Tugsjargal Purevdorj, Moeka Arata, Mari Nii, Shota Yamamoto, Hiroki Noguchi, Asuka Takeda, Hidenori Aoki, Hiroaki Inui, Tomohiro Kagawa, Riyo Kinouchi, Yuri Yamamoto, Kanako Yoshida and Takeshi Iwasa : Porcine Placental Extract Improves the Lipid Profile and Body Weight in a Post-Menopausal Rat Model Without Affecting Reproductive Tissues, Nutrients, 17, 6, 984, 2025.
Rie Masaki, Yuri Yamamoto, Kou Tamura, Hidenori Aoki, Hiroki Noguchi, Asuka Takeda, Saki Minato, Risa Tanano, Erika Yamanaka, Takaaki Maeda, Tatsuo Sugimoto, Hikari Sasada, Hiroaki Inui, Tomohiro Kagawa, Atsuko Yoshida, Ayuka Mineda, Riyo Kinouchi, Kanako Yoshida, Takashi Kaji and Takeshi Iwasa : Comparison of endogenous hypothalamic and serum OT levels between young and middle-aged perimenopausal female rats, The Journal of Medical Investigation : JMI, 71, 3.4, 246-250, 2024.
(要約)
Oxytocin (OT) regulates food intake and body weight, particularly in obese individuals. Decreases in the effects of OT have recently been implicated in metabolic disturbances, and the administration of estradiol (E2) increased serum OT levels. Although weight gain is frequently observed in perimenopausal women, endogenous OT levels remain unclear. Therefore, we herein compared endogenous levels of hypothalamic and serum OT between young and middle-aged perimenopausal female rats and examined the relationship between serum estrogen and leptin levels. Body weight and visceral and subcutaneous fat weights were higher in middle-aged rats. Although no significant differences were observed in serum OT and E2 levels, serum leptin levels and hypothalamic mRNA levels of OT and the OT receptor (OTR) were significantly higher in middle-aged rats than in young rats. Serum OT levels did not correlate with hypothalamic OT mRNA levels or serum E2 levels. E2 maintains serum OT levels in perimenopausal rats, and other factors may elevate hypothalamic OT/OTR mRNA levels. Increases in body and fat weights in perimenopausal rats may be attributed to factors other than OT. Therefore, the administration of OT alone may not be sufficient to prevent metabolic disorders induced by the perimenopausal status. J. Med. Invest. 71 : 246-250, August, 2024.
Polycystic ovary syndrome (PCOS) is associated with an increased risk of psychological distress as well as enhanced responses to psychosocial stress. Recently, it was hypothesized that PCOS patients may be at high risk of novel COVID-19 infections and worse clinical presentations during such infections. Here, we evaluated the effects of PCOS on stress responses to bacterial and viral mimetics using dihydrotestosterone-induced PCOS model rats. Lipopolysaccharide (LPS; a bacterial mimetic) or polyinosinic-polycytidylic acid (Poly-IC; a viral mimetic) was injected into PCOS model rats (PCOS) and non-PCOS rats (control), and the rats' stress responses were evaluated. In the PCOS group, the rats' anorectic and febrile responses to LPS injection were enhanced, whereas their anorectic and febrile responses to Poly-IC injection were unaltered. The PCOS group also exhibited greater changes in peripheral cytokine levels in response to LPS, but not Poly-IC. On the contrary, after the injection of Poly-IC depressed locomotor activity was more evident in the PCOS group, whereas no such changes were observed after LPS injection. These findings indicate that although the stress responses of PCOS model rats to infection may be enhanced, the patterns of change in stress responses and their underlying mechanisms may differ between bacterial and viral infections.
Tomohiro Kagawa, Ayuka Mineda, Tomotaka Nakagawa, Ayaka Shinohara, Ryosuke Arakaki, Hiroaki Inui, Hiroki Noguchi, Atsuko Yoshida, Riyo Kinouchi, Yuri Yamamoto, Kanako Yoshida, Takashi Kaji, Masato Nishimura and Takeshi Iwasa : New treatment strategies for uterine sarcoma using secreted frizzledrelated proteins, Experimental and Therapeutic Medicine, 27, 5, 231, 2024.
(要約)
Secreted frizzled-related proteins (SFRPs) are involved in the development of various types of cancer and function by suppressing the Wnt signaling pathway. To elucidate the clinical implications of SFRPs in uterine sarcoma, SFRP expression levels and their effects on uterine leiomyosarcoma cells were examined. Immunostaining for SFRP4 was performed on uterine smooth muscle, uterine fibroid and uterine leiomyosarcoma tissues. Additionally, the effects of SFRP4 administration on cell viability, migration and adhesion were evaluated in uterine leiomyosarcoma SKN cells using the WST-1 assay (Roche Diagnostics) and the CytoSelect™ 24-well Cell Migration Assay Kit and the CytoSelect™ 48-well Cell Adhesion Assay Kit. The expression levels of SFRP4 in uterine leiomyosarcoma tissues were lower than those in normal smooth muscle and uterine fibroid tissues. In addition, SFRP4 suppressed the viability and migration, and increased the adhesion ability of uterine leiomyosarcoma cells compared with in the control group. In conclusion, SFRP4 may suppress the viability and migration, and enhance the adhesion of sarcoma cells. These results suggested that SFRP4 could be considered as a novel therapeutic target for uterine sarcoma.
Ayako Suto, Yuya Yano, Yuri Yamamoto, Hiroki Noguchi, Asuka Takeda, Shota Yamamoto, Tomohiro Kagawa, Kanako Yoshida, Kenji Hinokio, Akira Kuwahara, Toshiyuki Yasui and Takeshi Iwasa : Effects of activation with a Ca ionophore and roscovitine on the development of human oocytes that failed to fertilize after ICSI., The Journal of Medical Investigation : JMI, 70, 3.4, 321-324, 2023.
(要約)
Sequential treatment with an Ca ionophore and roscovitine activates oocytes that remain unfertilized after ICSI. In TESE-ICSI, the activation rate tended to be increased by the co-administration of roscovitine with a Ca ionophore. J. Med. Invest. 70 : 321-324, August, 2023.
Akiko Abe, Masao Yuasa, Yoshie Imai, Tomohiro Kagawa, Ayuka Mineda, Masato Nishimura, Chisato Tonoiso, Akiko Kubo, Takashi Kawanaka, Hitoshi Ikushima and Takeshi Iwasa : Extreme leanness, lower skeletal muscle quality, and loss of muscle mass during treatment are predictors of poor prognosis in cervical cancer treated with concurrent chemoradiation therapy, International Journal of Clinical Oncology, 27, 5, 983-991, 2022.
(要約)
Human papillomavirus vaccination is not widespread in Japan, and the low screening rates result in many cases of locally advanced cervical cancer. We investigated the prognostic significance of sarcopenia in patients with cervical cancer to guide healthcare policies to improve treatment outcomes. This retrospective study included 83 patients with cervical cancer without distant metastasis who underwent primary concurrent chemoradiotherapy between 2013 and 2018. We analyzed the indicators of physical condition and muscle quantity using the SYNAPSE VINCENT software. Muscle mass and the relationship between treatment toxicity and prognosis were evaluated. The patients' median age was 60 (range 33-80) years. Cancer stage distribution was as follows: cT2b or higher, 84.3%; N1, 65.1%; and MA, 27.7%. The overall sarcopenia (skeletal muscle index [SMI] < 38.5) rate was 30.1%, and the rate was 33.9 and 22.2% in patients aged < 64 and ≥ 65 years, respectively. No correlation was observed between clinical stage and musculoskeletal indices. Treatment resulted in decreased body weight and SMI; after treatment, the sarcopenia rate increased to 37.3%. A higher intramuscular adipose tissue content (IMAC) reduced the number of chemotherapy cycles needed. Treatment-associated SMI decreases of ≥ 7% indicated poor prognosis, with significant differences in progression-free survival and overall survival (p = 0.013 and p = 0.012, respectively). Patients who were very lean (body mass index < 18.5 kg/m) before treatment had a poor prognosis (p = 0.016 and p < 0.001). Our findings emphasize the importance of assessing original nutritional status and maintaining muscle mass and quality during the treatment of patients with cervical cancer.
Shuhei Kamada, Yuri Yamamoto, Hidenori Aoki, Kou Tamura, Asuka Takeda, Saki Minato, Rie Masaki, Rie Yanagihara, Noriko Hayashi, Yuya Yano, Junki Imaizumi, Tomohiro Kagawa, Atsuko Yoshida, Takako Kawakita, Minoru Irahara and Takeshi Iwasa : A novel PCOS rat model and an evaluation of its reproductive, metabolic, and behavioral phenotypes., Reproductive Medicine and Biology, 21, 1, e12416, 2021.
(要約)
Although animal models of PCOS have been used in many studies, none of them can reproduce both the reproductive and metabolic phenotypes of PCOS. In addition, behavioral parameters have not been evaluated in PCOS animal models. We tried to produce an improved rat model of PCOS, and the reproductive, metabolic, and behavioral phenotypes of the model rats were evaluated. Female rats were implanted with silicon tubes containing oil-dissolved dihydrotestosterone (Oil-DHT) as a new PCOS model. Their phenotypes were compared with those of conventional PCOS model rats (DHT), into which tubes containing crystalline DHT were implanted, and non-DHT-treated rats (control). Both the Oil-DHT and DHT rats showed greater body weight gain, food intake, and fat depot weight than the control rats. Furthermore, these groups showed fewer estrous stages and increased numbers of cystic follicles. The DHT rats exhibited lower ovarian and uterine weights than the control rats, whereas no such changes were observed in the Oil-DHT rats. The Oil-DHT and DHT rats showed less locomotor activity in the light phase than the control rats. Our proposed PCOS model reproduced both the reproductive and metabolic phenotypes of PCOS and may have potential for PCOS research.
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, 17, 3, 2242-2246, 2019.
(要約)
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.
Takeshi Iwasa, Hiroki Noguchi, Risa Tanano, Erika Yamanaka, Asuka Takeda, Kou Tamura, Hidenori Aoki, Tatsuro Sugimoto, Hikari Sasada, Takaaki Maeda, Saki Minato, Shota Yamamoto, Hiroaki Inui, Tomohiro Kagawa, Atsuko Yoshida, Ayuka Mineda, Mari Nii, Riyo Kinouchi, Kanako Yoshida, Yuri Yamamoto and Takashi Kaji : Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals., International Journal of Molecular Sciences, 24, 23, 16567, 2023.
(要約)
In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and β-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.
Akiko Abe, Akira Kuwahara, Tomohiro Kagawa, Ayuka Mineda and Masato Nishimura : A survey of germline mutations with epithelial ovarian cancer in Japanese patients., ESGO Annual Meeting 2019, Greece, Nov. 2019.