The Flavonoid Phloretin Suppresses Stimulated Expression of Endothelial Adhesion Molecules and Reduces Activation of Human Platelets

Abstract

Atherosclerosis is a chronic inflammatory disease accompanied by the expression of endothelial adhesion molecules. Phloretin is a plant-derived phytochemical that is mainly present in apples. Because phloretin is reported to promote antioxidative activities, we investigated the effects of phloretin on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in human umbilical vein endothelial cells (HUVECs). Phloretin prevented TNF-alpha-stimulated upregulation of VCAM-1, ICAM-1, and E-selectin expression in a concentration-dependent manner. To the same extent as for TNF-alpha, phloretin also inhibited IL-1beta-induced upregulation in expression of all 3 adhesion molecules. Inhibition of cytokine-induced adhesion molecule expression for VCAM-1, ICAM-1, and E-selectin was detected already at the level of mRNA. Preincubation with phloretin dose-dependently attenuated TNF-alpha-stimulated adhesion of monocytic THP-1 cells to HUVECs and human aortic endothelial cells. Phloretin did not affect TNF-alpha-stimulated activation of nuclear factor kappaB (NF-kappaB) but inhibited activation of interferon regulatory factor 1, a transcription factor involved in the regulation of endothelial cell adhesion molecule expression. In human platelets, phloretin diminished adenosine diphosphate (ADP) and thrombin receptor-activating peptide-stimulated expression of the activated form of the GPIIb/IIIa complex and reduced platelet aggregation stimulated by ADP. Thus phloretin may have beneficial effects in the onset and progression of cardiovascular diseases.

Anti-inflammatory Activity of the Synthetic Chalcone Derivatives: Inhibition of Inducible Nitric Oxide Synthase-Catalyzed Nitric Oxide Production from Lipopolysaccharide-Treated RAW 264.7 Cells

“…17) Phloretin suppresses the stimulated expression of endothelial adhesion molecules. 18) All this regulatory activity of proinflammatory molecules including iNOS by certain chalcones may contribute to their anti-inflammatory activity.…”

Apple Flavonoid Phloretin Inhibits Escherichia coli O157:H7 Biofilm Formation and Ameliorates Colon Inflammation in Rats

“…Phloretin accounts in part for the antioxidant capacity of apples, and phloretin has also been revealed to have anticarcinogenic activities (50) and in vitro anti-inflammatory activity on colon epithelial cells (17) and on vein endothelial cells (41). In a previous study, it was shown that phloretin downregulated the mRNA levels of most tested proinflammatory genes (NF-B, TNF-␣, interleukin-8, CXCL3, CXCL10, signal transducer and activator of transcription 1, and interferon gamma-induced protein 10) in human colon epithelial cells in vitro (17).…”

“…Among numerous flavonoids, phloretin is a dihydrochalcone, a type of polyphenol mainly found in apples (about 5 mg/100 g of fresh apple) and strawberries. Phloretin has various biological functions, such as antioxidative (36), anticarcinogenic (50), and estrogenic (6) activities and inhibition of cardiovascular disease (10,41). Recently, several other flavonoids showed the ability to inhibit the biofilm formation of Streptococcus mutans (22), Aeromonas hydrophila (18), and Escherichia coli O157:H7 (48).…”

Evaluation of Apoptotic and Growth Inhibitory Activity of Phloretin in BGC823 Gastric Cancer Cell

“…Phloretin is mainly found in apples and strawberries [8][9][10]. It has numerous biological properties, including reduction of human platelets activity, competitive inhibition of sodium-glucose cotransporters (SGLTs), inhibition of cardiovascular disease and anticarcinogenic activity [11,12]. Compared with other flavonoids, however, few studies have investigated the anti-tumor potential of phloretin.…”