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Three Polymethoxyflavones Purified from Ougan (Citrus reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line via the JAK2/STAT3 Pathway.
Nutrients. 2019 Apr 05; 11(4)N

Abstract

In order to establish an efficient method for separation of polymethoxyflavones (PMFs) and explore the anti-inflammatory mechanism of PMF monomers, a citrus variety rich in PMFs, Ougan (Citrus reticulata cv. Suavissima), was selected, and three monomers, including nobiletin, tangeretin, and 5-demethylnobiletin, were purified by ultrasonic-assisted extraction, solid phase extraction, and high-speed countercurrent chromatography separation. UPLC-MS was used to identify the three monomers. UPLC determined purities of 99.87% to nobiletin, 99.76% to tangeretin, and 98.75% to 5-demethylnobiletin with the standard curve method. A lipopolysaccharide (LPS)-induced NO releasing model was performed in the mouse microglia BV-2 cell line. Results illustrated that PMF monomers inhibited the NO release and the inflammation-related cytokines, including IL-1β, IL-6, and TNFα elevation. QRT-PCR revealed that PMFs alleviated LPS-induced upregulation of iNOS, IL-6, JAK2, TNFα, IL-1β, and NF-κB and LPS-induced downregulation of IκBα, while they did not affect TLR1, TLR2, TLR4, and TLR6. STAT3 expression was repressed by tangeretin and 5-demethylnobiletin, but not by nobiletin. Western blot assay also showed a suppression of expression and phosphorylation of JAK2 by all three PMF monomers, while STAT3 phosphorylation was restrained by tangeretin and 5-demethylnobiletin. The mechanism was primarily verified by the JAK2 inhibitor Ruxolitinib and the STAT3 inhibitor Stattic.

Authors+Show Affiliations

Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China. fruit@zju.edu.cn.Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China. zangwj@zju.edu.cn.Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China. jishiyu@zju.edu.cn.Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China. caojinpingabc@126.com.Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China. adesun2006@zju.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30959824

Citation

Wang, Yue, et al. "Three Polymethoxyflavones Purified From Ougan (Citrus Reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line Via the JAK2/STAT3 Pathway." Nutrients, vol. 11, no. 4, 2019.
Wang Y, Zang W, Ji S, et al. Three Polymethoxyflavones Purified from Ougan (Citrus reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line via the JAK2/STAT3 Pathway. Nutrients. 2019;11(4).
Wang, Y., Zang, W., Ji, S., Cao, J., & Sun, C. (2019). Three Polymethoxyflavones Purified from Ougan (Citrus reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line via the JAK2/STAT3 Pathway. Nutrients, 11(4). https://doi.org/10.3390/nu11040791
Wang Y, et al. Three Polymethoxyflavones Purified From Ougan (Citrus Reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line Via the JAK2/STAT3 Pathway. Nutrients. 2019 Apr 5;11(4) PubMed PMID: 30959824.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Three Polymethoxyflavones Purified from Ougan (Citrus reticulata Cv. Suavissima) Inhibited LPS-Induced NO Elevation in the Neuroglia BV-2 Cell Line via the JAK2/STAT3 Pathway. AU - Wang,Yue, AU - Zang,Wenjing, AU - Ji,Shiyu, AU - Cao,Jinping, AU - Sun,Chongde, Y1 - 2019/04/05/ PY - 2019/03/01/received PY - 2019/03/26/revised PY - 2019/04/02/accepted PY - 2019/4/10/entrez PY - 2019/4/10/pubmed PY - 2019/8/28/medline KW - 5-demethylnobiletin KW - Citrus reticulata cv. Suavissima KW - JAK2/STAT3 pathway KW - NO release KW - neuroglia KW - nobiletin KW - polymethoxyflavone KW - purification KW - tangeretin JF - Nutrients JO - Nutrients VL - 11 IS - 4 N2 - In order to establish an efficient method for separation of polymethoxyflavones (PMFs) and explore the anti-inflammatory mechanism of PMF monomers, a citrus variety rich in PMFs, Ougan (Citrus reticulata cv. Suavissima), was selected, and three monomers, including nobiletin, tangeretin, and 5-demethylnobiletin, were purified by ultrasonic-assisted extraction, solid phase extraction, and high-speed countercurrent chromatography separation. UPLC-MS was used to identify the three monomers. UPLC determined purities of 99.87% to nobiletin, 99.76% to tangeretin, and 98.75% to 5-demethylnobiletin with the standard curve method. A lipopolysaccharide (LPS)-induced NO releasing model was performed in the mouse microglia BV-2 cell line. Results illustrated that PMF monomers inhibited the NO release and the inflammation-related cytokines, including IL-1β, IL-6, and TNFα elevation. QRT-PCR revealed that PMFs alleviated LPS-induced upregulation of iNOS, IL-6, JAK2, TNFα, IL-1β, and NF-κB and LPS-induced downregulation of IκBα, while they did not affect TLR1, TLR2, TLR4, and TLR6. STAT3 expression was repressed by tangeretin and 5-demethylnobiletin, but not by nobiletin. Western blot assay also showed a suppression of expression and phosphorylation of JAK2 by all three PMF monomers, while STAT3 phosphorylation was restrained by tangeretin and 5-demethylnobiletin. The mechanism was primarily verified by the JAK2 inhibitor Ruxolitinib and the STAT3 inhibitor Stattic. SN - 2072-6643 UR - https://www.unboundmedicine.com/medline/citation/30959824/Three_Polymethoxyflavones_Purified_from_Ougan__Citrus_reticulata_Cv__Suavissima__Inhibited_LPS_Induced_NO_Elevation_in_the_Neuroglia_BV_2_Cell_Line_via_the_JAK2/STAT3_Pathway_ L2 - https://www.mdpi.com/resolver?pii=nu11040791 DB - PRIME DP - Unbound Medicine ER -