The bKlotho-FGFR4 partnership causes a depression of Akt signaling. Consistent with this, we showed that bKlotho overexpression reduced the phosphorylation of Akt and subsequent phosphorylation of GSK-3b, indicating Akt inactivation and GSK-3b activation respectively. This might contribute to cyclin D1 degradation because GSK-3b is a critical regulator of cyclin D1 expression. Moreover, the Akt/GSK-3b signaling also plays an important role in HCC. Thus, our data suggested the Akt/GSK-3b/cyclin D1 signaling pathway mediated the function of bKlotho in hepatoma cells proliferation and hepatocarcinogenesis. In summary, we identified that bKlotho could suppress tumor growth in HCC, and our investigation suggested that restoration of bKlotho would be a potential molecular target for HCC therapy. Activation of enteric neural 5-HT4-receptors by mosapride citrate promotes the reconstruction of an enteric neural circuit injured after surgery, leading to the recovery of the ��defecation reflex�� in the distal gut of guinea pigs. This neural plasticity involves neural stem cells. Recently, we also revealed that MOS enhances neural network formation in gut-like organs differentiated from mouse embryonic stem cells. Other 5-HT4 receptor agonists also increase neuronal numbers and length of neurites in enteric neurons developing in vitro from immunoselected neural crest-derived precursors. 5-HT4 receptor-mediated neuroprotection and neurogenesis has also been demonstrated in the enteric nervous system of adult mice. We therefore explored the ability of MOS to promote the generation of new enteric neurons at resected sites of the mouse small intestine in vivo. The new neurons are typically located in regions of granulation tissue, which is new connective tissue formed by growth of fibroblasts and blood capillaries into injured tissue after transection and reanastomosis of the gut. Unfortunately, it is impossible for traditional fluorescence microscopy including confocal microscopy to perform highresolution deep imaging of the 300�C400 mm thick granulation tissue that is formed during the tissue repairing process at the anastomotic site after transection of the gut. Even in in vitro whole mount preparations, in which the mucosal, submucosal and circular muscle layers were removed, imaging of newly formed neurons and axons is severely limited. Nonlinear optical microscopy, in particular two photon-excited fluorescence microscopy, offers a means to overcome this limitation by providing enhanced optical penetration. Two-photon microscopy allows cellular imaging several hundred microns deep in various organs of living animals and ex vivo specimens. In the present study, we employed 2PM to obtain 3-dimensional reconstructions of impaired enteric neural circuits within the thick granulation tissue in the ileum of Thy1-GFP mice, in which the GFP is expressed in the cytoplasm of enteric neurons. Although in vivo imaging of the muscularis propria and myenteric neurons with probe-based confocal laser endomicroscopy in porcine models has been recently reported, we obtained the first ever clear three-dimensional imaging of newly generated enteric neurons within the thick granulation tissue at the anastomosis, indicating that 2PM allows enteric neural imaging several hundred microns deep in the gut of the living mouse. The most critical challenge was to suppress movement artifacts to allow for microscopy in the living gut.
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