Identification of Interleukin-8-Reducing Lead Compounds Based on SAR Studies on Dihydrochalcone-Related Compounds in Human Gingival Fibroblasts (HGF-1 cells) In Vitro

Abstract

Background: In order to identify potential activities against periodontal diseases, eighteen dihydrochalcones and structurally related compounds were tested in an established biological in vitro cell model of periodontal inflammation using human gingival fibroblasts (HGF-1 cells). Methods: Subsequently to co-incubation of HGF-1 cells with a bacterial endotoxin (Porphyromonas gingivalis lipopolysaccharide, pgLPS) and each individual dihydrochalcone in a concentration range of 1 µM to 100 µM, gene expression of interleukin-8 (IL-8) was determined by qPCR and cellular interleukin-8 (IL-8) release by ELISA. Results: Structure–activity analysis based on the dihydrochalcone backbone and various substitution patterns at its aromatic ring revealed moieties 2′,4,4′,6′-tetrahydroxy 3-methoxydihydrochalcone (7) to be the most effective anti-inflammatory compound, reducing the pgLPS-induced IL-8 release concentration between 1 µM and 100 µM up to 94%. In general, a 2,4,6-trihydroxy substitution at the A-ring and concomitant vanilloyl (4-hydroxy-3-methoxy) pattern at the B-ring revealed to be preferable for IL-8 release inhibition. Furthermore, the introduction of an electronegative atom in the A,B-linker chain led to an increased anti-inflammatory activity, shown by the potency of 4-hydroxybenzoic acid N-vanillylamide (13). Conclusions: Our data may be feasible to be used for further lead structure designs for the development of potent anti-inflammatory additives in oral care products.

Human Gingival Fibroblasts as a Novel Cell Model Describing the Association between Bitter Taste Thresholds and Interleukin-6 Release

“…Appropriate controls of cell culture medium treated cells only always contained 0.1% (v/v) DMSO. For inducing a pro-inflammatory IL-6 release, HGF-1 cells were treated with Pg -LPS in a final concentration of 10 μg/mL for 6 h. − …”

“…Fibroblasts are located in connective tissues and represent an important key player in the inflammatory responses to external stimuli . They are involved in processes of tissue repair via the extra cellular matrix as well as regulating processes during acute and adaptive immunity. − Human gingival fibroblasts of the HGF-1 cell line are well established for the identification of anti-inflammatory plant components by reducing the release of the pro-inflammatory proteins tumor necrosis factor α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) − after exposure to lipopolysaccharides (LPS) . Expression of human bitter taste receptors (TAS2Rs) and their involvement in inflammatory processes in HGF-1 cells has been demonstrated by the following two very recent studies: Zhou et al.…”

The Anti-Biofilm Properties of Phloretin and Its Analogs against Porphyromonas gingivalis and Its Complex Flora

“…Most of these polyphenols have a flavonoid structure. Among them, potential structure-activity relationships have been reported for chalcones in inhibiting several oral pathogenic bacteria, including differences in antibacterial properties and changes in anti-inflammatory capabilities [23,24]. However, there are no reports exploring the effect of the structure-activity relationship on the ability of chalcones to inhibit P. gingivalis biofilms.…”