Glutamate excitotoxicity via N-methyl-D-aspartate (NMDA) receptors is thought to be a factor involved in the loss of retinal neuronal cells, including retinal ganglion cells, in retinal diseases such as diabetic retinopathy and acute angle closure glaucoma. Herein we report the protective effect of systemic administration of ML233, an apelin receptor agonist, against retinal neuronal cell death induced by the intravitreal injection of NMDA into mice. Intraperitoneal administration of ML233 prevented the NMDA-induced reduction in the amplitude of scotopic threshold responses (STR), which mainly reflect the activity of the retinal ganglion cells. Immunohistochemical staining showed that ML233 inhibited the NMDA-induced loss of retinal ganglion cells and amacrine cells. In addition, ML233 suppressed the breakdown of spectrin αII, a neuronal cytoskeleton protein cleaved by calpain activation, in the retina after intravitreal injection of NMDA. Intraperitoneal administration of ML233 increased the phosphorylation of Akt, a potent anti-apoptotic protein in neurons, in the retina. Furthermore, oral administration of ML233 protected against the decrease in the STR amplitudes and the loss of retinal ganglion cells caused by NMDA. These results suggest that systemic administration of ML233 protected retinal neurons from NMDA receptor-mediated excitotoxicity and that drugs activating the apelin receptor may be a new candidate for preventing the progression of these retinal diseases.

2019-02-01·Tissue & cell4区 · 生物学

Apelin receptor (Aplnr) signaling promotes fibroblast migration

4区 · 生物学

Article

作者: Doğan, Ayşegül

Cell migration is one of the major cellular processes in development, tissue regeneration, wound healing, cancer and immune function. Underlying molecular mechanism behind the fibroblast cell migration and matrix interactions generates the basis of tissue homeostasis. The role of Apelin receptor (Aplnr) signaling in gastrulation movements has emerged in recent years but how Aplnr regulates cell movement remains unclear. In the current study, the migratory activity of Aplnr signaling has been shown in cultured fibroblast cells in vitro by scratch assay, gene and protein expression analyses. Aplnr signaling was activated and knocked down in MEFs and NIH-3T3 mouse fibroblast cells to analyze whether cell migration is affected by Aplnr signalling. Activation of Aplnr signaling by Apelin peptide and small molecule ML-233 increased cell movement and expression of migration related gene and proteins including Actin and Vimentin. Similarly, reducing the expression of Aplnr and Apelin (Apln) by siRNA exposure inhibited cell migration of mouse fibroblast cells. Application of Apelin peptide and small molecule ML-233 to human fibroblast cells enhanced scratch closure rate significantly compared to control. This study demonstrated that activation of Aplnr signaling promotes cell migration of fibroblast cells in vitro. Aplnr signaling could be a potential therapeutic candidate as a migration related regulatory mechanism in cancer and wound healing for further research.

Communications Biology

The small molecule ML233 is a direct inhibitor of tyrosinase function

Article

作者: Graber, Joel H ; Madelaine, Romain ; Strickland, James ; Halluin, Caroline ; Kuhn, Sadie ; Baanannou, Aissette ; Morse, Dexter ; Menard, Romain

Melanogenesis is the biological process regulating the synthesis of melanin pigments in melanocytes. Defective melanogenesis is associated with numerous human skin diseases, including, but not limited to, albinism, vitiligo, melasma, and hypo- and hyperpigmentation disorders. Tyrosinase is the rate-limiting enzyme controlling melanogenesis, and hence tremendous efforts have been made to identify potent and safe inhibitors of tyrosinase function. However, despite decades of research, currently there is no effective treatment that inhibits melanogenesis or tyrosinase activity with no adverse side effects. In this study, we report the characterization of the ML233 chemical as a potent inhibitor of tyrosinase activity in vivo and in vitro. We demonstrate that ML233 reduces melanin production in the zebrafish model with no observable significant toxic side effects, and in murine melanoma cells. We also predict that these effects are mediated through direct tyrosinase-ML233 interaction, i.e., binding of the ML233 molecule to the active site of the protein to inhibit its function. Together, our results reveal that ML233 plays roles in both healthy and pathological skin cells via inhibition of melanin production. ML233-mediated tyrosinase inhibition is a potentially safe and effective approach to alleviate the symptoms of melanocyte-associated diseases and thereby substantially improve human health.

100 项与 ML233 相关的药物交易

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