BCI-215, a Dual-Specificity Phosphatase Inhibitor, Reduces UVB-Induced Pigmentation in Human Skin by Activating Mitogen-Activated Protein Kinase Pathways.

BACKGROUND: The dysregulation of melanin production causes skin-disfiguring ultraviolet (UV)-associated hyperpigmented spots. Previously, we found that the activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), inhibited melanogenesis. METHODS: We selected BCI-215 as it may modify MAPK expression via a known function of a dual-specificity phosphatase (DUSP) 1/6 inhibitor. B16F10 melanoma cells, Mel-ab cells, human melanocytes, and a coculture were used to assess the anti-melanogenic activity of BCI-215. The molecular mechanisms were deciphered by assaying the melanin content and cellular tyrosinase activity via immunoblotting and RT-PCR. RESULTS: BCI-215 was found to suppress basal and cAMP-stimulated melanin production and cellular tyrosinase activity in vitro through the downregulation of microphthalmia-associated transcription factor (MITF) protein and its downstream enzymes. The reduction in MITF expression caused by BCI-215 was found to be due to all three types of MAPK activation, including extracellular signal-regulated kinase (ERK), JNK, and p38. The degree of activation was greater in ERK. A phosphorylation of the ß-catenin pathway was also demonstrated. The melanin index, expression of MITF, and downstream enzymes were well-reduced in UVB-irradiated ex vivo human skin by BCI-215. CONCLUSIONS: As BCI-215 potently inhibits UV-stimulated melanogenesis, small molecules of DUSP-related signaling modulators may provide therapeutic benefits against pigmentation disorders.

TGF-beta-induced protein beta ig-h3 is upregulated by high glucose in vascular smooth muscle cells.

TGF-beta-induced gene-h3 (beta ig-h3) is an adhesive molecule that interacts with integrins. Because TGF-beta plays an important role in diabetic complications and beta ig-h3 serves as a cell substrate, we hypothesized that diabetic conditions might increase beta ig-h3 synthesis in vascular smooth muscle cells (VSMCs), which may subsequently contribute to the pathogenesis of diabetic angiopathy. The concentrations of beta ig-h3 and TGF-beta were measured in conditioned media using an enzyme-linked immunosorbent assay. An immunohistochemical study showed that beta ig-h3 was expressed in the VSMCs and the matrix of rat aortas. TGF-beta stimulated beta ig-h3 production, and high glucose induced beta ig-h3 as well as TGF-beta production in the VSMCs. The high glucose-induced beta ig-h3 expression was almost entirely blocked by an anti-TGF-beta antibody. beta ig-h3 protein mediated the adhesion, spreading, migration, and proliferation of rat VSMCs. These results suggest that the high glucose-induced beta ig-h3 in VSMCs regulates VSMC functions and may play an important role in diabetic angiopathy.