Flavones are an important class of bioactive constituents in foods, and their structural diversity enables them to interact with different targets. In particular, flavones are known for their anti-inflammatory activity. Herein, we summarized commonly applied in vitro, in vivo, and clinical models in testing anti-inflammatory activity of flavones. The anti-inflammatory structure−activity relationship of flavones was systematically mapped and supported with cross comparisons of that with flavanones, flavanols, and isoflavones. Hydroxyl groups (−OH) are indispensable for the anti-inflammatory function of flavones, and −OH at the C-5 and C-4′ positions enhance while −OH at the C-6, C-7, C-8, and C-3′ positions attenuate their activity. Moreover, the C2−C3 single bond, −OH at the C-3 and B-ring positions undermine flavone aglycones' activity. Most of the flavone aglycones function through NF-κB, MAPK, and JNK-STAT pathways, and their possible cell binding targets are kinase, aryl hydrocarbon receptor (AhR), G-protein coupled receptors, and estrogen receptors. However, the structure and anti-inflammatory activity relationship of flavones were unclear, and further research shall be conducted to close the gap in order to guide development of evidence-based functional foods.

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Inflammation plays an essential role in the human immune system, and anti-inflammatory compounds are important to promote health. However, the in vitro screening of these compounds is largely dependent on flat biology. Herein, we report our efforts in establishing a 3D inflammation murine macrophage model. Murine macrophage RAW 264.7 cells were cultured on poly­(ε-caprolactone) (PCL) scaffolds fabricated through an electrohydrodynamic jetting 3D printer and their behavior were examined. Cells on PCL scaffolds showed a 3D shape and morphology with multilayers and a lower proliferation rate. Moreover, macrophages were not activated by scaffold material PCL and 3D microenvironment. The 3D cells showed greater sensitivity to lipopolysaccharide stimulation with higher production activity of nitric oxide (NO), nitric oxide synthases (iNOS), and cyclooxygenase-2 (COX-2). Additionally, the 3D macrophage model showed lower drug sensitivity to commercial anti-inflammatory drugs including aspirin, ibuprofen, and dexamethasone, and natural flavones apigenin and luteolin with higher IC50 for NO production and lower iNOS and COX-2 inhibition efficacy. Overall, the 3D macrophage model showed promise for higher accurate screening of anti-inflammatory compounds. We developed, for the first time, a 3D macrophage model based on a 3D-printed PCL scaffold that provides an extracellular matrix environment for cells to grow in the 3D dimension. 3D-grown RAW 264.7 cells showed different sensitivities and responses to anti-inflammatory compounds from its 2D model. The 3D cells have lower sensitivity to both commercial and natural anti-inflammatory compounds. Consequently, our 3D macrophage model could be applied to screen anti-inflammatory compounds more accurately and thus holds great potential in next-generation drug screening applications.

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