Blockage of metallothionein synthesis via adrenaline ß receptor activation invalidates dehydroeffusol-mediated prevention of amyloid ß1-42 toxicity.

Dehydroeffusol, a major phenanthrene in Juncus effusus, protects neurodegeneration induced by intracellular Zn2+ ferried by extracellular amyloid ß1-42 (Aß1-42). Here we focused on adrenaline ß receptor activation and the induction of metallothioneins (MTs), intracellular Zn2+-binding proteins to test the protective mechanism of dehydroeffusol. Isoproterenol, an agonist of adrenergic ß receptors elevated the level of MTs in the dentate granule cell layer 1 day after intracerebroventricular (ICV) injection. When Aß1-42 was injected 1 day after isoproterenol injection, pre-injection of isoproterenol protected Aß1-42 toxicity via reducing the increase in intracellular Zn2+ after ICV injection of Aß1-42. On the basis of the effect of increased MTs by isoproterenol, dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 2 days. On day later, dehydroeffusol elevated the level of MTs and prevented Aß1-42 toxicity via reducing Aß1-42-mediated increase in intracellular Zn2+. In contrast, propranolol, an antagonist of adrenergic ß receptors reduced the level of MTs increased by dehydroeffusol, resulting in invalidating the preventive effect of dehydroeffusol on Aß1-42 toxicity. The present study indicates that blockage of MT synthesis via adrenaline ß receptor activation invalidates dehydroeffusol-mediated prevention of Aß1-42 toxicity. It is likely that MT synthesis via adrenaline ß receptor activation is beneficial to neuroprotection and that oral intake of dehydroeffusol preventively serves against the Aß1-42 toxicity.

The mechanosensitive ion channel PIEZO1 promotes satellite cell function in muscle regeneration.

Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscles, play an essential role in muscle regeneration. After skeletal muscle injury, quiescent MuSCs are activated to enter the cell cycle and proliferate, thereby initiating regeneration; however, the mechanisms that ensure successful MuSC division, including chromosome segregation, remain unclear. Here, we show that PIEZO1, a calcium ion (Ca2+)-permeable cation channel activated by membrane tension, mediates spontaneous Ca2+ influx to control the regenerative function of MuSCs. Our genetic engineering approach in mice revealed that PIEZO1 is functionally expressed in MuSCs and that Piezo1 deletion in these cells delays myofibre regeneration after injury. These results are, at least in part, due to a mitotic defect in MuSCs. Mechanistically, this phenotype is caused by impaired PIEZO1-Rho signalling during myogenesis. Thus, we provide the first concrete evidence that PIEZO1, a bona fide mechanosensitive ion channel, promotes proliferation and regenerative functions of MuSCs through precise control of cell division.

Isoproterenol, an adrenergic ß receptor agonist, induces metallothionein synthesis followed by canceling amyloid ß1-42-induced neurodegeneration.

Adrenergic ß receptor activation may ameliorate amyloid ß toxicity. We examined whether isoproterenol, an adrenergic ß receptor agonist reduces neurodegeneration caused by Aß1-42, for which intracellular Zn2+ dysregulation is a trigger. Neurodegeneration was assessed in the dentate granule cell layer 14 days after intracerebroventricular injection of human Aß1-42 into the mouse brain. Neurodegeneration was canceled after co-injection of isoproterenol. Isoproterenol did not affect Aß staining (uptake) in the dentate granule cell layer 1 h after Aß injection. In contrast, isoproterenol reduced intracellular Zn2+ level increased by Aß. The synthesis of intracellular metallothioneins (MTs), Zn2+-binding proteins was not enhanced in the dentate granule cell layer 24 h after Aß1-42 injection, but significantly enhanced after co-injection of isoproterenol. These data indicate that isoproterenol enhances MT synthesis and cancels neurodegeneration via intracellular Zn2+ toxicity after Aß1-42 injection. It is likely that MT synthesis enhanced by adrenergic ß receptor-mediated signaling contributes to ameliorating Aß1-42 toxicity in the brain.

CXCL17-mediated downregulation of type I collagen via MMP1 and miR-29 in skin fibroblasts possibly contributes to the fibrosis in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is characterized by excessive deposition of collagen in the skin and internal organs. Recent studies have shown that chemokine (C-X-C motif) ligands (CXCLs) are involved in the pathogenesis of SSc. OBJECTIVE: Our aim was to examine the anti-fibrotic potential of CXCL17, a newly discovered chemokine, in cultured skin fibroblasts and in a bleomycin-induced SSc mouse model. Moreover, we examined serum level of CXCL17 in patients with SSc. METHODS: Type I collagen expression was evaluated in SSc skin and cultured fibroblasts treated with CXCL17 using immunoblotting and quantitative reverse transcription-PCR. Serum CXCL17 levels were determined using enzyme-linked immunosorbent assay in 63 patients with SSc and 17 healthy subjects. A bleomycin-induced SSc mouse model was used to evaluate the effect of CXCL17 on skin fibrosis. RESULTS: CXCL17 reduced the expression of type I collagen in healthy control fibroblasts. CXCL17 also induced matrix metalloproteinase 1 (MMP1) and miR-29 expression in fibroblasts, indicating that CXCL17 regulates type I collagen expression in part via post-transcriptional mechanisms through MMP1 and miR-29. We found that local injection of CXCL17 attenuated bleomycin-induced skin fibrosis in mice. CXCL17 levels in SSc skin were lower than those in healthy controls, in contrast to the high serum CXCL17 levels in patients with SSc. The low expression of CXCL17 in SSc skin possibly affects type I collagen accumulation in this disease. CONCLUSION: Our data indicate that understanding CXCL17 signaling may lead to a better therapeutic approach for SSc.

Royal jelly regulates the proliferation of human dermal microvascular endothelial cells through the down-regulation of a photoaging-related microRNA.

Although royal jelly is believed to prevent skin aging, the underlying mechanism is not known in detail. In the present study, we investigated the plausibility of the involvement of microRNAs in the manifestation of this effect of royal jelly. The expression of microRNAs was determined by PCR array analysis and real-time PCR and the number of cells was counted with a cell counter. Using PCR array, we identified four microRNAs that were downregulated by royal jelly in cultured human dermal microvascular endothelial cells (HDMEC). Upon comparison of the expression of the four microRNAs between young and senescent facial skin, miR-129-5p was found to be significantly upregulated in senescent skin. Consistently, the expression of miR-129-5p in HDMEC was significantly increased by UVB radiation, suggesting that this microRNA is related to photoaging. The royal jelly treatment increased the number of HDMEC. Furthermore, forced overexpression of miR-129-5p resulted in significant decrease in the number of HDMEC, and its forced downregulation increased the number of cells. The number and density of vessels is reported to be decreased in aged skin. Our results indicate that miR-129-5p is induced in damaged endothelial cells upon exposure to UV radiation, which decreases the cell number. Furthermore, administration of royal jelly downregulated the expression of miR-129-5p in endothelial cells, and might prevent skin aging by maintaining the number of cells. The present study elucidates the mechanism of vessel aging caused by UV exposure and the anti-aging effects of royal jelly through the involvement of microRNA.

Correlations between Photovoltaic Characteristics, Adsorption Number, and Regeneration Kinetics in Dye-Sensitized Solar Cells Revealed by Scanning Photocurrent Microscopy.

Newly developed simultaneous scanning photocurrent and luminescence microscopy was applied to ruthenium-based dye-sensitized solar cells (DSCs) comprising a cover glass photoanode with a 100 nm thick TiO2 layer. Using this, we have investigated the lateral variations of several parameters of these DSCs under short-circuit conditions. Simultaneous measurement of photocurrent and luminescence images for the same area of the DSC demonstrated submicrometric lateral resolution of our photocurrent microscopy, which is approximately 10 times better than the resolution of photocurrent microscopy used in past studies. The photovoltaic parameters, such as short-circuit current density, open-circuit voltage, and charge-collection efficiency, were thus evaluated for local (or submicrometric) regions of the DSCs. Furthermore, the photocurrent saturation behavior of the DSCs was examined as a function of the excitation rate and analyzed on the basis of a three-state kinetic model. This protocol allowed for quantification of the dye-adsorption number and dye-regeneration rate constant for any local area of the DSCs. Consequently, the correlations between the dye adsorption number, photovoltaic parameters, and regeneration rate constant, which are difficult to address through examination of the entire cell, were revealed by the "zoom-in" approach utilizing this high-resolution photocurrent microscopy.