Faculty Profiles - WATANABE Shogo

Papers - WATANABE Shogo

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Distribution and Incorporation of Extracellular Vesicles into Chondrocytes and Synoviocytes Reviewed

Takashi Ohtsuki, Ikumi Sato, Ren Takashita, Shintaro Kodama, Kentaro Ikemura, Gabriel Opoku, Shogo Watanabe, Takayuki Furumatsu, Hiroshi Yamada, Mitsuru Ando, Kazunari Akiyoshi, Keiichiro Nishida, Satoshi Hirohata

International Journal of Molecular Sciences 25 ( 22 ) 11942 2024.11

ベタメタゾン添加OUMS-27による細胞外小胞のマトリックス分解酵素抑制効果 Reviewed

井口和香, 佐藤生弥, 安達嘉奈子, 岩本結衣, 中村早希, 中野愛梨, ハシブ・ファルハナ, 池村健太郎, オッポク・ガブリエル, 山元修成, 渡辺彰吾, 廣畑聡

日本生化学会大会プログラム・講演要旨集 96回 [2P - 525] 2023.10

Selective autophagy associated with iron overload aggravates non-alcoholic steatohepatitis via ferroptosis. Reviewed International journal

Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Toshiaki Ohara, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Moe Fujii, Shusei Yamamoto, Shang Ran, Shogo Watanabe

Experimental biology and medicine (Maywood, N.J.) 15353702231191197 - 15353702231191197 2023.8

Language：English Publishing type：Research paper (scientific journal)

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that causes cirrhosis and hepatocellular carcinoma. Iron is an essential trace element in the body; however, excess iron can cause tissue damage and dysfunction. Iron overload is often observed in patients with NASH, and the amount of iron accumulated in the liver positively correlates with the histological severity of NASH. Ferroptosis, a novel form of iron-dependent cell death, is caused by the accumulation of lipid peroxidation and oxidative stress and is related to NASH. In addition, ferroptosis is closely related to autophagy, an intracellular self-degradation process. Although autophagy has many beneficial effects, it may also be harmful to the organism, for example, inducing ferroptosis. It is unclear whether iron overload aggravates NASH via autophagy. The aim of this research is to determine the mechanism by which iron overload induces ferroptosis via autophagy and aggravates NASH. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet for eight weeks. Iron dextran was administered to the Fe group in addition to the HFC diet. Blood analysis, histological staining, calcineurin activity assay, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and electron microscopy were performed. The results showed that iron overload promoted autophagy via nuclear translocation of transcription factor EB (TFEB) and induced ferritinophagy, which is the autophagic degradation of ferritin. In addition, the HFC diet induced lipophagy, the autophagic degradation of lipid droplets. The Fe group also exhibited promoted ferroptosis and aggravated hepatic inflammation and fibrosis. In conclusion, iron overload accelerates ferritinophagy and lipophagy, aggravating NASH pathology via ferroptosis. These findings indicate the therapeutic potential of inhibiting autophagy and ferroptosis for treating NASH.

DOI： 10.1177/15353702231191197

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Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats. Reviewed International journal

Mai Kakimoto, Moe Fujii, Ikumi Sato, Koki Honma, Hinako Nakayama, Sora Kirihara, Taketo Fukuoka, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Shusei Yamamoto, Shogo Watanabe

Journal of applied biomedicine 21 ( 2 ) 80 - 90 2023.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Xanthine oxidase (XO) generates reactive oxygen species during uric acid production. Therefore, XO inhibitors, which suppress oxidative stress, may effectively treat non-alcoholic steatohepatitis (NASH) and atherosclerosis via uric acid reduction. In this study, we examined the antioxidant effect of the XO inhibitor febuxostat on NASH and atherosclerosis in stroke-prone spontaneously hypertensive 5 (SHRSP5/Dmcr) rats. METHODS: SHRSP5/Dmcr rats were divided into three groups: SHRSP5/Dmcr + high-fat and high-cholesterol (HFC) diet [control group, n = 5], SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) [fructose group, n = 5], and SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) + febuxostat (1.0 mg/kg/day) [febuxostat group, n = 5]. Glucose and insulin resistance, blood biochemistry, histopathological staining, endothelial function, and oxidative stress markers were evaluated. RESULTS: Febuxostat reduced the plasma uric acid levels. Oxidative stress-related genes were downregulated, whereas antioxidant factor-related genes were upregulated in the febuxostat group compared with those in the fructose group. Febuxostat also ameliorated inflammation, fibrosis, and lipid accumulation in the liver. Mesenteric lipid deposition decreased in the arteries, and aortic endothelial function improved in the febuxostat group. CONCLUSIONS: Overall, the XO inhibitor febuxostat exerted protective effects against NASH and atherosclerosis in SHRSP5/Dmcr rats.

DOI： 10.32725/jab.2023.009

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Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model Reviewed

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoru Tamura, Minoru Ueda, Satoshi Hirohata, Shogo Watanabe

Canadian Journal of Physiology and Pharmacology 2023.5

Publishing type：Research paper (scientific journal) Publisher：Canadian Science Publishing

The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRβ, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRβ-specific agonist. We aimed to examine whether OBG specifically affects LXRβ in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (－) group, and (IV) OBG (+) group. All groups’ rats were intraperitoneally administered L-NAME. The L-NAME/OBG groups’ rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) groups’ rats were administered OBG, while the OBG (－) groups’ rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRβ-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.

DOI： 10.1139/cjpp-2022-0532

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SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet develop disease-induced sarcopenia as nonalcoholic steatohepatitis progresses. Reviewed International journal

Shusei Yamamoto, Koki Honma, Moe Fujii, Mai Kakimoto, Sora Kirihara, Hinako Nakayama, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Shogo Watanabe

Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 152104 - 152104 2023.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Secondary sarcopenia develops as a result of a bedridden state and illnesses, such as cachexia, liver disease, and diabetes. However, there is a lack of animal models to investigate the underlying mechanisms and potential treatments for secondary sarcopenia. Recently, secondary sarcopenia has been associated with the prognosis of nonalcoholic steatohepatitis. This study aimed to investigate whether stroke-prone spontaneously hypertensive rat 5 (SHRSP5/Dmcr) which developed severe nonalcoholic steatohepatitis by a high-fat and high-cholesterol (HFC; containing 2% cholic acid) diet is a useful model of secondary sarcopenia. METHODS: SHRSP5/Dmcr rats were divided into 6 groups fed with a Stroke-Prone (SP: normal chow) or HFC diets for different periods (4, 12, and 20 weeks), and WKY/Izm rats were divided into 2 groups fed an SP or HFC diet. Body weight, food intake, and muscle force were measured weekly for all rats. After the end of the diet period, skeletal muscle strength evoked by electrical stimulation was recorded, blood was collected, and organ weight was measured. The sera were used for biochemical analysis and the organs were used for histopathological analysis. RESULTS: SHRSP5/Dmcr rats fed an HFC diet developed nonalcoholic steatohepatitis, and their skeletal muscles, especially fast muscles, showed atrophy, indicating that muscle atrophy is aggravated by the progression of nonalcoholic steatohepatitis. In contrast, WKY/Izm rats fed an HFC diet did not exhibit sarcopenia. CONCLUSIONS: This study suggests that SHRSP5/Dmcr rats could be a useful novel model for investigate the mechanism of secondary sarcopenia disorder associated with nonalcoholic steatohepatitis.

DOI： 10.1016/j.aanat.2023.152104

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高脂肪食誘導性NASH動物モデルにおける腸内細菌叢とLeaky gutの評価 Reviewed

桐原空, 中山日菜子, 福岡威人, 本間宏基, 藤井萌, 廣畑聡, 山元修成, 渡辺彰吾

腸内細菌学雑誌 37 ( 2 ) 103 - 103 2023.4

高脂肪食が腸内細菌叢および肝臓NLRP3インフラマソームに与える影響 Reviewed

中山日菜子, 桐原空, 福岡威人, 本間宏基, 藤井萌, 廣畑聡, 山元修成, 渡辺彰吾

腸内細菌学雑誌 37 ( 2 ) 104 - 104 2023.4

Increased Glycine-conjugated and Unconjugated Bile Acid Levels Associated with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease in SHRSP5/Dmcr Rat. Reviewed

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Natsumi Akiyama, Miku Sakai, Natsuki Fukuhama, Shota Kumazaki, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe

Acta medica Okayama 77 ( 1 ) 29 - 36 2023.2

Language：English Publishing type：Research paper (scientific journal)

The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

DOI： 10.18926/AMO/64358

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Uric acid elevation by fructose overload exacerbates NASH and atherosclerosis via oxidative stress Reviewed

Fujii M, Kakimoto M, Sato I, Honma K, Kirihara S, Nakayama H, Fukuoka T, Hirohata S, Kitamori K, Ran S, Yamamoto S, Watanabe S

Current nutrition and food science 2023

非アルコール性脂肪肝炎モデル動物であるSHRSP5/Dmcrラットは二次性サルコペニアを発症する Reviewed

山元修成, 本間宏基, 藤井萌, 柿本麻衣, 桐原空, 中山日菜子, 佐藤生弥, 廣畑聡, 渡辺彰吾

日本サルコペニア・フレイル学会雑誌 6 ( Suppl. ) 180 - 180 2022.10

Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism. Reviewed International journal

Ikumi Sato, Shusei Yamamoto, Mai Kakimoto, Moe Fujii, Koki Honma, Shota Kumazaki, Mami Matsui, Hinako Nakayama, Sora Kirihara, Shang Ran, Shinichi Usui, Ryoko Shinohata, Kazuya Kitamori, Satoshi Hirohata, Shogo Watanabe

Pharmacological reports : PR 74 ( 4 ) 669 - 683 2022.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.

DOI： 10.1007/s43440-022-00380-1

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Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study. Reviewed International journal

Junko Inagaki, Airi Nakano, Omer Faruk Hatipoglu, Yuka Ooka, Yurina Tani, Akane Miki, Kentaro Ikemura, Gabriel Opoku, Ryosuke Ando, Shintaro Kodama, Takashi Ohtsuki, Hirosuke Yamaji, Shusei Yamamoto, Eri Katsuyama, Shogo Watanabe, Satoshi Hirohata

International journal of molecular sciences 23 ( 5 ) 2022.2

Language：English Publishing type：Research paper (scientific journal)

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

DOI： 10.3390/ijms23052681

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Basic characteristics between mechanomyogram and muscle force during twitch and tetanic contractions in rat skeletal muscles Reviewed

Ikumi Sato, Shusei Yamamoto, Mai Kakimoto, Moe Fujii, Koki Honma, Shota Kumazaki, Mami Matsui, Hinako Nakayama, Sora Kirihara, Shang Ran, Satoshi Hirohata, Shogo Watanabe

Journal of Electromyography and Kinesiology 62 ( 102627 ) 2022.1

A high-fat/high-cholesterol diet, but not high-cholesterol alone, increases free cholesterol and apoE-rich HDL serum levels in rats and upregulates hepatic ABCA1 expression Reviewed

Biochimie 2022.1

Glycine-conjugated and Unconjugated Bile Acid Levels Increased in SHRSP5/Dmcr Rat with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease Reviewed

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Natsumi Akiyama, Miku Sakai, Natsuki Fukuhama, Shota Kumazaki, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe

Acta Medica Okayama 2022

Osteopontin silencing attenuates bleomycin-induced murine pulmonary fibrosis by regulating epithelial-mesenchymal transition. Reviewed International journal

Omer Faruk Hatipoglu, Eyyup Uctepe, Gabriel Opoku, Hidenori Wake, Kentaro Ikemura, Takashi Ohtsuki, Junko Inagaki, Mehmet Gunduz, Esra Gunduz, Shogo Watanabe, Takashi Nishinaka, Hideo Takahashi, Satoshi Hirohata

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 139 ( 11 ) 111633 - 111633 2021.7

Language：English Publishing type：Research paper (scientific journal)

Idiopathic pulmonary fibrosis (IPF) is the most common and most deadly form of interstitial lung disease. Osteopontin (OPN), a matricellular protein with proinflammatory and profibrotic properties, plays a major role in several fibrotic diseases, including IPF; OPN is highly upregulated in patients' lung samples. In this study, we knocked down OPN in a bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model using small interfering RNA (siRNA) to determine whether the use of OPN siRNA is an effective therapeutic strategy for IPF. We found that fibrosing areas were significantly smaller in specimens from OPN siRNA-treated mice. The number of alveolar macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid was also reduced in OPN siRNA-treated mice. Regarding the expression of epithelial-mesenchymal transition (EMT)-related proteins, the administration of OPN-siRNA to BLM-treated mice upregulated E-cadherin expression and downregulated vimentin expression. Moreover, in vitro, we incubated the human alveolar adenocarcinoma cell line A549 with transforming growth factor (TGF)-β1 and subsequently transfected the cells with OPN siRNA. We found a significant upregulation of Col1A1, fibronectin, and vimentin after TGF-β1 stimulation in A549 cells. In contrast, a downregulation of Col1A1, fibronectin, and vimentin mRNA levels was observed in TGF-β1-stimulated OPN knockdown A549 cells. Therefore, the downregulation of OPN effectively reduced pulmonary fibrotic and EMT changes both in vitro and in vivo. Altogether, our results indicate that OPN siRNA exerts a protective effect on BLM-induced PF in mice. Our results provide a basis for the development of novel targeted therapeutic strategies for IPF.

DOI： 10.1016/j.biopha.2021.111633

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ポータブル腸電位計と腹部エコーを用いた腸蠕動の可視化と看護実践のイノベーション Invited Reviewed

修文大学紀要 12 1 - 13 2021.3

Low plasma apolipoprotein E-rich high-density lipoprotein levels in patients with metabolic syndrome. Reviewed International journal

Ryoko Shinohata, Yuhei Shiga, Shin-Ichiro Miura, Satoshi Hirohata, Misako Shibakura, Tomoe Ueno-Iio, Shogo Watanabe, Yujiro Arao, Shinichi Usui

Clinica chimica acta; international journal of clinical chemistry 510 531 - 536 2020.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents a small portion of plasma HDL. We recently established a method for measuring plasma apoE-rich HDL. This study aimed to investigate the relationship between metabolic syndrome (MetS) and apoE-rich HDL levels. METHODS: The apoE-rich HDL-cholesterol (HDL-C) levels and metabolic characteristics of 113 patients were analyzed. RESULTS: The MetS group (n = 58) had significantly lower apoE-rich HDL-C and a lower apoE-rich HDL-C/HDL-C ratio (apoE-HDL (%)) compared to the non-MetS group. The prevalence of MetS was increased when apoE-HDL (%) decreased. In simple regression analyses, apoE-HDL (%) was significantly inversely correlated with visceral fat area (rs = -0.370, P < 0.001) and plasma triglycerides (rs = -0.447, P < 0.001) and positively correlated with low-density lipoprotein (LDL) mean particle size (rs = 0.599, P < 0.001) and HDL mean particle size (rs = 0.512, P < 0.001). Stepwise multiple regression analysis revealed that LDL mean particle size, a component of the atherogenic lipoprotein profile, was an independent predictor of apoE-HDL (%) (adjusted R2 = 0.409). CONCLUSIONS: Plasma apoE-rich HDL levels might be a valuable indicator of MetS. These findings may help further understand HDL subfraction analysis in cardiometabolic diseases.

DOI： 10.1016/j.cca.2020.08.020

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Clinical importance of respiratory muscle fatigue in patients with cardiovascular disease Reviewed

Taya, M., Amiya, E., Hatano, M., Saito, A., Nitta, D., Maki, H., Hosoya, Y., Minatsuki, S., Tsuji, M., Sato, T., Murakami, H., Narita, K., Konishi, Y., Watanabe, S., Yokota, K., Haga, N. & Komuro, I

Medicine 99 ( 34 ) e21794 2020.8

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Papers - WATANABE Shogo