Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression
Background: Propolis and its preparations are components of TCM and functional food sources for antihyperlipidemia therapy. However, due to the metabolic properties of propolis, its individual components remain ambiguous, especially those that are therapeutically active. Purpose: The study presented...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | Phytomedicine Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667031320300063 |
| _version_ | 1818574041270714368 |
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| author | Zhao Chen Wenhui Luo Dongmei Sun Xiaoli Bi Xiaohui Zeng Guanlin Xiao Aili Xu Weitao Chen Jieyi Jiang Xiyuan Li Lizhong Cao |
| author_facet | Zhao Chen Wenhui Luo Dongmei Sun Xiaoli Bi Xiaohui Zeng Guanlin Xiao Aili Xu Weitao Chen Jieyi Jiang Xiyuan Li Lizhong Cao |
| author_sort | Zhao Chen |
| collection | DOAJ |
| description | Background: Propolis and its preparations are components of TCM and functional food sources for antihyperlipidemia therapy. However, due to the metabolic properties of propolis, its individual components remain ambiguous, especially those that are therapeutically active. Purpose: The study presented here identified the primary target (PXR/CYP3A4) of propolis activity against hyperlipidemia and evaluated individual compounds of propolis to select a quality control marker based on this activity. Methods: Mice fed a high-fat diet were used to study the efficacy of propolis, followed by identification of substantially influenced glycolipid regulatory target(s) by propolis. Since propolis had the strongest effect on PXR expression, we took advantage of its downstream target CYP3A4, the drug metabolism activity of such enzyme is affected by alterations in PXR expression. Thus, we used the production of 1’-hydroxy-midazolam as an indicator. Compounds found by UHPLC-TOF-MS were added to a HepG2 cell solution (transfected by PXR mRNA and the CYP3A4 plasmid to simulate drug metabolism in the body) in the form of a monomer, followed by the addition of midazolam. Changes in the amount of “indicator” were used to investigate each compound's qualitative (promote or suppress) and quantitative activity. Compounds with obvious effects were quantified in propolis extract, as confirmed via Western Blot analysis regarding their PXR regulatory activity, and subjected to pharmacokinetic analysis to biter understand their metabolism in the body. Finally, components passing these screens could be regarded as quality control markers capable of indicating the efficacy of antihyperlipidemic activity via PXR/CYP3A4 regulation. Results: The use of propolis was effective in lowering TG and TC levels in mice, as well as in repairing their injured livers; its activity was comparable to the chemical and TCM positive controls. Propolis mainly suppressed PXR expression compared with other regulatory targets that were tested. Most of the individual compounds from propolis (13 out of 15) showed obvious regulatory activity of PXR/CYP3A4; however, content quantification and pharmacokinetic analyses narrowed the selection to 2 compounds, kaempferol and chrysin, as the main active components responsible for the antihyperlipidemic effect of propolis. In other words, this study suggested that propolis mainly acts on the PXR/CYP3A4 pathway to regulate glycolipid metabolism, and the 2 compounds mentioned above can be used as quality control markers (QM) to evaluate the efficacy of this activity. Conclusion: Propolis's antihyperlipidemic effect relies on its regulation of PXR/CYP3A4 expression. Kaempferol and chrysin can be regarded as QMs. In addition, the metabolite-based method for evaluating regulatory activity is much faster, more effective, and more reliable than the conventional screening method, paving the way for its future applications. |
| first_indexed | 2024-12-15T00:21:09Z |
| format | Article |
| id | doaj.art-7b70e8f12c7f4eb2a815e5cc552ddfe6 |
| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-15T00:21:09Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
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| series | Phytomedicine Plus |
| spelling | doaj.art-7b70e8f12c7f4eb2a815e5cc552ddfe62022-12-21T22:42:18ZengElsevierPhytomedicine Plus2667-03132021-02-0111100006Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expressionZhao Chen0Wenhui Luo1Dongmei Sun2Xiaoli Bi3Xiaohui Zeng4Guanlin Xiao5Aili Xu6Weitao Chen7Jieyi Jiang8Xiyuan Li9Lizhong Cao10The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Yifang Pharmaceutical co. ltd., 69 jinfeng rd., Foshan 528244, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Yifang Pharmaceutical co. ltd., 69 jinfeng rd., Foshan 528244, China; Corresponding authors at: The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China.The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, ChinaThe School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, 14214, NY, USAThe Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China; Corresponding authors at: The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd., Guangzhou 510095, China.Background: Propolis and its preparations are components of TCM and functional food sources for antihyperlipidemia therapy. However, due to the metabolic properties of propolis, its individual components remain ambiguous, especially those that are therapeutically active. Purpose: The study presented here identified the primary target (PXR/CYP3A4) of propolis activity against hyperlipidemia and evaluated individual compounds of propolis to select a quality control marker based on this activity. Methods: Mice fed a high-fat diet were used to study the efficacy of propolis, followed by identification of substantially influenced glycolipid regulatory target(s) by propolis. Since propolis had the strongest effect on PXR expression, we took advantage of its downstream target CYP3A4, the drug metabolism activity of such enzyme is affected by alterations in PXR expression. Thus, we used the production of 1’-hydroxy-midazolam as an indicator. Compounds found by UHPLC-TOF-MS were added to a HepG2 cell solution (transfected by PXR mRNA and the CYP3A4 plasmid to simulate drug metabolism in the body) in the form of a monomer, followed by the addition of midazolam. Changes in the amount of “indicator” were used to investigate each compound's qualitative (promote or suppress) and quantitative activity. Compounds with obvious effects were quantified in propolis extract, as confirmed via Western Blot analysis regarding their PXR regulatory activity, and subjected to pharmacokinetic analysis to biter understand their metabolism in the body. Finally, components passing these screens could be regarded as quality control markers capable of indicating the efficacy of antihyperlipidemic activity via PXR/CYP3A4 regulation. Results: The use of propolis was effective in lowering TG and TC levels in mice, as well as in repairing their injured livers; its activity was comparable to the chemical and TCM positive controls. Propolis mainly suppressed PXR expression compared with other regulatory targets that were tested. Most of the individual compounds from propolis (13 out of 15) showed obvious regulatory activity of PXR/CYP3A4; however, content quantification and pharmacokinetic analyses narrowed the selection to 2 compounds, kaempferol and chrysin, as the main active components responsible for the antihyperlipidemic effect of propolis. In other words, this study suggested that propolis mainly acts on the PXR/CYP3A4 pathway to regulate glycolipid metabolism, and the 2 compounds mentioned above can be used as quality control markers (QM) to evaluate the efficacy of this activity. Conclusion: Propolis's antihyperlipidemic effect relies on its regulation of PXR/CYP3A4 expression. Kaempferol and chrysin can be regarded as QMs. In addition, the metabolite-based method for evaluating regulatory activity is much faster, more effective, and more reliable than the conventional screening method, paving the way for its future applications.http://www.sciencedirect.com/science/article/pii/S2667031320300063PropolisPXR/CYP3A4 pathwayGlycolipid metabolismQuality control markers |
| spellingShingle | Zhao Chen Wenhui Luo Dongmei Sun Xiaoli Bi Xiaohui Zeng Guanlin Xiao Aili Xu Weitao Chen Jieyi Jiang Xiyuan Li Lizhong Cao Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression Phytomedicine Plus Propolis PXR/CYP3A4 pathway Glycolipid metabolism Quality control markers |
| title | Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression |
| title_full | Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression |
| title_fullStr | Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression |
| title_full_unstemmed | Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression |
| title_short | Selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating PXR/CYP3A4 expression |
| title_sort | selection and evaluation of quality control markers in propolis based on its hyperlipidemia therapy via regulating pxr cyp3a4 expression |
| topic | Propolis PXR/CYP3A4 pathway Glycolipid metabolism Quality control markers |
| url | http://www.sciencedirect.com/science/article/pii/S2667031320300063 |
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