Luteolin-7-O-ß-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes.

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-ß-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.

Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin.

Ichthyosis Hystrix of Curth-Macklin (IH-CM) is a rare manifestation of epidermolytic ichthyosis (EI) that is characterised by generalised spiky or verrucous hyperkeratosis. The disorder is further distinguished by the presence of binucleated cells in the affected skin, whereas epidermolysis and clumping of tonofilaments, as seen in EI, are absent. While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain. Here, we studied a female sporadic patient who was born with diffused erythrodermic hyperkeratosis and who presented at the age of 13 months with an intense and widespread hyperkeratosis with a papillomatous appearance and typical palmoplantar keratoderma. Genetic analysis demonstrated a "de novo" mutation in the keratin 10 gene (KRT10) consisting of a three-base-pair deletion, resulting in the substitution of amino acids p.Glu445 and p.Ile446 by Asp at the end of the 2B domain of the protein. We performed structural and functional studies showing that this mutation modifies the structure of the paired 2B and V2 K1/10 domains, leading to the disease phenotype. Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration.