Language：English   Publisher：名古屋大学医学部  

薬剤誘発性のヒト胎児由来口蓋間葉(HEPM)細胞の増殖阻害に対するクマザサ抽出エキス(SE)の保護効果を検討した。all-trans-レチノイン酸(atRA)はHEPM細胞の増殖を濃度依存性に阻害したのに対し、デキサメタゾンはHEPM細胞の増殖に影響を与えなかった。atRAによるHEPM細胞の増殖抑制は、SEの添加により抑制された。SEはHEPM細胞においてatRAにより抑制されたサイクリンD1発現を回復させた。さらにSEはHEPM細胞においてatRAによるmiR-4680-3pの発現亢進を抑制し、atRAにより抑制されたmiR-4680-3pの下流遺伝子(ERBB2、JADE1)の発現を回復させた。これらの結果より、SEはatRAによる細胞増殖阻害に対し、miR-4680-3pの発現調節を介して保護効果を発現することが示された。

Language：English   Publisher：(一社)日本毒性学会  

ヒト胎児口蓋間葉系(HEPM)細胞におけるフェニトイン(PHE)誘発性細胞増殖阻害に及ぼすマイクロRNA(miRNA)の関与を調べ、PHEは用量依存的にHEPM細胞の増殖を阻害することを明らかにした。PHE処理はHEPM細胞におけるサイクリンD1とサイクリンEの発現を低下させ、PHEはmiR-4680-3pの発現を増加させて、2種類の下流遺伝子(ERBB2とJADE1)を減少させた。miR-4680-3p特異的阻害剤はHEPM細胞の増殖を回復させ、PHE処理した細胞でERBB2とJADE1の発現を変化させた。以上兎より、PHEがmiR-4680-3p発現の調節を介して細胞増殖を抑制すると考えられた。

Language：English   Publisher：Biochemical and Biophysical Research Communications  

Cleft palate (CP) is one of the most common congenital diseases, and is accompanied by a complicated etiology. Medical exposure in women is among one of the reasons leading to CP. Recently, it has been reported that microRNA (miRNA) plays a crucial role in palate formation and the disruption of miRNA that influence the development of CP. Although association with pharmaceuticals and miRNAs were suggested, it has remained largely unknow. The aim of the current investigation is to elucidate upon the miRNA associated with the inhibition of phenobarbital (PB)-induced cell proliferation in human embryonic palatal mesenchymal (HEPM) cells. We showed that PB inhibited HEPM cell viability in a dose-dependent manner. We demonstrated that PB treatment suppressed cyclin-D1 expression in HEPM cells. Furthermore, PB upregulated let-7c-5p expression and downregulated the expression of two downstream genes (BACH1 and PAX3). Finally, we demonstrated that the let-7c-5p inhibitor alleviated PB-induced inhibition of cell proliferation and altered BACH1 and PAX3 expression levels. These results suggest that PB suppresses cell viability by modulating let-7c-5p expression.

DOI： 10.1016/j.bbrc.2024.149516

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Language：English   Publishing type：Research paper (scientific journal)  

Cleft palate (CP) is one of the most common congenital diseases, and is accompanied by a complicated etiology. Medical exposure in women is among one of the reasons leading to CP. Recently, it has been reported that microRNA (miRNA) plays a crucial role in palate formation and the disruption of miRNA that influence the development of CP. Although association with pharmaceuticals and miRNAs were suggested, it has remained largely unknow. The aim of the current investigation is to elucidate upon the miRNA associated with the inhibition of phenobarbital (PB)-induced cell proliferation in human embryonic palatal mesenchymal (HEPM) cells. We showed that PB inhibited HEPM cell viability in a dose-dependent manner. We demonstrated that PB treatment suppressed cyclin-D1 expression in HEPM cells. Furthermore, PB upregulated let-7c-5p expression and downregulated the expression of two downstream genes (BACH1 and PAX3). Finally, we demonstrated that the let-7c-5p inhibitor alleviated PB-induced inhibition of cell proliferation and altered BACH1 and PAX3 expression levels. These results suggest that PB suppresses cell viability by modulating let-7c-5p expression.

DOI： doi.org/10.1016/j.bbrc.2024.149516

Language：English   Publisher：Nagoya Journal of Medical Science  

Cleft palate is the most common facial birth defect worldwide. It is caused by environmental factors or genetic mutations. Environmental factors such as pharmaceutical exposure in women are known to induce cleft palate. The aim of the present study was to investigate the protective effect of Sasa veitchii extract against medicine-induced inhibition of proliferation of human embryonic palatal mesenchymal cells. We demonstrated that all-trans-retinoic acid inhibited human embryonic palatal mesenchymal cell proliferation in a dose-dependent manner, whereas dexamethasone treatment had no effect on cell proliferation. Cotreatment with Sasa veitchii extract repressed all-trans-retinoic acid-induced toxicity in human embryonic palatal mesenchymal cells. We found that cotreatment with Sasa veitchii extract protected all-trans-retinoic acid-induced cyclin D1 downregulation in human embryonic palatal mesenchymal cells. Furthermore, Sasa veitchii extract suppressed all-trans-retinoic acid-induced miR-4680-3p expression. Additionally, the expression levels of the genes that function downstream of the target genes (ERBB2 and JADE1) of miR-4680-3p in signaling pathways were enhanced by cotreatment with Sasa veitchii extract and all-trans-retinoic acid compared to all-trans-retinoic acid treatment. These results suggest that Sasa veitchii extract suppresses all-trans-retinoic acid-induced inhibition of cell proliferation via modulation of miR-4680-3p expression.

DOI： 10.18999/nagjms.86.2.223

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Language：English   Publisher：The Japanese Society of Toxicology  

<p>Cleft palate (CP) is one of the most common birth defects and is caused by a combination of genetic and/or environmental factors. Environmental factors such as pharmaceutical exposure in pregnant women are known to induce CP. Recently, microRNA (miRNA) was found to be affected by environmental factors. The aim of the present study was to investigate the involvement of miRNA against phenytoin (PHE)-induced inhibition of proliferation in human embryonic palatal mesenchymal (HEPM) cells. We demonstrated that PHE inhibited HEPM cell proliferation in a dose-dependent manner. We found that treatment with PHE downregulated cyclin-D1 and cyclin-E expressions in HEPM cells. Furthermore, PHE increased <i>miR-4680-3p</i> expression and decreased two downstream genes (<i>ERBB2</i> and <i>JADE1</i>). Importantly, an <i>miR-4680-3p</i>-specific inhibitor restored HEPM cell proliferation and altered expression of <i>ERBB2</i> and <i>JADE1</i> in cells treated with PHE. These results suggest that PHE suppresses cell proliferation via modulation of <i>miR-4680-3p</i> expression.</p>

DOI： 10.2131/jts.49.1

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Language：English   Publisher：International Journal of Oral and Maxillofacial Surgery  

The aim of this study was to clarify the correlation between imaging findings obtained using intraoral ultrasonography (US) and pathological findings of tongue cancers, and to examine the predictive value of intraoral US findings with respect to occult nodal metastasis. This was a retrospective study based on the medical records of 123 patients with T1–2N0 tongue cancer. The depth of invasion (DOI) on intraoral US was positively correlated with the pathological invasion depth (PID) (ρ = 0.7080, P < 0.0001). Receiver operating characteristic analyses revealed an optimal DOI cut-off value of 4.1 mm and optimal PID cut-off value of 3.9 mm to detect nodal metastasis. Regarding the margin shape of the primary tumour on intraoral US, the incidence of nodal metastasis was significantly higher for the permeated type than for the pressure type (P < 0.001) and wedge-shaped type (P = 0.002). Furthermore, tumours with peritumoural vascularity assessed by power Doppler US had a significantly higher incidence of nodal metastasis than tumours without (P = 0.003). The sensitivity, specificity, and accuracy of the permeated type to predict nodal metastasis was 53.6%, 95.8%, and 86.2%, respectively. These results suggest that intraoral US findings closely reflect pathological findings and could be useful to predict occult nodal metastasis in patients with early-stage tongue cancer.

DOI： 10.1016/j.ijom.2022.08.021

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Language：English   Publisher：Biomedical Research Press  

<p>A cleft lip, with or without a cleft palate, is a common birth defect caused by environmental factors or genetic mutations. Environmental factors, such as pharmaceutical exposure in pregnant women, are known to induce cleft lip, with or without cleft palate in the child. This study aimed to investigate the protective effect of Sasa veitchii extract (SE) on phenytoin-induced inhibition of cell proliferation in human lip mesenchymal cells (KD cells) and human embryonic palatal mesenchymal cells (HEPM cells). We demonstrated that cell proliferation was inhibited by phenytoin in a dose-dependent manner in both KD and HEPM cells. Co-treatment with SE restored phenytoin-induced toxicity in KD cells but did not protect HEPM cells against phenytoin-induced toxicity. Several microRNAs (<i>miR-27b</i>, <i>miR-133b</i>, <i>miR-205</i>, <i>miR-497-5p</i>, and <i>miR-655-3p</i>) is reported to associate with cell proliferation in KD cells. We measured the seven kinds of microRNAs (<i>miR27b-3p</i>, <i>miR-27b-5p</i>, <i>miR-133b</i>, <i>miR-205-3p</i>, <i>miR-205-5p</i>, <i>miR-497-5p</i>, and <i>miR-655-3p</i>) and found that SE suppressed <i>miR-27b-5p</i> induced by phenytoin in KD cells. Furthermore, co-treatment with SE enhanced the expression of <i>miR-27b-5p</i> downstream genes (<i>PAX9</i>, <i>RARA</i>, and <i>SUMO1</i>). These results suggest that SE protects phenytoin-induced cell proliferation inhibition by modulating <i>miR-27b-5p</i>.</p>

DOI： 10.2220/biomedres.44.73

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Language：English   Publisher：バイオメディカルリサーチプレス  

ヒト口唇間葉系細胞のKD細胞とヒト胚口蓋間充織細胞のHEPM細胞を用いて、フェニトイン誘発細胞増殖阻害に対するクマザサ抽出物(SE)の防護作用について検討した。その結果、KD細胞とHEPM細胞の増殖はフェニトインにより用量依存的に阻害された。また、KD細胞のフェニトイン誘発細胞増殖阻害はSEにより濃度依存的に抑制されたが、HEPM細胞のフェニトイン誘発細胞増殖阻害はSEにより抑制されなかった。次に、KD細胞で細胞増殖との関連性が報告されている7種類のマイクロRNA発現を調べたところ、フェニトインによりmiR-27b-5pとmiR-205-3pが上方制御され、フェニトイン誘発によるmiR-27b-5p発現は、SEにより抑制されることが確認された。他にも、miR-27b-5pの下流遺伝子であるPAX9遺伝子、RARA遺伝子およびSUMO1遺伝子の発現は、SEにより増加することも明らかにされた。以上より、SEはmiR-27b-5pを調節することにより、フェニトイン誘発による細胞増殖阻害からヒト口唇間葉細胞を防護することが示唆された。

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p><b><u>Background:</u></b> Cleft palate (CP) is the second most common birth defect in humans worldwide. Previous studies have identified gene mutations, chromosomal abnormalities, and teratogens in CP. In addition to genetic mutations, genetic background (e.g. ethnicity, population of origin, and gender), substantially influences CP prevalence. Maternal age, smoking, alcohol consumption, obesity, and micronutrient deficiencies are known, or strongly suspected, experimental risk factors for CP. Therefore, the etiology of CP is complex, and its risk factors are still being elucidated. Folic acid is known to decrease the risk of CP. Although dietary intake of folic acid is first choice to prevent CP, searching the alternative method is also important for the patients such as folic acid metabolism anomaly. In the present study, we examined the protective effects of Sasa vetichii extract (SE) in all trans-retinoic acid (atRA)-induced cell proliferation inhibition in human embryonic palatal mesenchymal cells (HEPM cells). </p><p><b><u>Results and Discussion</u></b>: We demonstrated that atRA induced cell proliferation inhibition in a dose dependent manner in HEPM cells. We found that SE did not affect cell proliferation. Co-treatment with SE restored atRA-induced toxicity. Furthermore, we found that atRA-induced miR-4680-3p and co-treatment with SE downregulated miR-4680-3p. Additionally, downstream gene (ERBB2 and JADE1) of miR-4680-3p was potentiated by co-treatment with SE. These results suggested that SE protected atRA-induced cell proliferation inhibition by modulating miR-4680-3p</p>

DOI： 10.14869/toxpt.50.1.0_p2-114

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Language：English   Publisher：Spandidos Publications  

Mixed tumor of the skin (MTS) is a rare neoplasm derived from the sweat glands with a reported frequency of 0.01‑0.098% among all primary skin tumors. MTS often occurs in the head and neck region and is characterized by a mixture of epithelial, myoepithelial and stromal components. MTS also shows various morphological patterns, thus the presence of variants with rare components and its rarity make the clinical diagnosis even more difficult. A 47‑year‑old man was referred due to a painless, slowly growing, exophytic swelling intracutaneous mass of the upper lip. Magnetic resonance imaging revealed that the mass was a solid tumor with a fatty component in the proximal portion, while the distal portion was cystic and possibly contained highly viscous fluid. The mass was located between the skin and the orbicularis oris muscle in the upper lip. Excisional biopsy was performed and the lesion showed two intriguing features: A tumor with extensive lipomatous stroma and some large cysts. It was histopathologically diagnosed as lipomatous MTS with cystic formation in the upper lip. No evident signs of recurrence were observed during follow‑up. The present report describes this case and includes a brief literature review of reported cases in the lip, since MTS can be confused with various skin lesions in clinical settings due to this rarity. Recognition by clinicians of different variants of MTSs, including the present case, is important for preventing erroneous diagnosis and treatment.

DOI： 10.3892/etm.2022.11600

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/etm.2022.11600.

Language：English   Publisher：Pathology Research and Practice  

We recently demonstrated that Semaphorin 3 A (Sema3A), the expression of which is negatively regulated by Wnt/β-catenin signaling, promotes odontogenic epithelial cell proliferation, suggesting the involvement of Sema3A in tooth germ development. Salivary glands have a similar developmental process to tooth germ development, in which reciprocal interactions between the oral epithelium and adjacent mesenchyme proceeds via stimulation with several growth factors; however, the role of Sema3A in the development of salivary glands is unknown. There may thus be a common mechanism between epithelial morphogenesis and pathogenesis; however, the role of Sema3A in salivary gland tumors is also unclear. The current study investigated the involvement of Sema3A in submandibular gland (SMG) development and its expression in adenoid cystic carcinoma (ACC) specimens. Quantitative RT-PCR and immunohistochemical analyses revealed that Sema3A was expressed both in epithelium and in mesenchyme in the initial developmental stages of SMG and their expressions were decreased during the developmental processes. Loss-of-function experiments using an inhibitor revealed that Sema3A was required for AKT activation-mediated cellular growth and formation of cleft and bud in SMG rudiment culture. In addition, Wnt/β-catenin signaling decreased the Sema3A expression in the rudiment culture. ACC arising from salivary glands frequently exhibits malignant potential. Immunohistochemical analyses of tissue specimens obtained from 10 ACC patients showed that Sema3A was hardly observed in non-tumor regions but was strongly expressed in tumor lesions, especially in myoepithelial neoplastic cells, at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the Sema3A-AKT axis promotes cell growth, thereby contributing to morphogenesis and pathogenesis, at least in ACC, of salivary glands.

DOI： 10.1016/j.prp.2022.153991

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ol.2018.9115.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00432-017-2398-2

Language：Japanese