慶應義塾研究者情報データベース

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• Acute and chronic effects of imeglimin on peripheral circadian clocks in mice

  Shi Y., Xu P., Morishige J.I., Yang Y., Iba T., Nagata N., Hosono T., Miyazaki R., Sakane N., Ono M., Fujiwara T., Fujiwara H., Ando H.

  Journal of Pharmacological Sciences 160 （ 1 ） 51 - 58 2026年01月

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  OBJECTIVE: This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle. METHODS: Female C57BL/6J mice were administered imeglimin either as a single oral dose at Zeitgeber time (ZT) 0 or 12 (acute study) or via a 0.2 % admixture in chow for 4 weeks (chronic study). Clock gene mRNA expression in skeletal muscle and liver was analyzed by quantitative real-time PCR. RESULTS: Acute imeglimin administration at ZT 12 increased the peak mRNA expression of clock genes (Nr1d1 and Dbp in skeletal muscle; Per2 in liver), whereas dosing at ZT 0 decreased Nr1d1 and Dbp in both tissues. In the chronic study, imeglimin decreased the peak expression of Nr1d1 and Dbp in skeletal muscle, while liver rhythms remained unchanged. Nampt and Sirt1 expression was unaffected in either tissue. CONCLUSION: In this study, we demonstrated that imeglimin alters peripheral clock gene expression in healthy mice under both acute bolus administration and chronic mixed-feeding conditions. Further studies are warranted to clarify underlying mechanisms and their physiological relevance.

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• Assisted Reproductive Technology in Japan: A Summary Report for 2023 by the Committee on Professional Scientific Conduct and Clinical Ethics of the Japan Society of Obstetrics and Gynecology

  Katagiri Y., Jwa S.C., Kuwahara A., Iwasa T., Ono M., Kato K., Kishi H., Kuwabara Y., Taniguchi F., Harada M., Iwase A., Sugino N.

  Reproductive Medicine and Biology 25 （ 1 ）  2026年01月

  ISSN  14455781

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  Purpose: To summarize assisted reproductive technology (ART) data for 2023 collected through the Japan Society of Obstetrics and Gynecology registry. Methods and Results: 625 out of 638 registered ART facilities took part in the study, documenting 561 664 treatment cycles and 85 048 newborns (+3.3% and +10.2% increases from 2022). The average age of women undergoing treatment was 37.3 years (standard deviation: 4.8); 205 986 cycles (36.7%) involved women aged ≥ 40 years. Among fresh cycles, oocyte retrieval was performed in 281 665 cycles, including 168 343 freeze-all cycles (59.8%). A total of 2329 pregnancies and 3375 newborns resulted from in vitro fertilization and intracytoplasmic sperm injection cycles, yielding 1772 and 2502 newborns, respectively. The overall rates for single embryo transfer (SET) and singleton delivery were 80.5% and 96.5%. Frozen–thawed embryo transfer accounted for 271 361 cycles, resulting in 109 850 pregnancies and 80 774 newborns, with a SET rate of 84.7% and a singleton delivery rate of 96.3%. Conclusions: In 2023, the second year of insurance coverage, the registry recorded the highest numbers of treatment cycles and newborns. Effective registry systems planned for 2026 will enable comprehensive evaluation of emerging trends in Japanese ART practice.

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• Laeverin is Cell-Surface Target for Liquid-Phase Metastasizing Cancer Cells

  Kasama H., Sakai Y., Kagami K., Iizuka T., Kanda T., Suzuki T., Kayahashi K., Ono M., Fujiwara T., Yagi S., Inaki N., Matsumoto I., Yamazaki R., Abiko K., Matsumura N., Hattori A., Daikoku T., Fujiwara H.

  Advanced Science 12 （ 47 ）  2025年12月

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  Laeverin (LVRN) is a cell-surface immunoregulatory factor that is specifically expressed in embryo-derived extravillous trophoblast, which invades maternal spiral arteries without immune rejection during human placentation. Here, it is found that various epithelial cancer cell lines upregulated LVRN expression in association with the expression of POU5F1 after spheroid formation under floating conditions. Immunohistochemically, LVRN expression is detected in the lesions of vascular, lymphatic, and peritoneal invasion of ovarian, cervical, endometrial, breast, and lung cancers. LVRN-positive circulating tumor cells are also identified in the blood of uterine cervical and endometrial cancers, showing that LVRN expression is induced in cancer cells in the distant metastatic phase. Monomethylauristatin E-conjugated anti-LVRN antibody induced cell death in ovarian cancer-derived cell lines in the liquid phase in vitro and inhibited their peritoneal dissemination in nude mice in vivo. These findings indicate that LVRN is a unique and promising cell-surface target molecule for liquid-phase metastasizing cancer cells.

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• Modified screening of MYC promotor region elements using the CRISPR library in ovarian cancer

  Yamamoto A., Tanaka Y., Ishibashi S., Ikeda M., Sugita K., Ono M., Nishi H., Kurata M.

  Journal of Ovarian Research 18 （ 1 ）  2025年12月

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  Ovarian cancer remains one of the most lethal gynecological malignancies owing to its high recurrence rate and chemotherapeutic resistance. MYC is a well-known proto-oncogene that is frequently amplified in ovarian cancer and has been implicated in drug resistance. Previously, we established a new promoter–reporter system combined with a CRISPR activation library to identify unknown MYC regulators, and M1AP was identified as a novel MYC regulator. However, considering the insufficient explanation for the absence of guide RNA (gRNA) of MYC, this present study explored methods to prevent the gRNA of MYC itself from binding. This study first modified the promoter–reporter vector to improve its quality, then conducted CRISPR screening and analyzed candidate genes as MYC promoter regulators using next-generation sequencing in OVSAHO ovarian cancer cells. Eighty-six genes had ≥ 1000 reads, and Pearson’s correlation coefficient analysis was performed on the cBioPortal of the Cancer Genomics database. Fourteen genes were identified as candidate MYC regulators with positive and significant correlations with MYC. Seven genes, including CYP4v2, ASPH, ANP32D, PCED1A, ABI1, FUZ, and HOOK2, demonstrated significantly higher luciferase activity than the control genes. Four genes, including ABI1, PCED1A, HOOK2, and CYP4v2, activated the MYC promoter, which showed over twofold higher activity than the control when overexpressed using a vector. In conclusion, four genes that activate MYC promoters were identified in an ovarian cancer cell line using the CRISPR library system with a modified promoter–reporter tool. These results will prove helpful in the development of novel treatment strategies for ovarian cancer.

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• Novel Subtype Classification of Diffuse Uterine Leiomyomatosis Based on a Nationwide Survey in Japan

  Ishikawa H., Asano R., Ono M., Kitade M., Kusumi M., Tsuji S., Nakamura T., Maekawa R., Goto Y., Takada A., Koga K.

  Journal of Obstetrics and Gynaecology Research 51 （ 12 ）  2025年12月

  ISSN  13418076

  　概要を見る

  Aim: Diffuse uterine leiomyomatosis (DUL) is characterized by numerous uterine leiomyomas within and diffusely replacing the myometrium. However, because of its rarity, the prevalence, diagnostic criteria, and standard treatment for patients with DUL who wish to preserve their fertility remain unknown. This study aimed to clarify the current status of the diagnosis of DUL in Japan. Methods: We conducted a web-based survey targeting 1080 Obstetrics and Gynecology training institutions registered with the Japanese Medical Specialty Board. We asked them whether they had treated patients with DUL over the past 10 years (2013–2022). We obtained magnetic resonance imaging (MRI) scans from institutions that reported clinical experience with DUL, and conducted a central review to determine whether each case was consistent with DUL. We also investigated whether DUL could be classified into subtypes. Results: Responses were obtained from 428 institutions, of which 128 reported clinical experience with DUL or DUL-like multiple uterine leiomyomas, totaling 653 cases. MRI scans from 408 cases were centrally reviewed by a subcommittee, and 307 cases were confirmed as DUL. Based on the imaging characteristics, DUL was classified into three subtypes: total replacement, myometrial replacement, and submucosal-dominant. Conclusions: This survey revealed that 653 cases of DUL or DUL-like multiple uterine leiomyomas were managed over a 10-year period in Japan. Based on a central review of MRI scans, DUL can be classified into three distinct subtypes. Given the differences between these subtypes, treatment approaches for patients wishing to preserve fertility may vary, highlighting the need for further investigation.

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• Influence of lifestyle and the circadian clock on reproduction

  Ono M., Dai Y., Fujiwara T., Fujiwara H., Daikoku T., Ando H., Kuji N., Nishi H.

  Reproductive Medicine and Biology 24 （ 1 ）  2025年01月

  ISSN  14455781

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  Background: The biological reproductive process requires the precise coordination of annual and daily signals to adapt to environmental shifts. Humans and animals have developed shared neuroendocrine systems that have adapted to process daily and seasonal light signals within the hypothalamic–pituitary —gonadal axis. However, the stability of circadian and seasonal biological processes is at risk due to industrialization and contemporary round-the-clock lifestyles. These threats include skipping breakfast, excessive artificial illumination during inappropriate hours because of irregular work schedules, nighttime urban lighting, and widespread environmental pollution from endocrine-disrupting chemicals. This review aimed to explore the interplay between lifestyle factors, circadian rhythms, and reproductive functions. Methods: This review examined the reciprocal influences of circadian clocks on reproductive hormones, exploring the underlying mechanisms and their implications for fertility and reproductive health. We emphasized key findings regarding molecular clock components, endocrine pathways, and the critical importance of synchronizing circadian rhythms with hormonal cycles. Main Findings: The intersection of reproductive endocrinology and circadian biology reveals complex interactions between hormonal regulation and circadian rhythms. Circadian rhythm misalignments due to environmental factors, including late-night work and skipping breakfast, negatively impact endocrine and reproductive functions. Conclusions: More strategies are needed to mitigate the effects of circadian disruption on reproductive functions.

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• Correction to: Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases (International Journal of Clinical Oncology, (2022), 27, 2, (301-309), 10.1007/s10147-021-02082-9)

  Ono M., Matsumoto K., Boku N., Fujii N., Tsuchida Y., Furui T., Harada M., Kanda Y., Kawai A., Miyachi M., Murashima A., Nakayama R., Nishiyama H., Shimizu C., Sugiyama K., Takai Y., Fujio K., Morishige K.I., Osuga Y., Suzuki N.

  International Journal of Clinical Oncology 27 （ 4 ） 825 - 826 2022年04月

  ISSN  13419625

  　概要を見る

  The article, Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases written by Masanori Ono, Kimikazu Matsumoto, Narikazu Boku, Nobuharu Fujii, Yumi Tsuchida, Tatsuro Furui, Miyuki Harada, Yoshinobu Kanda, Akira Kawai, Mitsuru Miyachi, Atsuko Murashima, Robert Nakayama, Hiroyuki Nishiyama, Chikako Shimizu, Kazuhiko Sugiyama, Yasushi Takai, Keishi Fujio, Ken‑Ichirou Morishige, Yutaka Osuga, and Nao Suzuki was originally published Online First without Open Access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on February 16, 2022 to © Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0. The original article has been corrected.

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• Guidelines for Reproductive Medicine in Japan

  Yamada M., Ishikawa T., Iwasa T., Oishi H., Osuka S., Oka K., Ono S., Ono M., Orisaka M., Kanasaki H., Kawano Y., Kawamura K., Kishi H., Kimura F., Kuroda S., Kuwahara A., Kobayashi H., Komiya A., Saito H., Sato K., Sato S., Shiraishi K., Shirasawa H., Suzuki T., Takai Y., Takae S., Takahashi T., Takiuchi T., Tachibana M., Tamura I., Tamura H., Jwa S.C., Baba T., Harada M., Hirata T., Fukui A., Fukuda Y., Fukuhara S., Maruyama T., Yumura Y., Yoshino O., Hirota Y., Tsujimura A., Kuji N., Osuga Y.

  Reproductive Medicine and Biology 21 （ 1 ）  2022年01月

  ISSN  14455781

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