Papers - Kimura, Masaki

The Effects of Continuous and Withdrawal Voluntary Wheel Running Exercise on the Expression of Senescence-Related Genes in the Visceral Adipose Tissue of Young Mice.

Masaki Kimura, Seiya Suzuki, Atsushi Moriya, Kazuki Nogami, Ryoei Uchida, Yoshimasa Saito, Hidetsugu Saito

Int. J. Mol. Sci. 2021, 22(1), 264 (International Journal of Molecular Sciences)  22 ( 1 ) 264 - 12 2020.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  16616596

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Obesity has become a global medical problem. The upregulation of senescence-related markers in adipose tissue may cause impairment of adipose tissue and disorders of systemic me-tabolism. Weight control through diet has been found to ameliorate senescence in the adipose tissue. Exercise is also important in maintaining a healthy lifestyle, however, very few researchers have examined the relationship between senescence-related markers in adipose tissue. Dietary restriction is also reported to have a legacy effect, wherein the effects are maintained for some periods after the termination of the intervention. However, very few researchers have examined the relationship between exercise and senescence-related markers in adipose tissue. Besides, there is no study on the long-term effects of exercise. Hence, we investigated whether the exercise could change the expression of senescence-related genes in the visceral adipose tissue of young mice and whether there was a legacy effect of exercise for 10 weeks after the termination of exercise. Four-week-old male ICR mice were assigned to one of the three groups: 20 weeks of sedentary condition, 20 weeks of voluntary wheel running exercise, or 10 weeks of exercise followed by 10 weeks of sedentary condition. The mice showed decreased expression in genes related to senescence and senescence-associated secretory phenotype, such as p53, p16, and IL-6, in the visceral adipose tissue in response to exercise. These effects were maintained for 10 weeks after the mice stopped exercising. Our study is the first report that exercise reduces the expression of senescence-related genes in the visceral adipose tissue of young mice, and that exercise causes the legacy effect.

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Glucose Depletion Enhances the Stem Cell Phenotype and Gemcitabine Resistance of Cholangiocarcinoma Organoids through AKT Phosphorylation and Reactive Oxygen Species.

Yoshikawa N, Saito Y, Manabe H, Nakaoka T, Uchida R, Furukawa R, Muramatsu T, Sugiyama Y, Kimura M, Saito H.

Cancers (Basel). (Cancers)  11 ( 12 ) e1993 2019.12

Research paper (scientific journal), Joint Work, Accepted

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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions.

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Effects of combined therapy of ACE inhibitor and exercise on cardiovascular functions and morphology of the heart and kidneys in SHR.

Masato Suzuki, Noriko Hozumi, Hidefumi Waki, Masaki Kimura, Tetsuya Seino, Naoko Onuma, Daisuke Shindo.

J. Phys. Fitness Sports Med. 8 ( 5 ) 229 - 240 2019.08

Research paper (scientific journal), Joint Work, Accepted

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Coffee brew intake can prevent the reduction of lens glutathione and ascorbic acid levels in hfd-fed animals

Nakazawa Y., Ishimori N., Oguchi J., Nagai N., Kimura M., Funakoshi-Tago M., Tamura H.

Experimental and Therapeutic Medicine (Experimental and Therapeutic Medicine)  17 ( 2 ) 1420 - 1425 2019.02

ISSN  17920981

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© 2018, Spandidos Publications. All rights reserved. The lens has high concentrations of glutathione (GSH) and ascorbic acid (AsA) to maintain redox activity and prevent cataract formation, which is the leading cause of visual impairment worldwide. Metabolic syndrome is reported to be linked with a higher risk of age-associated cataract. As it was demonstrated previously that coffee consumption improved high-fat diet (HFD) -induced metabolic symptoms, it was hypothesized that coffee intake could delay the onset of obesity related-cataract; however, the effect of coffee consumption on this type of cataract remains unknown. Four-week-old male C57BL/6JJms SLC mice were divided into two groups and were provided ad libitum access to either a control diet (control groups) or a HFD (HFD groups). The control groups and HFD groups were further divided into three or four subgroups for each experiment. Coffee intake markedly reduced the increase in body weight in a roasting-time and concentration-dependent manner. Coffee consumption also prevented the HFD-induced decrease in the concentration of GSH and AsA, and treatment with pyrocatechol or caffeine also restored the reduction of antioxidant compounds. Plasma cholesterol and triglycerides were significantly higher in HFD groups; however, coffee brew or coffee constituent treatment in the HFD-fed mice group prevented elevation of these levels. Caffeine is a major coffee component and pyrocatechol is generated thought the roasting process. These results revealed that caffeine and pyrocatechol in coffee brew may be the key constituents responsible for preventing the reduction of lens GSH and AsA in HFD-fed animals.

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Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging

Uchida R, Saito Y, Nogami K, Kajiyama Y, Suzuki Y, Kawase Y, Nakaoka T, Muramatsu T, Kimura K, Saito H

Aging and Mechanisms of Disease (npj Aging and Mechanisms of Disease)  doi: 10.1038/s41514-018-0031-5 ( 1 )  2018.11

Research paper (scientific journal), Joint Work, Accepted

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© 2018, The Author(s). To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a (p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD+ intermediate. As a result, the organoids showed a higher NAD+ level, increased cell proliferative ability, activation of Lgr5 and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.

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Nrf2-mediated anti-oxidant effects contribute to suppression of non-alcoholic steatohepatitis-associated hepatocellular carcinoma in murine model

Yamada S, Kimura M, Saito Y, Saito H.

Journal of Clinical Biochemistry and Nutrition (Journal of Clinical Biochemistry and Nutrition)  63 ( 2 ) 123 - 128 2017.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09120009

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©2018 JCBN. The exact mechanisms of hepatocellular carcinoma development in nonalcoholic steatohepatitis remain unclear. In this study, we used a new class of highfat diet, which could induce hepatocellular carcinoma development without the use of general chemical carcinogens or knockout mice. We investigated the correlation between hepatocellular carcinoma and oxidative stress/anti oxidant effects after depletion of the gut microbiota by treatment with antibiotics. Mice fed with the steatohepatitisinducing high fat diet (STHD01) for 41 weeks developed hepatocellular carci noma. Antibiotictreatment in mice fed with STHD01 significantly depleted the gut microbiota and significantly ameliorated liver injury/histology. The tumor numbers of hepatocellular carcinoma were dramatically decreased by the antibioticstreatment. We analyzed the factors involved in oxidative stress and antioxidant effects. Oxidative stress was elevated in mice fed with STHD01, whereas some antioxidant factors were significantly elevated after antibiotics treatment. These results suggest that the gut microbiota is a key factor in improving oxidative stress induced by STHD01 feeding.

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Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis

Yamada S, Kamada N, Amiya T, Nakaoka T, KIMURA M, Saito Y, Ejima C, Kanai T, Saito H

BMC Gastroenterol 17 ( 1 ) 136 2017.11

Research paper (scientific journal), Joint Work, Accepted

Coffee extract inhibits adipogenesis in 3T3-L1 preadipocyes by interrupting insulin signaling through the downregulation of IRS1.

Maki C, Funakoshi-Tago M, Aoyagi R, Ueda F, KIMURA M, Kobata K, Tago K, Tamura H

PLoS One 12 ( 3 ) e0173264 2017.02

Research paper (scientific journal), Joint Work, Accepted

Cluster microRNAs miR-194 and miR-215 suppress the tumor igenicity of intestinal tumor organoids

Nakaoka T, Saito Y, Shimamoto Y, Muramatsu T, Kimura M, Kanai Y, Saito H

Cancer Sci 108 ( 4 ) 678 - 684 2017.01

Research paper (scientific journal), Joint Work, Accepted

microRNA-mediated resistance to hypoglycemia in the HepG2 human hepatoma cell line.

Ueki S, Murakami Y, Yamada S, Kimura M, Saito Y, Saito H.

BMC Cancer 16 ( 1 ) 732 - 744 2016.09

Research paper (scientific journal), Joint Work, Accepted

Inhibition of DNA methylation suppresses intestinal Tumor Organoids by inducing an Anti-Viral response.

Saito Y, Nakaoka T, Sakai K, Muramatsu T, Toshimitsu K, Kimua M, Kanai T, Sato T, Saito H.

Sci Rep 6   25311 2016.04

Research paper (scientific journal), Joint Work, Accepted

Induction of heme-oxygenase-1 (HO-1) does not enhance adiponectin production in human adipocytes: Evidence against a direct HO-1 - Adiponectin axis.

Mengliu Yang, Masaki Kimura, Choaping Ng, Jingjing He, Sahar Keshvari, Felicity J. Rose, Johanna L. Barclay, Jonathan P. Whitehead.

Molecular and Cellular Endocrinology 413   209 - 216 2015.06

Research paper (scientific journal), Joint Work, Accepted

Astaxanthin Supplementation Effects on Adipocyte Size and Lipid Profile in OLETF rats with Hyperphagia and Visceral Fat Accumulation.

Kimura M, Iida M, Yamauchi H, Suzuki M, Shibasaki T, Saito Y, Saito H.

The Journal of Functional Foods 11   114 - 120 2014.08

Research paper (scientific journal), Joint Work, Accepted

Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis.

Takaki Y, Saito Y, Takasugi A, Toshimitsu K, Yamada S, Muramatsu T, Kimura M, Sugiyama K, Suzuki H, Arai E, Ojima H, Kanai Y, Saito H.

Cancer Science 105(10)   1254 - 1260 2014.08

Research paper (scientific journal), Joint Work, Accepted

Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells.

Hibino S, Saito Y, Muramatsu T, Otani A, Kasai Y, Kimura M, Saito H.

Oncogenesis 3   e104 2014.04

Research paper (scientific journal), Accepted

Suppressive effect of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on hepatitis C virus replication.

Sato A, Saito Y, Sugiyama K, Sakasegawa N, Muramatsu T, Fukuda S, Yoneya M, Kimura M, Ebinuma H, Hibi T, Ikeda M, Kato N, Saito H.

The Journal of Cell Biochemistry 114   1987-1996 2013.03

Research paper (scientific journal), Joint Work, Accepted

Genes and molecules related to obesity and lifestyle-related disease and exercise.

Kimura M.

J Phys Fitness Sports Med 2(1)   111 - 115 2013.01

Research paper (scientific journal), Single Work, Accepted

Derangement of ghrelin secretion after long-term high-fat diet feeding in rats.

Sugiishi A, Kimura M, Kamiya R, Ueki S, Yoneya M, Saito Y, Saito H.

Hepatol Res 43(10)   1105-1114 2012.12

Research paper (scientific journal), Joint Work, Accepted

Down-regulation of EGFR Prolonged Cell Growth of Glioma but Did Not Increase the Sensitivity to Temozolomide.

Inaba N, Fujioka K, Saito H, Kimura M, Ikeda K, Inoue Y, Ishizawa S, Manome Y.

Anticancer Research 31(10)   3253-3257 2011.08

Research paper (scientific journal), Joint Work, Accepted

肥満が腎臓における尿酸輸送に関わるトランスポーターの発現量に与える影響.

浅沼すみれ、滝上裕一、細山田真、木村真規、齋藤英胤.

蛋白質と核酸代謝 35(1)   60-61 2011.05

Research paper (scientific journal), Joint Work, Accepted