RESUMO
The red maple and sugar maple (Acer rubrum and A. saccharum, respectively) contain acertannins (ginnalins and maplexins), galloylated derivatives of 1,5-anhydro-d-glucitol (1,5-AG, 1). These compounds have a variety of potential medicinal properties and we have shown that some of them promote the expression of ceramide synthase 3. We now report on the beneficial effects of ginnalin B, (6-O-galloyl-1,5-AG, 5), leading to acceleration of skin metabolism and reduction of the turnover time. Ginnalin B dose-dependently increased the relative amount of keratin 10, keratin 1, and filaggrin gene, with maximal increase of 1.7-, 2.9, and 5.2-fold at 100⯵M, respectively. The validation study showed that it had superior capacity to induce multiple stages of keratinocyte differentiation and significantly elevated the immunostaining site of keratin 10 and filaggrin in a 3-dimensional cultured human skin model, by 1.2 and 2.8-fold, respectively. Furthermore, ginnalin B caused the arrest of proliferation at the G0/G1 phase but it did not induce apoptotic cell death in normal human keratinocytes. Molecular studies revealed that ginnalin B up-regulated the levels of NOTCH1 and a concomitant increase p21 expression. Ginnalin B, therefore, represents a new class of promising functional and medical cosmetic compound and it could contribute to the maintenance of homeostasis of the epidermis.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Receptor Notch1/metabolismo , Pele/efeitos dos fármacos , Sorbitol/análogos & derivados , Antígenos de Diferenciação/metabolismo , Linhagem Celular , Proteínas Filagrinas , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Queratina-1/metabolismo , Queratina-10/metabolismo , Sorbitol/farmacologiaRESUMO
The location, orientation, and dynamics of hydrophobic small molecules in lipid membranes are studied through combined use of solution-state (1)H-NMR and MD simulation. 1-Naphthol and 1-methylnaphthalene were adopted as the small molecules with or without hydrophilic groups. The nuclear Overhauser effect (NOE) measurement was performed for large unilamellar vesicles (100 nm in diameter) composed of dimyristoylphosphatidylcholine (DMPC) and the naphthalene derivative. The transient NOE-SE (spin-echo) scheme previously reported (J. Phys. Chem. B, 2011, 115, 9106-9115) was employed to quantitatively determine the NOE cross relaxation rate constant between DMPC and the naphthalene derivative. The observed NOE shows that both the naphthalene derivatives distribute over a wide domain across the normal of the essentially planar membrane ranging from the hydrophobic core to the hydrophilic headgroup. The experimental NOE information was further refined in combination with the analysis of time correlation functions in MD simulation. It was found that 1-naphthol exhibits a slight preference for pointing its OH group toward the hydrophilic domain of the membrane and that no definite preference can be concluded for the orientation of 1-methylnaphthalene. When 1-naphthol and 1-methylnaphthalene are compared, the NOE is stronger for 1-naphthol due to the restricted motion of the OH group. The slowdown of the 1-naphthol motion is also evidenced by the (1)H spectral line width.
Assuntos
Dimiristoilfosfatidilcolina/metabolismo , Lipídeos de Membrana/metabolismo , Simulação de Dinâmica Molecular , Naftalenos/metabolismo , Naftóis/metabolismo , Lipossomas Unilamelares/metabolismo , Dimiristoilfosfatidilcolina/química , Espectroscopia de Ressonância Magnética , Lipídeos de Membrana/química , Naftalenos/química , Naftóis/química , Lipossomas Unilamelares/químicaRESUMO
Motional correlation times between the hydrophilic and hydrophobic terminal groups in lipid membranes are studied over a wide range of curvatures using the solution-state (1)H NMR-nuclear Overhauser effect (NOE) and molecular dynamics (MD) simulation. To enable (1)H NMR-NOE measurements for large vesicles, the transient NOE method is combined with the spin-echo method, and is successfully applied to a micelle of 1-palmitoyl-lysophosphatidylcholine (PaLPC) with diameter of 5 nm and to vesicles of dipalmitoylphosphatidylcholine (DPPC) with diameters ranging from 30 to 800 nm. It is found that the NOE intensity increases with the diameter up to â¼100 nm, and the model membrane is considered planar on the molecular level beyond â¼100 nm. While the NOE between the hydrophilic terminal and hydrophobic terminal methyl groups is absent for the micelle, its intensity is comparable to that for the neighboring group for vesicles with larger diameters. The origin of NOE signals between distant sites is analyzed by MD simulations of PaLPC micelles and DPPC planar bilayers. The slow relaxation is shown to yield an observable NOE signal even for the hydrophilic and hydrophobic terminal sites. Since the information on distance and dynamics cannot be separated in the experimental NOE alone, the correlation time in large vesicles is determined by combining the experimental NOE intensity and MD-based distance distribution. For large vesicles, the correlation time is found to vary by 2 orders of magnitude over the proton sites. This study shows that NOE provides dynamic information on large vesicles when combined with MD, which provides structural information.