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Published on: August 14, 2019
Identification and Structure-Activity Relationships of Dietary Flavonoids as Human Macrophage Migration Inhibitory
Liu Yang1, Deyin Guo1,2, Chengpeng Fan1
1School of Basic Medical Sciences, Wuhan University, Wuhan 430072, P. R. China.
Abstract:
Dietary flavonoids are known to have anti-inflammatory and anticancer effects, but their influences on human macrophage migration inhibitory factor (MIF), a vital proinflammatory cytokine recognized as a therapeutic target for infectious diseases and cancers, have been rarely reported. Here, we identified 24 dietary flavonoids that could inhibit the tautomerase activity of MIF, five of which exerted IC50 values lower than the positive control ISO-1 in the micromolar range: morin (IC50 = 11.01 ± 0.45 μM) and amentoflavone (IC50 = 13.32 ± 0.64 μM) exhibited the most potent efficacy followed by apigenin (IC50 = 42.74 ± 4.20 μM), naringin (IC50 = 51.38 ± 2.12 μM), and fisetin (IC50 = 51.99 ± 0.63 μM). X-ray crystallography, molecular docking, and cellular experiments were utilized to illustrate the molecular binding details and structure-activity relationships. Scaffold modifications of flavonoids significantly influenced the potency. What stands out for morin is the unique 2'-OH substitution. In addition, amentoflavone situated at the MIF trimer pore may impact MIF-CD74 signaling. The results also showed that flavonoids could suppress cell chemotaxis and nitric oxide production in RAW264.7 cells. Our results elucidate the molecular mechanism of flavonoids acting on MIF and shed light on developing lead compounds against MIF-involved diseases.
Insights
Dietary flavonoids can inhibit macrophage migration inhibitory factor (MIF), a key target for diseases. Morin and amentoflavone show potent inhibition, offering potential for new therapeutic lead compounds.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Dietary flavonoids possess anti-inflammatory and anticancer properties.
- Macrophage migration inhibitory factor (MIF) is a crucial proinflammatory cytokine and a therapeutic target for infectious diseases and cancers.
- The effect of dietary flavonoids on MIF activity has been underexplored.
Purpose of the Study:
- To investigate the inhibitory effects of dietary flavonoids on the tautomerase activity of MIF.
- To elucidate the molecular mechanisms and structure-activity relationships of flavonoid-MIF interactions.
- To assess the impact of flavonoids on MIF-mediated cellular functions like chemotaxis and nitric oxide production.
Main Methods:
- Screening of 24 dietary flavonoids for MIF tautomerase inhibition.
- Determination of IC50 values for potent inhibitors.
- Utilizing X-ray crystallography, molecular docking, and cellular assays (RAW264.7 cells) to analyze binding and function.
- Structure-activity relationship analysis based on scaffold modifications.
Main Results:
- Five flavonoids, including morin and amentoflavone, demonstrated significant MIF inhibition in the micromolar range.
- Morin's potent activity is linked to its unique 2'-OH substitution.
- Amentoflavone's interaction with the MIF trimer pore suggests potential impact on MIF-CD74 signaling.
- Flavonoids suppressed cell chemotaxis and nitric oxide production in RAW264.7 cells.
Conclusions:
- Dietary flavonoids effectively inhibit MIF tautomerase activity and downstream cellular functions.
- Specific structural features of flavonoids, like morin's 2'-OH group, enhance inhibitory potency.
- Flavonoids represent promising lead compounds for developing novel therapeutics against MIF-related diseases.
