Erythropoietin signaling and neuroprotection

Erythropoietin (Epo) plays an essential role in the regulation of erythropoiesis by stimulating growth, preventing apoptosis, and promoting terminal differentiation of erythroid progenitors. The Epo receptor belongs to the cytokine receptor superfamily. Epo and its receptor have been localized to several nonhematopoietic tissues and cells, including the central and peripheral nervous systems, endothelial cells and heart. Epo exerts neuronal, vascular and cardiac protection through multiple signaling pathways in different models of tissue and cell injury in vitro and in vivo, such as ischemia, hypoxia. inflammation and oxidative stress. As a result, Epo has been suggested as a possible candidate in the treatment of neurological and cardiac disorders. A better understanding of cellular pathways and molecules modulated by Epo signaling is crucial in determining the potential therapeutic application of recombinant human Epo and may provide further insights in the development of both better synergistic therapies as well as new molecular targets. In this review, we summarize the current knowledge on the signaling pathways by which Epo offers neuroprotection and cytoprotection, signal transduction systems modulated by Epo and negative regulation of Epo signaling in the nervous system

Melatonin Prevents UVB-Induced Skin Photoaging by Inhibiting Oxidative Damage and MMP Expression through JNK/AP-1 Signaling Pathway in Human Dermal Fibroblasts

Exposure to ultraviolet (UV) irradiation causes damage to the skin and induces photoaging. UV irradiation stimulates production of reactive oxygen/nitrogen species, which results in activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPK) in fibroblasts. MAPKs are responsible for activation of activator protein-1 (AP-1), which subsequently upregulates expression of matrix metalloproteinases (MMPs). Melatonin is a potent free radical scavenger which is known to have photoprotective effects. The aim of this study is to investigate the underlying molecular mechanisms for the photoprotective effects of melatonin in UVB-irradiated primary human dermal fibroblasts (HDFs) in terms of EGFR activation, oxidative/nitrosative damage, JNK/AP-1 activation, MMP activities, and the levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) and type I procollagen (PIP-C). In this study, HDFs were pretreated with 1 μM of melatonin and then irradiated with 0.1 J/cm2 of UVB. Changes in the molecules were analyzed at different time points. Melatonin inhibited UVB-induced oxidative/nitrosative stress damage by reducing malondialdehyde, the ratio of oxidized/reduced glutathione, and nitrotyrosine. Melatonin downregulated UV-induced activation of EGFR and the JNK/AP-1 signaling pathway. UVB-induced activities of MMP-1 and MMP-3 were decreased and levels of TIMP-1 and PIP-C were increased by melatonin. These findings suggest that melatonin can protect against the adverse effects of UVB radiation by inhibiting MMP-1 and MMP-3 activity and increasing TIMP-1 and PIP-C levels, probably through the suppression of oxidative/nitrosative damage, EGFR, and JNK/AP-1 activation in HDFs