論文 - 菱川 善隆
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HMGB2 Promotes De Novo Lipogenesis to Accelerate Hepatocyte Proliferation During Liver Regeneration. 査読あり
Choijookhuu N, Yano K, Lkham-Erdene B, Shirouzu S, Kubota T, Fidya, Ishizuka T, Kai K, Chosa E, Hishikawa Y
J. Histochem. Cytochem 72 ( 4 ) 245 - 264 2024年4月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Histochemistry and Cytochemistry
Liver regeneration is a well-orchestrated compensatory process that is regulated by multiple factors. We recently reported the importance of the chromatin protein, a high-mobility group box 2 (HMGB2) in mouse liver regeneration. However, the molecular mechanism remains unclear. In this study, we aimed to study how HMGB2 regulates hepatocyte proliferation during liver regeneration. Seventy-percent partial hepatectomy (PHx) was performed in wild-type (WT) and HMGB2-knockout (KO) mice, and the liver tissues were used for microarray, immunohistochemistry, quantitative polymerase chain reaction (qPCR), and Western blotting analyses. In the WT mice, HMGB2-positive hepatocytes colocalized with cell proliferation markers. In the HMGB2-KO mice, hepatocyte proliferation was significantly decreased. Oil Red O staining revealed the transient accumulation of lipid droplets at 12–24 hr after PHx in the WT mouse livers. In contrast, decreased amount of lipid droplets were found in HMGB2-KO mouse livers, and it was preserved until 36 hr. The microarray, immunohistochemistry, and qPCR results demonstrated that the expression of lipid metabolism–related genes was significantly decreased in the HMGB2-KO mouse livers. The in vitro experiments demonstrated that a decrease in the amount of lipid droplets correlated with decreased cell proliferation activity in HMGB2-knockdown cells. HMGB2 promotes de novo lipogenesis to accelerate hepatocyte proliferation during liver regeneration:
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Ikenoue M, Choijookhuu N, Yano K, Fidya, Takahashi N, Ishizuka T, Shirouzu S, Yamaguma Y, Kai K, Higuchi K, Sawaguchi A, Nanashima A, Hishikawa Y.
Histochem Cell Biol 161 ( 4 ) 325 - 336 2024年4月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Histochemistry and Cell Biology
Su (var) 3–9, enhancer of seste, trithorax (SET)-domain bifurcated histone lysine methyltransferase (SETDB1) plays a crucial role in maintaining intestinal stem cell homeostasis; however, its physiological function in epithelial injury is largely unknown. In this study, we investigated the role of SETDB1 in epithelial regeneration using an intestinal ischemia/reperfusion injury (IRI) mouse model. Jejunum tissues were sampled after 75 min of ischemia followed by 3, 24, and 48 h of reperfusion. Morphological evaluations were performed using light microscopy and electron microscopy, and the involvement of SETDB1 in epithelial remodeling was investigated by immunohistochemistry. Expression of SETDB1 was increased following 24 h of reperfusion and localized in not only the crypt bottom but also in the transit amplifying zone and part of the villi. Changes in cell lineage, repression of cell adhesion molecule expression, and decreased histone H3 methylation status were detected in the crypts at the same time. Electron microscopy also revealed aberrant alignment of crypt nuclei and fusion of adjacent villi. Furthermore, increased SETDB1 expression and epithelial remodeling were confirmed with loss of stem cells, suggesting SETDB1 affects epithelial cell plasticity. In addition, crypt elongation and increased numbers of Ki-67 positive cells indicated active cell proliferation after IRI; however, the expression of PCNA was decreased compared to sham mouse jejunum. These morphological changes and the aberrant expression of proliferation markers were prevented by sinefungin, a histone methyltransferase inhibitor. In summary, SETDB1 plays a crucial role in changes in the epithelial structure after IRI-induced stem cell loss.
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Choijookhuu N, Shibata Y, Ishizuka T, Xu Y, Koji T, Hishikawa Y
Acta Histochemica et Cytochemica. 2022 October 25;55(5):119-128 55 ( 5 ) 119 - 128 2022年10月
担当区分：最終著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Histochemica et Cytochemica
In situ hybridization (ISH) is a powerful method for detecting specific RNAs at the cellular level. Although conventional ISH using hapten-labeled probes are useful for detecting multiple RNAs, the detection procedures are still complex and required longer time. Therefore, we introduced a new application of fluorescence resonance energy transfer (FRET)-based molecular beacon (MB) probes for ISH. MCF-7 cells and C57BL/6J mouse uterus were used for ISH. MB probes for ERα mRNA and 28S rRNA were labeled with Cy3/BHQ-2 and 6-FAM/ DABCYL, and conventional probes were labeled with digoxigenin. Fluorescence measure-ments revealed that of more-rapid hybridization kinetics compared to conventional probes. In MCF-7 cells, 28S rRNA was detected in nucleolus and cytoplasm of all cells, whereas ERα mRNA was detected in some nucleolus. In the uterus, 28S rRNA was clearly detected using complementary MB probe, but there were no signals in control slides. Moreover, 28S rRNA was detected in all cells, whereas ERα mRNA was detected mainly in the epithelium. Fluorescence intensity of 28S rRNA was decreased significantly in 1 or 2 base-mismatched sequences, that indicates highly specific detection of target RNAs. In conclusion, the FRET-based MB probes are very useful for ISH, providing rapid hybridization, high sensitivity and specificity.
DOI： 10.1267/ahc.22-00075
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Yamaguma Y, Sugita N, Choijookhuu N, Yano K, Lee D, Ikenoue M, Fidya, Shirouzu S, Ishizuka T, Tanaka M, Yamashita Y, Chosa E, Taniguchi N, Hishikawa Y
Histochemistry and Cell Biology. 2022 Mar;157(3):359-369 157 ( 3 ) 359 - 369 2022年3月
担当区分：最終著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Histochemistry and Cell Biology
High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ERβ), but not ERα. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ERβ expression.
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Sugita N, Choijookhuu N, Yano K, Lee D, Ikenoue M, Fidya, Taniguchi N, Chosa E, Hishikawa Y
Biology of reproduction ;105(6) 105 ( 6 ) 1510 - 1520 2021年10月
担当区分：最終著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biology of Reproduction
High-mobility group box 2, a chromatin-associated protein that interacts with deoxyribonucleic acid, is implicated in multiple biological processes, including gene transcription, replication, and repair. High-mobility group box 2 is expressed in several tissues, including the testis; however, its functional role is largely unknown. Here, we elucidated the role of high-mobility group box 2 in spermatogenesis. Paraffin-embedded testicular tissues were obtained from 8-week-old and 1-year-old wild-type and knock-out mice. Testis weight and number of seminiferous tubules were decreased, whereas atrophic tubules were increased in high-mobility group box 2-depleted mice. Immunohistochemistry revealed that atrophic tubules contained Sertoli cells, but not germ cells. Moreover, decreased cell proliferation and increased apoptosis were demonstrated in high-mobility group box 2-depleted mouse testis. To elucidate the cause of tubule atrophy, we examined the expression of androgen and estrogen receptors, and the results indicated aberrant expression of androgen receptor and estrogen receptor alpha in Sertoli and Leydig cells. Southwestern histochemistry detected decreased estrogen response element–binding sites in high-mobility group box 2-depleted mouse testis. High-mobility group box 1, which has highly similar structure and function as high-mobility group box 2, was examined by immunohistochemistry and western blotting, which indicated increased expression in testis. These findings indicate a compensatory increase in high-mobility group box 1 expression in high-mobility group box 2 knock-out mouse testis. In summary, depletion of high-mobility group box 2 induced aberrant expression of androgen receptor and estrogen receptor alpha, leading to decreased germ cell proliferation and increased apoptosis which resulted in focal seminiferous tubule atrophy.
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Non-Cytotoxic Photodynamic Therapy with Talaporfin Sodium Reduces the Expression of CXCR4 and Enhances Chemotherapeutic Efficacy in Undifferentiated Gastric Cancer Cell Line HGC27 査読あり
Kai Kengo, Ishizuka Takumi, Matsumoto Jin, Shimamawari Koki, Mori Ryoma, Fidya, Lkham-Erdene Baljinnyam, Kubota Toshiki, Ikenoue Makoto, Higuchi Kazuhiro, Nanashima Atsushi, Hishikawa Yoshitaka
Ａｃｔａ Ｈｉｓｔｏｃｈｅｍｉｃａ ｅｔ Ｃｙｔｏｃｈｅｍｉｃａ 58 ( 2 ) 69 - 79 2025年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：日本組織細胞化学会
Gastric cancer (GC), particularly the undifferentiated type, is frequently associated with peritoneal metastasis, which significantly worsens prognosis due to its resistance to conventional treatments. Photodynamic therapy (PDT) is localized treatment using a photosensitizer (PS) activated by light of a specific wavelength to generate cytotoxic reactive oxygen species that induce cell death. Severe adverse events were reported from clinical trials investigating PDT for peritoneal dissemination conducted until the early 2000s, leaving its safety and clinical effectiveness unestablished. The present study explored whether “non-cytotoxic” PDT using talaporfin sodium (TS) could enhance efficacy of chemotherapeutic agents in undifferentiated GC cell line HGC27. Cell viability was evaluated with MTT assay following TS-PDT, and the synergistic effect between non-cytotoxic TS-PDT and anticancer drug SN-38 was assessed. Changes in expression of drug resistance markers were analyzed through qRT-PCR, Western blotting, and immunocytochemistry. We found that non-cytotoxic TS-PDT enhanced the efficacy of chemotherapy in the undifferentiated GC cell line and reduced the expression of C-X-C chemokine receptor type 4, a key marker associated with GC stem-like properties. These findings highlight the potential of non-cytotoxic TS-PDT as a synergistic treatment approach. We conclude that non-cytotoxic TS-PDT could enhance drug sensitivity and offers a promising therapeutic strategy for GC.
DOI： 10.1267/ahc.25-00002
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Non-Cytotoxic Photodynamic Therapy with Talaporfin Sodium Reduces the Expression of CXCR4 and Enhances Chemotherapeutic Efficacy in Undifferentiated Gastric Cancer Cell Line HGC27. 査読あり
Kengo Kai, Takumi Ishizuka, Jin Matsumoto, Koki Shimamawari, Ryoma Mori, Fidya, Baljinnyam Lkham-Erdene, Toshiki Kubota, Makoto Ikenoue, Kazuhiro Higuchi, Atsushi Nanashima, Yoshitaka Hishikawa
Acta Histochem. Cytochem 2025年3月
担当区分：責任著者 掲載種別：研究論文（学術雑誌）
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Kazuhiro Higuchi, Makoto Ikenoue, Takumi Ishizuka, Kengo Kai, Nobuyasu Takahashi, Toshiki Kubota, Shinichiro Shirouzu, Baljinnyam Lkham-Erdene, Kham Mo Aung, Michikazu Nakai, Akira Sawaguchi, Atsushi Nanashima, Yoshitaka Hishikawa
Acta Histochem. Cytochem 58 ( 1 ) 9 - 18 2025年2月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Histochemica et Cytochemica
SET domain bifurcated 1 (SETDB1), a histone H3K9-specific methyltransferase, is crucial for heterochromatin formation and intestinal homeostasis, but its role in intestinal ischemia-reperfusion injury (IRI) remains unclear. This study investigated changes in SETDB1-mediated nuclear chromatin regulation in intestinal epithelial cells (IECs) using an IRI mouse model. Jejunal samples were collected after 75 min of ischemia followed by 24 hr of reperfusion. Sinefungin was administered as a histone methyltransferase inhibitor. Morphologic changes were evaluated using hematoxylin-eosin staining and electron microscopy, and cell-adhesion molecule expression, including ZO-1, E-cadherin, integrin-β4, and laminin, was evaluated using immunohistochemistry. Super-resolution microscopy analyzed intranuclear SETDB1 localization and heterochromatin formation in IECs. IRI-affected jejunum exhibited massive IEC detachment, dilated intercellular spaces, basement membrane damage, and decreased expression of E-cadherin and integrin-β4. Sinefungin prevented these changes, however. The proportion of IECs expressing nuclear SETDB1 throughout the euchromatin was significantly higher in IRI-affected jejunum (77.8%) than sham-treated (3.0%) or sinefungin-treated, IRI-affected jejunum (2.7%). The proportion of IECs with decreased heterochromatin was significantly higher in sinefungin-treated, IRI-affected jejunum (84.3%) than untreated IRI-affected jejunum (15.6%). These findings suggest that SETDB1-mediated chromatin regulation is pivotal in intestinal IRI and represents a potential therapeutic target.
DOI： 10.1267/ahc.24-00061
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Baljinnyam Lkham-Erdene, Choijookhuu N, Kubota T, Uto T, Mitoma S, Shirouzu S, Ishizuka T, Kai K, Higuchi K, Aung K, Batmunkh J, Sato K, Hishikawa Y
Acta Histochem. Cytochem 57 ( 5 ) 175 - 188 2024年10月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Acta Histochemica et Cytochemica
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming a major health problem worldwide. Liver regeneration is crucial for restoring liver function, and is regulated by extraordinary complex process, involving numerous factors under both physiologic and pathologic conditions. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid synthesized by sphingosine kinase 1 (SphK1), plays an important role in liver function through S1P receptors (S1PRs)-expressing cells. In this study, we investigated the effect of lipid overload on hepatocyte proliferation in a mouse hepatic steatosis model induced by feeding a methionine-and choline-deficient (MCD) diet. After 50% partial hepatectomy (PHx), liver tissues were sampled at various timepoints and then analyzed by immunohistochemistry, oil Red-O staining, quantitative-polymerase chain reaction (qPCR), and flow cytometry. In mice fed the MCD-diet, significantly exacerbated hepatic steatosis and accelerated liver regeneration were observed. After PHx, hepatocyte proliferation peaked at 48 and 36 hr in the liver of chow-and MCD-diet fed mice, respectively. By contrast, increased expression of S1PR2 was observed in hepatic neutrophils and macrophages of MCD-diet fed mice. Flow cytome-try and qPCR experiments demonstrated that levels of HGF and FGF2 released by neutrophils and macrophages were significantly higher in MCD-diet fed mice. In conclusion, hepatic lipid overload recruits Kupffer cells and neutrophils that release HGF and FGF2 via SphK1/S1PR2 activation to accelerate hepatocyte proliferation.
DOI： 10.1267/ahc.24-00046
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Acceptance of Virtual Reality Simulation Training for Stoma Care by Healthcare Providers: A Pilot Questionnaire Study After Viewing Prototype Imagings. 査読あり
Kai K, Shinoda H, Takeiri E, Hamada T, Chikubu M, Kodama Y, Higuchi K, Nanashima A
Cureus 2024年7月
担当区分：責任著者 掲載種別：研究論文（学術雑誌）
DOI： 10.7759/cureus.65465
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蛍光共鳴エネルギー移動（FRET）現象を利用した高感度<i>in situ</i> hybridization 査読あり
石塚 匠, 柴田 恭明, 小路 武彦, 菱川 善隆
顕微鏡 58 ( 3 ) 117 - 122 2023年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：公益社団法人 日本顕微鏡学会
代表的な組織学的手法の一つである<i>in situ</i> hybridization法（ISH）は，組織切片上で特異的な塩基配列を有する核酸分子を視覚化し，「本来存在する場所（<i>in situ</i>）」で検出する方法である．ISHは多様な細胞により構成されている組織内で特定の遺伝子を同定するための方法論として，分子機構の解明や疾患の病態解明に貢献している．一方で，プローブや標識の種類などによっては検出感度が十分でない場合がある．本稿では，蛍光共鳴エネルギー移動（Fluorescence Resonance Energy Transfer: FRET）現象を利用した高感度蛍光標識プローブを用いたFRET based <i>in situ</i> hybridization（FRET-ISH）について紹介する．
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Protective role of estrogen through G-protein coupled receptor 30 in a colitis mouse model. 査読あり
Fidya, Choijookhuu N, Ikenoue M, Yano K, Yamaguma Y, Shirouzu S, Kai K, Ishizuka T, Hishikawa Y
Histochem Cell Biol 161 ( 1 ) 81 - 93 2023年10月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Histochemistry and Cell Biology
Estrogen and its receptors are involved in the pathogenesis of gastrointestinal diseases such as colitis. However, the role of the membrane estrogen receptor G-protein-coupled receptor 30 (GPR30) in colitis is poorly understood. We therefore investigated the effect of estrogen in dextran sulfate sodium (DSS)-induced colitis. Male C57BL/6 mice were administered 1.5% DSS for 5 days and treated with 17β-estradiol (E2), GPR30 agonist (G1), or GPR30 antagonist (G15) for 8 days. Inflammation grade was evaluated by disease activity index (DAI) and histomorphological score. Colon tissues were immunohistochemically analyzed and revealed high expression of membrane GPR30, histone 3 lysine 36 dimethylation, and lysine 79 trimethylation in normal mouse colon epithelial cells but significantly decreased expression in DSS-treated mice, whereas the expression was partially preserved after treatment with E2 or G1. Colon shortening and DAI were significantly lower in E2- and G1-treated mice compared to DSS-treated mice. Caudal type homeobox 2 (CDX2) expression and cell proliferation differed in normal colon epithelial cells but overlapped in those of DSS-treated mice. Administration of E2 and G1 reduced CDX2 expression and cell proliferation. Altered expression of claudin-2 and occludin were observed in the colonic epithelium of DSS-treated mice, and these changes were significantly lower in the colon of E2- and G1-treated mice. These results indicate that estrogen regulates histone modification, cell proliferation, and CDX2 expression through GPR30, which affects intestinal epithelial barrier function. We conclude that estrogen protects against intestinal epithelial damage through GPR30 by enhancing intestinal epithelial barrier function in DSS-induced colitis in mice.
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Tmem161a regulates bone formation and bone strength through the P38 MAPK pathway. 査読あり
Nagai T, Sekimoto T, Kurogi S, Ohta T, Miyazaki S, Yamaguchi Y, Tajima T, Chosa E, Imasaka M, Yoshinobu K, Araki K, Araki M, Choijookhuu N, Sato K, Hishikawa Y, Funamoto T
Sci Rep 13 ( 1 ) 14639 2023年9月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Bone remodeling is an extraordinarily complex process involving a variety of factors, such as genetic, metabolic, and environmental components. Although genetic factors play a particularly important role, many have not been identified. In this study, we investigated the role of transmembrane 161a (Tmem161a) in bone structure and function using wild-type (WT) and Tmem161a-depleted (Tmem161aGT/GT) mice. Mice femurs were examined by histological, morphological, and bone strength analyses. Osteoblast differentiation and mineral deposition were examined in Tmem161a-overexpressed, -knockdown and -knockout MC3T3-e1 cells. In WT mice, Tmem161a was expressed in osteoblasts of femurs; however, it was depleted in Tmem161aGT/GT mice. Cortical bone mineral density, thickness, and bone strength were significantly increased in Tmem161aGT/GT mice femurs. In MC3T3-e1 cells, decreased expression of alkaline phosphatase (ALP) and Osterix were found in Tmem161a overexpression, and these findings were reversed in Tmem161a-knockdown or -knockout cells. Microarray and western blot analyses revealed upregulation of the P38 MAPK pathway in Tmem161a-knockout cells, which referred as stress-activated protein kinases. ALP and flow cytometry analyses revealed that Tmem161a-knockout cells were resistant to oxidative stress. In summary, Tmem161a is an important regulator of P38 MAPK signaling, and depletion of Tmem161a induces thicker and stronger bones in mice.
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Kai K, Nakashima K, Kawakami H, Takeno S, Hishikawa Y, Ikenoue M, Hamada T, Imamura N, Shibata T, Noritomi T, Sasaki F, Nakamura Y, Nanashima A
Intern Med 63 ( 7 ) 903 - 910 2023年8月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Internal Medicine
Introduction Photodynamic therapy (PDT) is a salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Salvage PDT is the treatment available for vulnerable patients with various comorbidities at risk of salvage esophagectomy. This study assessed the impact of the Charlson comorbidity index (CCI) on the outcomes of salvage PDT using talaporfin sodium (TS) for esophageal cancer. Metohds Consecutive patients with esophageal cancer who underwent salvage TS-PDT from 2016 to 2022 were included in this retrospective study. We investigated the local complete response (L-CR), progressionfree survival (PFS) and overall survival (OS) and evaluated the relationship between the CCI and therapeutic efficacy. Results In total, 25 patients were enrolled in this study. Overall, 12 patients (48%) achieved an L-CR, and the 2-year PFS and OS rates were 24.9% and 59.4%, respectively. In a multivariate analysis, a CCI ≥1 (p= 0.041) and deeper invasion (p=0.048) were found to be significant independent risk factors for not achieving an L-CR. To evaluate the efficacy associated with comorbidities, we divided the patients into the CCI=0 group (n=11) and the CCI ≥1 group (n=14). The rate of an L-CR (p=0.035) and the 2-year PFS (p=0.029) and OS (p=0.018) rates in the CCI ≥1 group were significantly lower than those in the CCI=0 group. Conclusion This study found that the CCI was negatively associated with the efficacy of salvage TS-PDT for esophageal cancer.
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Clec4A4 Acts As A Negative Immune Checkpoint Regulator to Suppress Antitumor Immunity.
Uto T, Fukaya T, Mitoma S, Nishikawa Y, Tominaga M, Choijookhuu N, Hishikawa Y, Sato K
Cancer immunology research 11 ( 9 ) 1266 - 1279 2023年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cancer Immunology Research
Clec4A4 is a C-Type lectin receptor (CLR) exclusively expressed on murine conventional dendritic cells (cDC) to regulate their activation status. However, the functional role of murine Clec4A4 (mClec4A4) in antitumor immunity remains unclear. Here, we show that mClec4A4 serves as a negative immune checkpoint regulator to impair antitumor immune responses. Deficiency of mClec4A4 lead to a reduction in tumor development, accompanied by enhanced antitumor immune responses and amelioration of the immunosuppressive tumor microenvironment (TME) mediated through the enforced activation of cDCs in tumor-bearing mice. Furthermore, antagonistic mAb to human CLEC4A (hCLEC4A), which is the functional orthologue of mClec4A4, exerted protection against established tumors without any apparent signs of immunerelated adverse events in hCLEC4A-Transgenic mice. Thus, our findings highlight the critical role of mClec4A4 expressed on cDCs as a negative immune checkpoint molecule in the control of tumor progression and provide support for hCLEC4A as a potential target for immune checkpoint blockade in tumor immunotherapy.
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Fukaya T., Uto T., Mitoma S., Takagi H., Nishikawa Y., Tominaga M., Choijookhuu N., Hishikawa Y., Sato K.
Cell Reports 42 ( 5 ) 112431 2023年5月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cell Reports
While dysbiosis in the gut is implicated in the impaired induction of oral tolerance generated in mesenteric lymph nodes (MesLNs), how dysbiosis affects this process remains unclear. Here, we describe that antibiotic-driven gut dysbiosis causes the dysfunction of CD11c+CD103+ conventional dendritic cells (cDCs) in MesLNs, preventing the establishment of oral tolerance. Deficiency of CD11c+CD103+ cDCs abrogates the generation of regulatory T cells in MesLNs to establish oral tolerance. Antibiotic treatment triggers the intestinal dysbiosis linked to the impaired generation of colony-stimulating factor 2 (Csf2)-producing group 3 innate lymphoid cells (ILC3s) for regulating the tolerogenesis of CD11c+CD103+ cDCs and the reduced expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) on CD11c+CD103+ cDCs for generating Csf2-producing ILC3s. Thus, antibiotic-driven intestinal dysbiosis leads to the breakdown of crosstalk between CD11c+CD103+ cDCs and ILC3s for maintaining the tolerogenesis of CD11c+CD103+ cDCs in MesLNs, responsible for the failed establishment of oral tolerance.
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Dispensable role of Rac1 and Rac3 after cochlear hair cell specification. 査読あり
Nakamura T, Sakaguchi H, Mohri H, Ninoyu Y, Goto A, Yamaguchi T, Hishikawa Y, Matsuda M, Saito N, Ueyama T
Journal of molecular medicine (Berlin, Germany) 101 ( 7 ) 843 - 854 2023年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Molecular Medicine
Abstract: Rac small GTPases play important roles during embryonic development of the inner ear; however, little is known regarding their function in cochlear hair cells (HCs) after specification. Here, we revealed the localization and activation of Racs in cochlear HCs using GFP-tagged Rac plasmids and transgenic mice expressing a Rac1-fluorescence resonance energy transfer (FRET) biosensor. Furthermore, we employed Rac1-knockout (Rac1-KO, Atoh1-Cre;Rac1 flox/flox) and Rac1 and Rac3 double KO (Rac1/Rac3-DKO, Atoh1-Cre;Rac1 flox/flox ;Rac3 −/−) mice, under the control of the Atoh1 promoter. However, both Rac1-KO and Rac1/Rac3-DKO mice exhibited normal cochlear HC morphology at 13 weeks of age and normal hearing function at 24 weeks of age. No hearing vulnerability was observed in young adult (6-week-old) Rac1/Rac3-DKO mice even after intense noise exposure. Consistent with prior reports, the results from Atoh1-Cre;tdTomato mice confirmed that the Atoh1 promoter became functional only after embryonic day 14 when the sensory HC precursors exit the cell cycle. Taken together, these findings indicate that although Rac1 and Rac3 contribute to the early development of sensory epithelia in cochleae, as previously shown, they are dispensable for the maturation of cochlear HCs in the postmitotic state or for hearing maintenance following HC maturation. Key messages: Mice with Rac1 and Rac3 deletion were generated after HC specification.Knockout mice exhibit normal cochlear hair cell morphology and hearing.Racs are dispensable for hair cells in the postmitotic state after specification.Racs are dispensable for hearing maintenance after HC maturation.
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Kai K., Hamada T., Sato Y., Hiyoshi M., Imamura N., Yano K., Ikeda T., Ichihara A., Ogata S., Choijookhuu N., Hishikawa Y., Hosokawa A., Nanashima A.
Journal of Oncology 2023 1440257 - 8 2023年3月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Oncology
Background. Oxaliplatin (OX)-based chemotherapy induces sinusoidal obstruction syndrome (SOS) in the nontumorous liver parenchyma, which can increase the risk of liver resection due to colorectal liver metastasis (CRLM). The extracellular volume (ECV) calculated from contrast-enhanced computed tomography (CT) has been reported to reflect the morphological change of hepatic fibrosis. The present retrospective study aimed to evaluate the ECV fraction as a predictive factor for OX-induced SOS. Methods. Our study included 26 patients who underwent liver resection for CRLM after OX-based chemotherapy with a preoperative dynamic CT of appropriate quality. We investigated the relationship between the pathological SOS grade and the ECV fraction. Results. Overall, 26 specimens from the patients were graded with the SOS classification of Rubbia-Brandt et al. as follows: grade 0, n = 17 (65.4%); grade 1, n = 4 (15.4%); and grade 2, n = 5 (19.2%). No specimens showed grade 3 SOS. In a univariate analysis, the ECV fraction in grade 0 SOS was significantly lower than that in grade 1 + 2 SOS (26.3 ± 3.4% vs. 30.6 ± 7.0%; P = 0.025). The cutoff value and AUC value of the ECV fraction to distinguish between grades 0 and 1 + 2 were 27.5% and 0.771, respectively. Conclusions. Measurement of the ECV fraction was found to be a potential noninvasive diagnostic method for determining early-stage histopathological sinusoidal injury induced by OX-based chemotherapy.
DOI： 10.1155/2023/1440257
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Correction: Pivotal role of High-Mobility Group Box 2 in ovarian folliculogenesis and fertility.
Shirouzu S, Sugita N, Choijookhuu N, Yamaguma Y, Takeguchi K, Ishizuka T, Tanaka M, Fidya, Kai K, Chosa E, Yamashita Y, Koshimoto C, Hishikawa Y
Journal of ovarian research 16 ( 1 ) 21 2023年1月
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Kai K., Hiyoshi M., Imamura N., Hamada T., Yano K., Sato Y., Sakae T., Komi M., Nakamura T., Choijookhuu N., Hishikawa Y., Nanashima A.
Internal Medicine 62 ( 8 ) 1107 - 1115 2023年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Internal Medicine
Objective The extracellular volume (ECV) calculated based on contrast-enhanced computed tomography (CT) has been reported as a novel imaging parameter reflecting the morphological change of fibrosis in several parenchymal organs. Our retrospective study assessed the validity of the ECV fraction for diagnosing pancreatic fibrosis and the appropriate imaging condition as the “equilibrium phase”. Methods In 27 patients undergoing multiphasic CT and subsequent pancreaticoduodenectomy, we investigated pathological fibrotic changes related to the ECV fraction and conducted analyses using the value obtained by subtracting the equilibrium CT value of the portal vein from that of the abdominal aorta (AoPVequilibrium) to estimate eligibility of the equilibrium phase. Results In all patients, the ECV fraction showed a weak positive correlation with the collagenous compartment ratio (r=0.388, p=0.045). All patients were divided into two groups - the high-Ao-PVequilibrium group and low-Ao-PVequilibrium group - based on the median value. No significant correlation was found in the high-Ao-PVequilibrium group, whereas a significant correlation was observed in the low-Ao-PVequilibrium group (r=0.566, p= 0.035). Conclusion The ECV fraction is a possible predictive factor for histopathological pancreatic fibrosis. In its clinical application, the eligibility of the “equilibrium phase” may affect the diagnostic capability. It will be necessary to verify the imaging conditions in order to improve the accuracy of the diagnosis.