title: Luteolin and apigenin activate the Oct-4/Sox2 signal via NFATc1 in human periodontal ligament cells.
abstract: Identifying small molecules to activate the Oct-4/Sox2-derived pluripotency network represents a hopeful and safe method to pluripotency without genetic manipulation. Luteolin and apigenin, two major bioactive flavonoids, enhance reprogramming efficiency and increase expression of Oct-4/Sox2/c-Myc, albeit the detailed mechanism regulating pluripotency in dental-derived cells remains unknown. In the present study, to elucidate the effect of luteolin/apigenin on pluripotency of periodontal ligament cells (PDLCs) through interaction with downstream signals, we examined cell cycle, proliferation, apoptosis, expression of Oct-4/Sox2/c-Myc, and multilineage differentiation of PDLCs with luteolin/apigenin treatment. Moreover, we profiled the differentially expressed pluripotency genes by PCR arrays. Our results demonstrated that luteolin/apigenin restrained cell proliferation, increased apoptosis, and arrested PDLCs in G2/M and S phase. Luteolin and apigenin activated expression of Oct-4, Sox2, and c-Myc in a time- and dose-dependent pattern, and repressed lineage-specific differentiation. PCR arrays profiled multiple signals in PDLCs with luteolin/apigenin treatment, among which NFATc1 was the major upregulated gene. Notably, blocking of the NFATc1 signal with INCA-6 significantly decreased mRNA and protein expression of Oct-4, Sox2, and c-Myc in PDLCs with luteolin/apigenin treatment, indicating that NFATc1 may act as an upstream modulator of Oct-4/Sox2 signal. Taken together, this study showed that luteolin and apigenin effectively maintain pluripotency of PDLCs through activation of Oct-4/Sox2 signal via NFATc1.
authors.affiliation: Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, 56 Lingyuan Xi Rd, Guangzhou, 510055, Guangdong, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, 56 Lingyuan Xi Rd, Guangzhou, 510055, Guangdong, China.
authors.forename: Zhengjun
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, 56 Lingyuan Xi Rd, Guangzhou, 510055, Guangdong, China.
authors.forename: Haoquan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, 56 Lingyuan Xi Rd, Guangzhou, 510055, Guangdong, China.
authors.forename: Zhezhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Guangdong Province Key Laboratory of Stomatology, Sun Yat-Sen University, 56 Lingyuan Xi Rd, Guangzhou, 510055, Guangdong, China. weixi@mail.sysu.edu.cn.
authors.forename: Xi
authors.initials: X
authors.lastname: Wei
mesh_terms: D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003782:Dental Pulp / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C489427:MYC protein, human; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D047310:Apigenin; D047311:Luteolin
keywords: NFATc1; Oct-4/Sox2 signal; apigenin; luteolin; pluripotency