Abstract
Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant.
Highlights
IntroductionRecent literature data show interesting positive effects of plant-derived molecules in clinical trials regarding the treatment of inflammatory skin diseases [1,2], and a wide interest has been stimulated by flavonoids
Recent literature data show interesting positive effects of plant-derived molecules in clinical trials regarding the treatment of inflammatory skin diseases [1,2], and a wide interest has been stimulated by flavonoids.Flavonoids molecules (Figure S1) have been reported to have important effects in plant biochemistry
Our results show that LUT-7G, is able to impair the nuclear translocation of signal transducer and activator of transcription 3 (STAT3), but it blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity
Summary
Recent literature data show interesting positive effects of plant-derived molecules in clinical trials regarding the treatment of inflammatory skin diseases [1,2], and a wide interest has been stimulated by flavonoids. In our recent work [12] we demonstrated that luteolin, as luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce keratinocyte differentiation process in vitro, counteracting the proliferative effects of critical mediators in psoriasis, like IL-22 and IL6 [13]. This proliferative pathway is achieved by enhancing the transcription of signal transducer and activator of transcription 3 (STAT3). Keratinocytes undergo a transformation in corneocytes, which implies a strong modification of cell structure and function [15,16], losing their main internal structures, such as the nucleus, endoplasmic reticulum (RE), and Golgi [17,18] These changes involve, above all, metabolic pathways alteration. A complete metabolomics analysis has been performed using human primary keratinocytes (HEKn) treated with LUT-7G, and the results have been compared to normal keratinocyte differentiation
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