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    • The neuroprotective effect of hypoxic

    2018-11-12

    The neuroprotective effect of hypoxic preconditioning in the sphingosine kinase has been studied by several groups who found evidence for the involvement of HIF-1α and its downstream targets and/or Epo (He et al., 2008) (Liu et al., 2005; Theus et al., 2008) (Prass et al., 2003) (Bernaudin et al., 2002). In hyperbaric preconditioning there is tolerance after hypoxia that is linked to the upregulation of HIF-1α (Peng et al., 2008), and infusion of soluble EpoR reduced the protective effect seen in mouse brain (Prass et al., 2003). Stresses involving excitotoxicity are attenuated by hypoxic preconditioning through the upregulation of NF-κΒ and antioxidative enzymes (Wang et al., 2005). Indeed, the protective effect of Epo in hypoxic preconditioning was shown to be effected through Jak2-Stat5 and NF-κB (Liu et al., 2005). Given the involvement of HIF-1α, a plausible explanation to the link between system Xc− and hypoxia is through the hypoxia signaling cascade involving HIF-1α. As demonstrated by the localization, neurons tend to have a robust increase in system Xc− after hypoxic stimulation and this may involve HIF-1α. Thus, we targeted HIF-1α in B104 neuroblastoma cells with a siRNA probe designed to knockdown HIF-1α mRNA and subsequently protein. The correlation demonstrates that system Xc− is a downstream target of HIF1-α signaling. This is the first direct evidence linking system Xc− expression with HIF-1α. The current study shows that system Xc− appears to be regulated through the HIF-1α pathway and, by our previous report (Sims et al., 2010), through Epo. These data beg the question: can system Xc− alone produce neuroprotection? Shih et al. (2006) showed that xCT overexpression caused neuroprotection, further suggesting that this mechanism may be a novel neuroprotective strategy. We also determined if hypoxic preconditioning would occur if system Xc− was pharmacologically inhibited. Differentiated neural stem cells were exposed to hypoxia for 4h and then treated with a toxic concentration of glutamate. In the presence of hypoxic preconditioning, the cells survived while those not exposed to hypoxia showed significant cell loss. Moreover, when system Xc− was inhibited or glutathione biosynthesis blocked, hypoxic preconditioning was not protective and cells did not survive the excitotoxic conditions. These data support the hypothesis that system Xc− activity, and glutathione synthesis, is required for protective effects of hypoxic preconditioning. Future studies will be aimed at looking at other regulators of this important protein which could give better insight into a possible protective pathway.
    Materials and methods
    Acknowledgments Funding for this project is provided by the Robert Wood Johnson Harold Amos Medical Faculty Development Award and the CHRC K12 NICHD Training Grant.
    Introduction Cartilaginous tissue lacks an intrinsic regeneration capacity. The tissue engineering and cell-based approaches can be thus excellent alternatives to treat cartilage lesions (Ahmed and Hincke, 2010). Choosing the appropriate cell type for these therapies is a critical step. Chondrocytes are highly specialized cells responsible for the production of cartilage extracellular matrix (Huang, 1977), but articular chondrocytes are considered difficult to culture, have low proliferation capacity and may dedifferentiate in monolayer cultures, losing their chondrogenic phenotype (Kuo et al., 2006). In addition to articular cartilage, there are other sources of chondrocytes, such as ear (Malicev et al., 2009) and nasal septum, with some advantages as compared to articular chondrocytes, since they are easy to harvest with low iatrogenic morbidity (Chia et al., 2004). Perichondrium surrounds all mammalian cartilage tissues, with exception of fibrocartilage and articular cartilage, where the synovial fluid is present. Despite not having a perichondrium, articular cartilage contains a progenitor/stem cell population on its surface zone (Archer et al., 1990; Dowthwaite et al., 2004). In other cartilaginous tissues, perichondrium cambium layer seems to be the source of new cartilage (Upton et al., 1981) where chondroprogenitor cells dwell (Engkvist et al., 1979). However, some authors do not recognize the perichondrium internal zone or cambium layer as a separate layer from the adjacent cartilage (Bairati et al., 1996). In particular, human nasal septal perichondrium is considered to be a homogeneous structure without clearly distinguishable zones (Bleys et al., 2007), and the border between cartilage and perichondrium is not very clear (Bairati et al., 1996).