的評価のための基礎的研究 (一社)日本肝臓学会 肝臓 20200900 mayuko_nutri_pathol/presentations/37534753 諏訪 兼彦 山口 隆志 吉田 勝紀 村田 美樹 清水 真祐子 常山 幸一 関 寿人 岡崎 和一 非アルコール性脂肪肝炎患者のリン酸化Smadによる肝発癌のリスク評価 (一社)日本肝臓学会 肝臓 20200900 mayuko_nutri_pathol/presentations/34302523 市村 真祐子 大曲 勝久 常山 幸一 実験的モデル動物作成に用いられる高脂肪・コレステロール食に含まれるコール酸のNASH病態形成への影響 (一社)日本肝臓学会 肝臓 20200400 mayuko_nutri_pathol/presentations/34186236 市村 真祐子 松本 穣 尾矢 剛志 小川 博久 常山 幸一 平 修 NASH線維化肝におけるpathogen lipidsの同定 徳島医学会 四国医学雑誌 20200400 mayuko_nutri_pathol/presentations/34186234 清水 真祐子 平 修 松本 穣 尾矢 剛志 小川 博久 常山 幸一 イメージング質量分析によるNASH線維化肝で増加する脂質の同定 (一社)日本病理学会 日本病理学会会誌 20200300 mayuko_nutri_pathol/presentations/25334808 市村 真祐子 大曲 勝久 常山 幸一 食餌摂取による高度な線維化を伴うNASHモデルマウスの開発 (一社)日本肝臓学会 肝臓 20190400 mayuko_nutri_pathol/presentations/25334800 福田 歩美 佐々尾 真鈴 浅川 惠理 成田 純令 久野 萌偉 駿河 和仁 市村 真祐子 常山 幸一 田中 一成 大曲 勝久 高脂肪・高コレステロール(HFC)食を摂取したSDラットにおける非アルコール性脂肪肝炎(NASH)発症の検討 (公社)日本栄養・食糧学会 日本栄養・食糧学会大会講演要旨集 20190400 mayuko_nutri_pathol/presentations/25334799 飯田 綾香 甲斐 瑠衣子 倉貫 早智 市村 真祐子 常山 幸一 中村 強 C57BL/6Jマウスを用いたNAFLD/NASH発症モデルの作製法の検討 (公社)日本栄養・食糧学会 日本栄養・食糧学会大会講演要旨集 20190400 mayuko_nutri_pathol/presentations/25334798 市村 真祐子 大曲 勝久 常山 幸一 線維化を伴いうる非アルコール性脂肪肝炎を呈する食事誘導モデルマウスの確立 (公社)日本栄養・食糧学会 日本栄養・食糧学会大会講演要旨集 20190400 mayuko_nutri_pathol/presentations/40711778 杉谷 鮎美 高橋 立成 甲斐 幸樹 市村 真祐子 平 修 川口 誠 小川 博久 常松 貴明 常山 幸一 非アルコール性脂肪肝炎線維化モデル動物を用いた肝臓のマクロファージの集簇巣と線維化との関連性の検討 (一社)日本病理学会 日本病理学会会誌 20170300