Nuclear receptor 4A1 (NR4A1) upregulated by n-butylidenephthalide via the mitogen-activated protein kinase (MAPK) pathway ameliorates drug-induced gingival enlargement.

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY BioFactors Pub Date : 2024-05-22 DOI:10.1002/biof.2077
Tomoya Ueda, Shinji Matsuda, Yurika Ninomiya, Fuminori Nakashima, Keisuke Yasuda, Daisuke Furutama, Takumi Memida, Tetsuya Yoshimoto, Mikihito Kajiya, Kouji Ohta, Kazuhisa Ouhara, Noriyoshi Mizuno
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Abstract

Drug-induced gingival enlargement (DIGE) is a side effect of ciclosporin, calcium channel blockers, and phenytoin. DIGE is a serious disease that leads to masticatory and esthetic disorders, severe caries, and periodontitis but currently has no standard treatment. We recently reported that nuclear receptor 4A1 (NR4A1) is a potential therapeutic target for DIGE. This study aimed to evaluate the therapeutic effects of n-butylidenephthalide (BP), which increases the expression of NR4A1, on DIGE. In this study, NR4A1 mRNA expression was analyzed in the patients with periodontal disease (PD) and DIGE. We evaluated the effect of BP on NR4A1 expression in gingival fibroblasts and in a DIGE mouse model. RNA sequencing (RNA-seq) was conducted to identify the mechanisms by which BP increases NR4A1 expression. The results showed that NR4A1 mRNA expression in the patients with DIGE was significantly lower than the patients with PD. BP suppressed the upregulation of COL1A1 expression, which was upregulated by TGF-β. BP also ameliorated gingival overgrowth in DIGE mice and reduced Col1a1 and Pai1 expression. BP also decreased Il1β mRNA expression in gingival tissue in DIGE. RNA-seq results showed an increase in the expression of several genes related to mitogen-activated protein kinase including DUSP genes in gingival fibroblasts stimulated by BP. Treatment with ERK and JNK inhibitors suppressed the BP-induced increase in NR4A1 expression. In addition, BP promoted the phosphorylation of ERK in gingival fibroblasts. In conclusion, BP increases NR4A1 expression in gingival fibroblasts through ERK and JNK signaling, demonstrating its potential as a preventive and therapeutic agent against DIGE.

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正丁烯基苯酞通过丝裂原活化蛋白激酶(MAPK)途径上调的核受体 4A1 (NR4A1) 可改善药物诱发的牙龈增生。
药物性牙龈增生(DIGE)是环孢素、钙通道阻滞剂和苯妥英的一种副作用。DIGE 是一种严重的疾病,会导致咀嚼和美观障碍、严重龋齿和牙周炎,但目前尚无标准治疗方法。我们最近报道,核受体 4A1(NR4A1)是 DIGE 的潜在治疗靶点。本研究旨在评估增加 NR4A1 表达的正丁烯基苯酞(BP)对 DIGE 的治疗效果。本研究分析了牙周病(PD)患者和 DIGE 患者的 NR4A1 mRNA 表达。我们评估了 BP 对牙龈成纤维细胞和 DIGE 小鼠模型中 NR4A1 表达的影响。我们进行了 RNA 测序(RNA-seq),以确定 BP 增加 NR4A1 表达的机制。结果显示,DIGE 患者的 NR4A1 mRNA 表达量明显低于 PD 患者。BP 抑制了 TGF-β 上调的 COL1A1 表达。BP 还能改善 DIGE 小鼠的牙龈过度生长,减少 Col1a1 和 Pai1 的表达。BP 还降低了 DIGE 小鼠牙龈组织中 Il1β mRNA 的表达。RNA-seq 结果显示,在 BP 的刺激下,牙龈成纤维细胞中与丝裂原活化蛋白激酶相关的几个基因(包括 DUSP 基因)的表达量增加。ERK 和 JNK 抑制剂抑制了 BP 诱导的 NR4A1 表达增加。此外,BP 还能促进ERK 在牙龈成纤维细胞中的磷酸化。总之,BP 可通过 ERK 和 JNK 信号转导增加牙龈成纤维细胞中 NR4A1 的表达,这表明它具有预防和治疗 DIGE 的潜力。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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