Takeshi Iwasa, Toshiya Matsuzaki, Yiliyasi Mayila, Rie Yanagihara, Yuri Yamamoto, Takako Kawakita, Akira Kuwahara and Minoru Irahara : Oxytocin treatment reduced food intake and body fat and ameliorated obesity in ovariectomized female rats., Neuropeptides, Vol.75, 49-57, 2019.
(Summary)
Recent studies have shown that oxytocin reduces food intake and body weight gain and promotes lipolysis in some species, including humans. Interestingly, these effects of oxytocin are more marked in obese individuals. Although the menopausal loss of ovarian function induces increased visceral adiposity and some metabolic disorders, no safe medical interventions for these conditions have been established. In this study, we evaluated the effects of oxytocin on appetite, body weight, and fat mass in ovariectomized rats. Six-day oxytocin treatment attenuated cumulative food intake and body weight gain, and reduced visceral and subcutaneous fat weight and adipocyte cell area in ovariectomized rats. Blood examinations indicated that 6-day oxytocin treatment did not alter renal or hepatic functions. Instead, it might prevent ovariectomy-induced liver damage. In addition, acute oxytocin treatment did not affect body temperature or locomotor activity. These results indicate that oxytocin might be useful for treating or preventing menopause-induced metabolic disorders, without causing any adverse effects.
Kana Kasai, Takeshi Katou, Yuri Kadota, Otgontsetseg Erdenebayar, Kaoru Keyama, Takako Kawakita, Kanako Yoshida, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Intraperitoneal administration of activin A promotes development of endometriotic lesions in a mouse model of endometriosis., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 123-127, 2019.
(Summary)
This study aimed to investigate the effect of intraperitoneal administration of activin on the occurrence of endometriosis using a mouse model of endometriosis. A mouse model of endometriosis was prepared by intraperitoneally administering endometrial tissue and blood collected from donor mice to C57BL/6J 7-8- week-old recipient mice. A total of 400 μg of activin A was intraperitoneally administered to model mice in the activin group for 5 days. Intraperitoneal endometriotic lesions were confirmed macroscopically and IL-6 and TNF-α levels in washed ascites were measured by ELISA. Endometriotic lesions were observed in all mice. In the activin group, the maximum diameter of endometriotic lesions was significantly larger than that in control group (4.7?1.3 vs 2.9?0.9 mm, p?0.01). The total area of the lesion was also significantly higher in the activin group than in the control group (21.1?9.9 vs 8.8?5.4 mm,p?0.01). Furthermore, IL-6 and TNF-α levels in ascites were significantly higher in the activin group than in the control group (IL-6 : 85.8?15.3 vs 75.1?19.3 pg/ml, p?0.05 ; TNF-α : 629.8?15.4 vs 605.9?11.4 pg/ml, p?0.05). Activin promotes occurrence of endometriosis. Inflammatory cytokines are also elevated by activin administration,suggesting that they may contribute to progression of endometriosis J. Med. Invest. 66 : 123-127, February, 2019.
Ayuka Mineda, Masato Nishimura, Tomohiro Kagawa, Eri Takiguchi, Takako Kawakita, Akiko Abe and Minoru Irahara : Resveratrol suppresses proliferation and induces apoptosis of uterine sarcoma cells by inhibiting the Wnt signaling pathway., Experimental and Therapeutic Medicine, Vol.17, No.3, 2242-2246, 2019.
(Summary)
Resveratrol, a natural product and peroxisome proliferator-activated receptor (PPAR) agonist, has been reported to exert anti-cancer effects in several tumor models. A previous study by our group reported that prostaglandin J2, a PPARγ ligand, inhibited cell proliferation in a uterine sarcoma cell line. The aim of the present study was to investigate the role of the Wnt signaling pathway in resveratrol-induced apoptosis and inhibition of cell proliferation in the MES-SA human uterine sarcoma cell line. A WST-1 assay demonstrated that resveratrol inhibited cell proliferation in the MES-SA cell line, and flow cytometry revealed that the number of apoptotic cells increased in a resveratrol dose-dependent manner. The mechanisms underlying these effects of resveratrol were speculated to involve the expression of β-catenin and its target gene, c-myc, which were examined using western blot analysis. The results revealed a dose-dependent downregulation of this β-catenin and c-myc. This effect was blunted by a pharmacological inhibitor of glycogen synthase kinase 3β. Therefore, it is likely that resveratrol inhibited the cell proliferation and increased the number of apoptotic cells, at least partially, via the Wnt signaling pathway. The present results suggest that resveratrol is a potential candidate for the treatment of uterine sarcoma.
Kaoru Keyama, Takeshi Katou, Yuri Kadota, Otgontsetseg Erdenebayar, Kana Kasai, Takako Kawakita, Anna Tani, Sumika Matsui, Takeshi Iwasa, Kanako Yoshida, Masahiko Maegawa, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Lipopolysaccharide promotes early endometrial-peritoneal interactions in a mouse model of endometriosis., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 70-74, 2019.
(Summary)
The aims of this study were to clarify the effects of lipopolysaccharide (LPS) on the early development of endometriosis and on the production of cytokines and chemokines in the murine peritoneal cavity. Endometriotic lesions were induced in C57BL/6J adult female mice by intraperitoneal injection of endometrial fragments plus blood or endometrial fragments plus blood with LPS. On day 7, endometriotic lesions were assessed by gross and microscopic evaluations. Time-dependent changes in the secretion of TNF-α,IL-6,and CXCL2/MIP-2 in peritoneal lavage fluid after the intraperitoneal injection of LPS (50 µg/body) were measured by their respective enzyme-linked immunosorbent assays. The areas of endometriotic lesions in the LPS group (10.8 8.6 mm) were significantly larger than those in the control group (3.1 3.7 mm).The levels of TNF-α and IL-6 peaked within 2 hours and the level of MIP-2 reached a maximum on day 1 after the injection of LPS. LPS promotes development of the early stages of murine endometriotic lesions. J. Med. Invest. 66 : 70-74, February, 2019.
Eri Takiguchi, Masato Nishimura, Ayuka Mineda, Takako Kawakita, Akiko Abe and Minoru Irahara : Growth inhibitory effect of the Src inhibitor dasatinib in combination with anticancer agents on uterine cervical adenocarcinoma cells., Experimental and Therapeutic Medicine, Vol.14, No.5, 4293-4299, 2017.
(Summary)
Uterine cervical adenocarcinoma has a poor clinical prognosis when compared with squamous cell carcinoma. Therefore, the development of new treatment strategies for uterine cervical adenocarcinoma is necessary. Src is a proto-oncogene that is important in cancer progression. Dasatinib is a Src inhibitor that has been reported to be effective when used in combination with anticancer drugs. The present study aimed to confirm Src expression in human cervical adenocarcinoma cell lines and to determine the mechanism underlying the inhibitory effect of dasatinib on Src signaling . Western blot analysis was performed to investigate Src expression in cervical adenocarcinoma cell lines (HeLa and TCO-2 cells). The cells were cultured for 48 h with the addition of different concentrations of anticancer drugs (paclitaxel or oxaliplatin). Viable cell count was measured using a colorimetric (WST-1) assay. The concentrations of anticancer agents were fixed according to the results obtained, and the same experiments were performed using the drugs in combination with dasatinib at various concentrations to determine the concentrations that significantly affected the number of viable cells. The presence or absence of apoptosis was investigated using a caspase-3/7 assay. Signal transduction in each cell line was examined using western blotting. Src was activated in the two cell lines, and cell proliferation was significantly suppressed by each anticancer drug in combination with 10 µM dasatinib. Caspase-3/7 activity was also increased and Src signaling was suppressed by each anticancer drug in combination with dasatinib. In conclusion, Src is overexpressed in cervical adenocarcinoma cell lines, and dasatinib inhibits intracellular Src signaling and causes apoptosis. The results of the present study suggest that Src may be targeted in novel therapeutic strategies for cervical adenocarcinoma.
Takako Kawakita, Masato Nishimura, Eri Takiguchi, Akiko Abe and Minoru Irahara : Cytotoxic effects of 15-deoxy-Δ12,14-prostaglandin J2 alone and in combination with dasatinib against uterine sarcoma ., Experimental and Therapeutic Medicine, Vol.13, No.6, 2939-2945, 2017.
(Summary)
Effective chemotherapeutic strategies for uterine sarcoma are lacking; existing therapies achieve poor response rates. Previous studies have identified the prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) as a potential anticancer treatment; however, its effectiveness in uterine sarcoma has not been examined. Furthermore, the molecular mechanisms underlying the cytotoxic mechanism of 15d-PGJ2 remain unclear. Here, we evaluated the effects of 15d-PGJ2 alone and in combination with the tyrosine kinas inhibitor (TKI) dasatinib in uterine sarcoma cell lines (MES-SA, MES-SA/DX5 and SKN). 15d-PGJ2 inhibited cell growth and increased apoptosis. Western blotting demonstrated that 15d-PGJ2 treatment increased MEK and ERK phosphorylation, and decreased levels of phosphorylated AKT. Dasatinib in combination with 15d-PGJ2 significantly reduced cell proliferation compared with 15d-PGJ2 alone, and repressed both the AKT and MAPK pathways. The cell growth inhibition rate in the PGJ2 was 21.5±12.0, 35.3±5.4 and 28.3±4.2%, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the cell growth inhibition rate in the combination therapy was significantly higher compared with 15d-PGJ2 alone (MES-SA; 64.2±0.8, MES-SA/DX5;23.9±8.2 and SKN; 41.4±17.6%). The PGJ2 IC determined by MTT assay was 27.41,10.46 and 17.38 µmol/l, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the dasatinib IC was 6.68,17.30 and 6.25 µmol/l, respectively. Our findings demonstrate that 15d-PGJ2 suppresses proliferation by inactivating the AKT pathway in uterine sarcoma. Furthermore, combining 15d-PGJ2 with dasatinib produced a synergistic effect on cancer cell inhibition by repressing 15d-PGJ2-mediated activation of MAPK signaling, and further repressing AKT signaling. These results suggest that 15d-PGJ2 could be used in combination with dasatinib as a potential therapeutic approach for uterine sarcoma.
Akiko Abe, Masato Nishimura, Eri Takiguchi, Takako Kawakita, TANIGUCHI Yuka, Yuri Yamamoto, YAMASAKI Mikio, Takeshi Iwasa, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Survey on oncologist and gynecologist concerned with fertility for cancer survivors in reproductive age., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
2.
Masato Nishimura, Eri Takiguchi, Takako Kawakita, Akiko Abe, TANIGUCHI Yuka, Yuri Yamamoto, YAMASAKI Mikio, Takeshi Iwasa, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Efficacy and pregnant outcomes of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical endometrial hyperplasia in young women., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
Proceeding of Domestic Conference:
1.
Takako Kawakita : New mouse model of uterine adenomyosis, Acta Obstetrica et Gynaecologica Japonica, Vol.72, No.2, Feb. 2020.
2.
Takako Kawakita : Mental stress promote the endometriosis in mouse model, Acta Obstetrica et Gynaecologica Japonica, Vol.71, No.2, Feb. 2019.
3.
Kanako Yoshida, 門田 友里, Kana Kasai, Takako Kawakita, Takeshi Katou and Minoru Irahara : 妊娠中の腹腔鏡下卵巣腫瘍手術におけるアプローチ法の工夫, The Journal of Japan Society for Menopause and Women's Health, Vol.26, Oct. 2018.
4.
Kanako Yoshida, 門田 友里, Kana Kasai, Takako Kawakita, Takeshi Katou and Minoru Irahara : 妊娠中の腹腔鏡下卵巣腫瘍手術におけるアプローチ法の工夫, Japanese Journal of Gynecologic and Obstetric Endoscopy, Vol.34, 2018.