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Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

World Journal of Hepatology 2020年第7期12卷 350-362页

作者： Takayoshi Suga Ken Sato Tatsuya Ohyama Sho Matsui Takeshi Kobayashi Hiroki Tojima Norio Horiguchi Yuichi Yamazaki Satoru Kakizaki Ayaka Nishikido takashi okamura Masanobu Yamada TadahiroKitamura Toshio Uraoka Department of Gastroenterology and Hepatology Gunma University Graduate School of MedicineMaebashi 371-8511GunmaJapan Metabolic Signal Research Center Institute for Molecular and Cellular RegulationGunma UniversityMaebashi 371-8512GunmaJapan Department of Medicine and Molecular Science Gunma Graduate School of MedicineMaebashi 371-8511GunmaJapan

BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors are newly developed oral antidiabetic drugs.SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90%of the glucose filtered by the renal glomeruli.SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion.The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies.However,the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood.AIM To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice.METHODS We analyzed 8-wk-old male obese(ob/ob)mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin(3 mg/kg or 10 mg/kg)for 4 wk.We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liverhistology, immunoblotting, and reverse transcription-polymerase chain reactionanalyses were performed.RESULTSHepatic lipid accumulation was significantly ameliorated in ob/ob mice treatedwith 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective ofbody weight changes. Ipragliflozin had no appreciable effects on hepatic oxidativestress-related gene expression levels or macrophage infiltration, but significantlyreduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozinincreased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in theliver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γcoactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα),and fibroblast growth factor-21 (FGF21) were also significantly higher inipragliflozin-treated ob/ob mice than in untreated ob/ob mice.CONCLUSIONOur study suggests that the liver steatosis-ameliorating effects of ipragliflozin inob/ob mice may be

关键词： Selective sodium glucose cotransporter 2 Nonalcoholic fatty liver disease Sirtuin 1 Peroxisome proliferator-activated receptorγcoactivator 1α Peroxisome proliferator-activated receptorα Fibroblast growth factor-21

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Late-onset non-islet cell tumor hypoglycemia: A case report

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World Journal of Clinical Cases 2021年第1期9卷 163-169页

作者： Shunichi Matsumoto Eijiro Yamada Yasuyo Nakajima Naoki Yamaguchi takashi okamura Toshiki Yajima Satoshi Yoshino Kazuhiko Horiguchi Emi Ishida Masashi Yoshikawa Jun Nagaoka Sho Sekiguchi Mai Sue Shuichi Okada Izumi Fukuda Ken Shirabe Masanobu Yamada Department of Medicine and Molecular Science Gunma University Graduate School of MedicineMaebashi 371-8511GunmaJapan Division of General Thoracic Surgery Integrative Center of General SurgeryGunma University HospitalMaebashi 371-8511GunmaJapan Department of Endocrinology Diabetes and MetabolismGraduate School of Medicine Nippon Medical SchoolTokyo 1138602Japan

BACKGROUND Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia(NICTH).As NICTH is a rare lesion,the natural course of NICTH is not well understood.We report a case of NICTH that was observed 30 years before the onset of hypoglycemia.CASE SUMMARY A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination,but no further examination was undertaken because the lesion appeared benign.Thirty years after the tumor discovery,the patient was admitted to the hospital with symptoms of severe hypoglycemia,which was diagnosed as NICTH based on a complete examination.The tumor was resected and found to be a solitary fibrous mass(15.6 cm×13.7 cm×10.4 cm);thereafter,the patient’s blood glucose levels normalized and he completely recovered.CONCLUSION NICTH can have an acute onset,even if the tumor has been present and asymptomatic over a long time period.

关键词： Hypoglycemia Non-islet cell tumor hypoglycemia Blood glucose Solitary tumor Late onset Case report Insulin-like growth factor II

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Cell Origin Subtypes Predict Outcomes in Localized-Stage Diffuse Large B-Cell Lymphoma Treated with Curative Radiotherapy

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Journal of Cancer Therapy 2013年第3期4卷 475-484页

作者： Yuko Watanabe Hiroaki Suefuji Etsuyo Ogo Kensaku Sato Tadashi Nakashima takashi okamura Koichi Ohshima Naofumi Hayabuchi Biostastics Center Kurume University School of Medicine Kurume Japan Department of Hematology and Oncology Kurume University School of Medicine Kurume Japan Department of Otolaryngology Head and Neck Surgery Kurume University School of Medicine Kurume Japan Department of Pathology Kurume University School of Medicine Kurume Japan Department of Radiology Kurume University School of Medicine Kurume Japan

Diffuse large B-cell lymphoma (DLBCL) is regarded as a heterogeneous group of lymphomas. The aims of this study were to determine the clinical significance and prognostic value of different immunophenotypic profiles in localized-stage head and neck DLBCL treated with curative radiotherapy. We included 102 localized-stage head and neck DLBCL patients in this study. We classified DLBCL patients into germinal center B-cell (GCB) and non-GCB groups by immunohistochemical analysis. Statistical analysis was used to correlate the GCB and non-GCB subgroups, CD5 and Ki67 expression, B-ALPS (a modified International Prognostic Index for early stage lymphoma), chemotherapy regimen, and sex. Multivariate analysis was performed using the Cox proportional hazard regression model to compare cause-specific survival (CSS) and relapse-free rate (RFR) distributions. The cell of origin classification (GCB or non-GCB subtypes) was an independent predictor of CSS (p = 0.040) and RFR (p = 0.023). In the non-GCB group, chemotherapy with rituximab was an independent predictor of CSS. In conclusion, this study shows that the prognosis of the non-GCB group was significantly poorer than that of the GCB group, and that rituximab improved CSS in localized-stage head and neck DLBCL, especially in the non-GCB group.

关键词： GCB Non-GCB DLBCL Localized-Stage Prognosis

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Intramanchette transport during primate spermiogenesis： expression of dynein, myosin Va, motor recruiter myosin Va, VIIa-Rab27a/b interacting protein, and Rab27b in the manchette during human and monkey spermiogenesis

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Asian Journal of Andrology 2008年第4期10卷 561-568页

作者： Shinichi Hayasaka Yukihiro Terada Kichiya Suzuki Haruo Murakawa Ikuo Tachibana Tadashi Sankai takashi Murakami Nobuo Yaegashi Kunihiro okamura Department of Obstetrics and Gynecology Tohoku University School of Medicine Sendai Miyagi 980-8574 Japan Suzuki Memorial Hospital lwanuma Miyagi 989-2481 Japan Tsukuba Primate Research Center National Institute of Biomedical Innovation Tukuba Ibaraki 305-0843 Japan

Aim： To show whether molecular motor dynein on a microtubule track, molecular motor myosin Va, motor recruiter myosin Va, VIIa-Rab27a/b interacting protein （MyRIP）, and vesicle receptor Rab27b on an F-actin track were present during human and monkey spermiogenesis involving intramanchette transport （IMT）. Methods： Spermiogenic cells were obtained from three men with obstructive azoospermia and normal adult cynomolgus monkey （Macacafascieularis）. Immunocytochemical detection and reverse transcription-polymerase chain reaction （RT-PCR） analysis of the proteins were carried out. Samples were analyzed by light microscope. Results： Using RT-PCR, we found that dynein, myosin Va, MyRIP and Rab27b were expressed in monkey testis. These proteins were localized to the manchette, as shown by immunofluorescence, particularly during human and monkey spermiogenesis. Conclusion： We speculate that during primate spermiogenesis, those proteins that compose microtubule-based and actin-based vesicle transport systems are actually present in the manchette and might possibly be involved in intramanchette transport.

关键词： intramanchette transport manchette spermiogenesis

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Expression of Plectin-1 and Trichohyalin in Human Tongue Cancer Cells

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Open Journal of Stomatology 2018年第6期8卷 196-204页

作者： Isao Tamura Katsura Ueda Tetsunari Nishikawa Aiko Kamada Tomoharu okamura Yoshifumi Matsuda Kentaro Ueno Yoshihiro Yoshikawa Eisuke Domae Kazuya Tominaga Shunji Kumabe takashi Ikeo Akio Tanaka Department of Oral Anatomy School of Dentistry Osaka Dental University Hirakata Japan Department of Innovation in Dental Education School of Dentistry Osaka Dental University Hirakata Japan Department of Biochemistry School of Dentistry Osaka Dental University Hirakata Japan Department of Oral Pathology School of Dentistry Osaka Dental University Hirakata Japan Department of Pathology School of Dentistry Osaka Dental University Hirakata Japan

In basal squamous cells, plectin-1 interacts with intermediate filaments, whereas trichohyalin, which is distributed primarily in the medulla and inner root sheath cells of human hair follicles, plays a role in strengthening cells during keratinization. Although both cytoskeletal proteins occur in trace amounts in human tongue epithelial cells, there are minimal data on their expression in human tongue primary cancer cells. We therefore investigated the expression of plectin-1 and trichohyalin in human tongue epithelial cell line (DOK) and tongue cancer cell line (BICR31) using western blotting and FITC-labeled immunocytochemistry techniques. DOK and BICR31 cells were cultivated to subconfluence in Dulbecco’s Modified Eagle’s Medium containing 0.4 μg/ml of hydrocortisone and 10% fetal bovine serum, and the levels of trichohyalin and plectin-1 were determined by western blot analysis and immunocytochemical staining. Trichohyalin expression was clearly observed, with no differences between DOK and BICR31 cells. Although DOK cells expressed trace levels of plectin-1, obvious plectin-1 bands were detected in western blot analyses of BICR31 cells. Immunocytochemical staining revealed that trichohyalin and plectin-1 localize in the cytoplasm. Trichohyalin was diffusely distributed in both cell lines, and colocalization of trichohyalin and cytokeratin 1/10 was observed in almost all BICR31 cells. There were no correlations between western blot and immunocytochemical data for trichohyalin. Conversely, correlations in immunochemical reactions for plectin-1 were observed. Most DOK cells showed no localization of plectin-1, but strong reactions were detected in the cytoplasm of BICR31 cells. These results indicate that trichohyalin is expressed by cancerous tongue epithelial cells during various stages of malignancy and that plectin-1 provides an index of malignancy.

关键词： Tongue Cancer Plectin-1 Trichohyalin Diagnosis

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Dietary polyphenols and colorectal cancer risk:The Fukuoka colorectal cancer study

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World Journal of Gastroenterology 2013年第17期19卷 2683-2690页

作者： Zhen-Jie Wang Keizo Ohnaka Makiko Morita Kengo Toyomura Suminori Kono takashi Ueki Masao Tanaka Yoshihiro Kakeji Yoshihiko Maehara Takeshi okamura Koji Ikejiri Kitaroh Futami Takafumi Maekawa Yohichi Yasunami Kenji Takenaka Hitoshi Ichimiya Reiji Terasaka Department of Preventive Medicine Graduate School of Medical Sciences Kyushu University Department of Geriatric Medicine Graduate School of Medical Sciences Kyushu University Departments of Surgery and Oncology Graduate School of Medical Sciences Kyushu University Departments of Surgery and Science Graduate School of Medical Sciences Kyushu University Department of Gastroenterological Surgery National Kyushu Cancer Center Division of Surgery National Kyushu Medical Center Department of Surgery Fukuoka University Chikushi Hospital Department of Regenerative Medicine and Transplantation Faculty of Medicine Fukuoka University Division of Surgery Fukuoka City Hospital13-1 Yoshizuka-honmachi Hakata-ku Fukuoka 812-0046 Japan Division of Surgery Hamanomachi General Hospital Division of Surgery Fukuoka Red Cross Hospital

AIM:To investigate the associations between dietary intake of polyphenols and colorectal cancer. METHODS:The study subjects were derived from the Fukuoka colorectal cancer study, a community-based case-control study. The study subjects were 816 cases of colorectal cancer and 815 community-based controls. The consumption of 148 food items was assessed by a computer-assisted interview. We used the consumption of 97 food items to estimate dietary intakes of total, tea and coffee polyphenols. The Phenol-Explorer database was used for 92 food items. Of the 5 foods which were not listed in the Phenol-Explorer Database, polyphenol contents of 3 foods (sweet potatoes, satoimo and daikon) were based on a Japanese study and 2 foods (soybeans and fried potatoes) were estimated by ORAC-based polyphenol contents in the United States Department of Agriculture Database. Odds ratios (OR) and 95%CI of colorectal cancer risk according to quintile categories of intake were obtained by using logistic regression models with adjustment for age, sex, residential area, parental history of colorectal cancer, smoking, alcohol consumption, body mass index 10 years before, type of job, leisure-time physical activity and dietary intakes of calcium and n-3 polyunsaturated fatty acids.RESULTS:There was no measurable difference in total or tea polyphenol intake between cases and controls, but intake of coffee polyphenols was lower in cases than in controls. The multivariate-adjusted OR of colorectal cancer according to quintile categories of coffee polyphenols (from the first to top quintile) were 1.00 (referent), 0.81 (95%CI:0.60-1.10), 0.65 (95%CI:0.47-0.89), 0.65 (95%CI:0.46-0.89) and 0.82 (95%CI:0.60-1.10), respectively (P trend = 0.07). Similar, but less pronounced, decreases in the OR were also noted for the third and fourth quintiles of total polyphenol intake. Tea polyphenols and non-coffee polyphenols showed no association with colorectal cancer risk. The sitespecific analysis, based on 463 colon cancer cases and 340 rectal cancer case

关键词： Colorectal cancer Colon cancer Rectal cancer Polyphenols Coffee Tea

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Prophylactic lateral pelvic lymph node dissection in stage Ⅳ low rectal cancer

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World Journal of Clinical Oncology 2017年第5期8卷 412-419页

作者： Hiroshi Tamura Yoshifumi Shimada Hitoshi Kameyama Ryoma Yagi Yosuke Tajima Takuma okamura Mae Nakano Masato Nakano Masayuki Nagahashi Jun Sakata takashi Kobayashi Shin-ichi Kosugi Hitoshi Nogami Satoshi Maruyama Yasumasa Takii Toshifumi Wakai Division of Digestive and General Surgery Niigata University Graduate School of Medical and Dental Sciences Department of Digestive and General Surgery Uonuma Institute of Community MedicineNiigata University Medical and Dental Hospital Department of Surgery Niigata Cancer Center Hospital

AIM To assess the clinical significance of prophylactic lateral pelvic lymph node dissection (LPLND) in stage Ⅳ low rectal cancer.METHODS We selected 71 consecutive stage Ⅳ low rectal cancer patients who underwent primary tumor resection,and enrolled 50 of these 71 patients without clinical LPLN metastasis.The patients had distant metastasis such as liver,lung,peritoneum,and paraaortic LN.Clinical LPLN metastasis was defined as LN with a maximum diameter of 10 mm or more on preoperative pelvic computed tomography scan.All patients underwent primary tumor resection,27 patients underwent total mesorectal excision(TME) with LPLND(LPLND group),and 23 patients underwent only TME(TME group).Bilateral LPLND was performed simultaneously with primary tumor resection in LPLND group.R0 resection of both primary and metastatic sites was achieved in 20 of 50 patients.We evaluated possible prognostic factors for 5-year overall survival (OS),and compared 5-year cumulative local recurrence between the LPLND and TME groups.RESULTS For OS,univariate analyses revealed no significant benefit in the LPLND compared with the TME group (28.7% vs 17.0%,P = 0.523); multivariate analysis revealed that R0 resection was an independent prognostic factor.Regarding cumulative local recurrence,the LPLND group showed no significant benefit compared with TME group (21.4% vs 14.8%,P = 0.833).CONCLUSION Prophylactic LPLND shows no oncological benefits in patients with Stage Ⅳ low rectal cancer without clinical LPLN metastasis.

关键词： Prophylactic lateral pelvic lymph node dissection StageⅣ Low rectal cancer

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Pathophysiological and genetic analyses of Sendai rats, A new animal model of spontaneous nonobese Type 2 diabetes

Pathophysiological and genetic analyses of Sendai rats, A ne...

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中国实验动物学会第六届学术年会

作者： PEI Xianyuan , Tadashi okamura , Ichiro MIYOSHI , takashi AGUI and Noriyuki KASAI Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, Sendai, Japan. Center for Experimental Animal Science, Graduate School of Medicine, Nagoya city University, Nagoya, Japan. Laboratory for Experimental Animal Science, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan

A spontaneously diabetic rat with polyuria, polydipsia and nonobesity was discovered in an inbred colony ofLong-Evans Agouti (LEA) rats, and established as an animal model of type 2 diabetes by selective brother-sister mating using the males with high blood glucose level. We named it Sendai rat and examined the pathophysiological characteristics and genetic analyses of the model. Diabetes mellitus was observed in only males and blood glucose levels ranged between 200 - 300mg/dl at 120 min by oral glucose tolerance test (OGTT) . Plasma insulin levels of the rat were significantly lower than those of control rats. The fibrosis of the islets was observed at the age of 4 months, and deteriorated gradually with aging. The relative volume of pancreatic B cells of Sendai rats was significantly lower than that of control rats. The slight thickening of the basement membranes of glomeruli was observed from 12 months of age and nodular lesions were seen at the age of 24 months. For genetic analyses, we performed mapping quantitative Irak loci (QTLs) responsible for diabetes of Sendai rats, and identified three QTLs (Niddm/senl, Niddm/ sen2, Niddm/sen3) on Chromosomes 1, 14, 3, respectively. These results suggest that the Sendai rat could be a useful animal model for analyses of the pathogenesis and the cause of human type 2 diabetes mellitus.

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