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Hypopigmentation diseases are usually managed using UVB light which increases the patients' risk for skin cancer. Here, we evaluated the melanogenesis stimulatory effects of leaf extracts of Erica multiflora, a medicinal plant from the Mediterranean region, and its active component, lup-20 (29)-en-3-one, as possible therapeutic agents to address hypopigmentation disorders. B16 murine melanoma cells were treated with E. multiflora extracts or its active component lupenone to evaluate their effects on melanin biosynthesis. The mechanism underlying the observed effects was also determined. Bioactivity-guided fractionation of fifteen ethyl acetate fractions identified fraction 2 to have melanogenesis stimulatory effects due to its ability to decrease mitogen-activated protein kinase phosphorylated extracellular signal- regulated kinases 1 and 2 activation. Preparative TLC of ethyl acetate fraction 2 revealed the presence of lup-20(29)-en-3-one as the major bioactive component. B16 cells treated with lup-20(29)-en-3-one increased melanin content without cytotoxicity. To determine the mechanism for the observed effects of lup-20(29)-en-3-one, the tyrosinase enzyme activity, the tyrosinase protein expression, and the activation of phosphorylated extracellular signal-regulated kinases 1 and 2 were determined. In addition, the expression of the tyrosinase mRNA was quantified using real-time PCR. Results showed that lup-20(29)-en-3-one has no effect on the tyrosinase enzyme activity but can increase tyrosinase expression at both the transcriptional and translational levels. The increase in the tyrosinase mRNA expression was most likely due to the inhibited mitogen-activated protein kinase phosphorylated extracellular signal-regulated kinases 1 and 2 activation. We report for the first time that E. multiflora ethyl acetate extract and its active compound lup-20(29)-en-3-one stimulate melanogenesis by increasing the tyrosinase enzyme expression via mitogen-activated protein kinase phosphorylated extracellular signal-regulated kinases 1 and 2 phosphorylation inhibition, making it a possible treatment for hypopigmentation diseases. [ABSTRACT FROM AUTHOR]

To clarify the ß-1 selectivity of ß-adrenergic receptor blocking agents (ß-blocking agents) after typical oral doses, the relationships between the effects on exercise heart rate or FEV1and ß-1 or ß-2 receptor occupancies (F1,F2) of seven ß-blocking agents, acebutolol, atenolol, metoprolol, oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively. Nonlinear relationships between the pharmacologic effect andF1and between the pulmonary adverse effect andF2were obtained. Based on these findings, a new index of cardiovascular selectivity is proposed, given by the ratio of ß-1 receptor occupancy to ß-2 receptor occupancy (F1/F2). Using this new index, there was a little difference in ß-1 selectivity between acebutolol and pindolol (3.1:1.0), in contrast to a marked difference in ß-1 selectivity (320:1) as a conventional index between these two drugs. This finding indicates that even ß-1 selective drugs must be administered carefully to patients with pulmonary disease. Furthermore, the relationship between the pharmacologic or pulmonary effects andF1orF2has been analyzed quantitatively with a ternary complex model and used to develop rational dosage regimens for ß-1 selective ß-blocking agents, such as atenolol, to obtain the desired pharmacologic effects with minimum adverse pulmonary effects.