P38 and JNK signal pathways are involved in the regulation of phlorizin against UVB-induced skin damage.

Phlorizin is well known to inhibit sodium/glucose cotransporters in the kidney and intestine for the treatment of diabetes, obesity and stress hyperglycaemia. However, the effects of phlorizin against ultraviolet B (UVB) irradiation and its molecular mechanism are still unknown. We examined the effects of phlorizin on skin keratinocyte apoptosis, reactive oxygen species (ROS) production, pro-inflammatory responses after UVB irradiation and the changes of some signal molecules by in vitro and in vivo assay. We observed that phlorizin pretreatments inhibited HaCaT cell apoptosis and overproduction of ROS induced by UVB. Phlorizin also decreased the expression of UVB-induced pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and interleukin-8 (IL-8) at the mRNA level. Topical application of phlorizin on UVB-exposed skin of nude mice prevented the formation of scaly skin and erythema, inhibited the increase of epidermal thickness and reduced acute inflammation infiltration in skin. Additionally, PCR, Western blot and immunohistochemical data showed that phlorizin reversed the overexpression of cyclooxygenase-2 (Cox-2) induced by UVB irradiation both in vitro and in vivo. The activation of p38 and JNK mitogen-activated protein kinases (MAPK) after UVB irradiation was also inhibited by phlorizin. These findings suggest that phlorizin is effective in protecting skin against UVB-induced skin damage by decreasing ROS overproduction, Cox-2 expression and the subsequent excessive inflammation reactions. It seemed that p38 and JNK MAPK signal pathways are involved in the regulation of the protective function of phlorizin.

Daidzein stimulates collagen synthesis by activating the TGF-ß/smad signal pathway.

BACKGROUND/OBJECTIVES: The objective of this study was to investigate the effects of daidzein on collagen metabolism and its underlying mechanism in cultured skin fibroblast and nude mouse skin. METHODS: Skin fibroblasts were exposed to different concentrations of daidzein (0.5-50 µg/mL) for 24 h or 48 h, respectively. Female nude mice were treated topically with 200 µg/mL daidzein once a day for 6 weeks. Cell viability and cell cycle were determined by MTT and flow cytometer. The transcriptional activity of collagen type I was evaluated and the expression of procollagen, matrix metalloproteinase-1 (MMP1) and MMP2 were measured by real-time polymerase chain reaction. A Western blot analysis was applied to detect the levels of phosphorylated-Smad2 and Smad3. RESULTS: In the daidzein-treated cells the expression of type I procollagen increased markedly while the expressions of MMP1, and MMP2 was significantly inhibited. Additionally, the mouse skin showed more collagen deposition after daidzein treatment. The levels of transforming growth factor (TGF)-ß, phosphorylated-smad2 and smad3 were also higher in the daidzein treated skin fibroblasts than in the controls. CONCLUSIONS: The results showed that daidzein treatment can increase skin collagen synthesis and inhibit collagen degradation in vitro and in vivo. It seems that TGF-ß/smad signalling pathways play an important role in daidzein-induced collagen accumulation.

Gpr48 deficiency induces polycystic kidney lesions and renal fibrosis in mice by activating Wnt signal pathway.

G protein-coupled receptor 48 (Gpr48/Lgr4) is essential to regulate the development of multiple tissues in mice. The notion that Gpr48 functions in renal development prompted us to investigate the relation between Gpr48 and renal diseases. Using a Gpr48 knockout mice model, we observed that 66.7% Gpr48 null mice developed polycystic lesions in the kidney, while no cysts were observed in the kidneys of wild-type mice. Polycystic kidney disease 1 (PKD1) and PKD2 expressions were also markedly decreased in the Gpr48 knockout mice. Abnormal expressions of exra-cellular matrix protein lead to the progression of polycystic kidney disease and the formation of renal fibrosis in the Gpr48 null mice. The expressions of several Wnt molecules and its receptors were increased and marked ß-catenin nuclear accumulation was observed in the Gpr48 null mice. The inhibitors of Wnt/ß-catenin signal pathway such as GSK3ß and axin2 were loss of function. The Wnt/PCP signaling pathway is also activated in Gpr48 null mice. However, TGF-ß expression and phosphorylated Smad2/3 levels were not altered. Collectively, our results showed that Gpr48 null mice are at a greater risk of suffering from polycystic lesions and renal fibrosis. Moreover, the formation of polycystic lesions and renal fibrosis induced by Gpr48 deficiency involves the activation of Wnt signaling pathway but not the TGF-ß/Smad pathway.