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    • In this study we have employed mouse NSCs

    2018-11-12

    In this study, we have employed mouse NSCs rather than human NSCs to explore the effects of PA. In view of this, further study would be desirable to ascertain if comparable effects of PA occur in human NSCs. In addition, elevated FFA level is intimately associated with oxidative stress and high level of ROS. Therefore, the roles of oxidative stress in the activation and regulation of JNK and its specific effect on downstream associated transcription factors are worth pursuing in PA-induced apoptosis of NSCs. It is also desirable to extend the study in vivo such as to feed the mice with high fat diet for further exploration of the possible association between elevation of FFAs and BLZ945 disorders. In summary, this study has demonstrated that PA can induce apoptosis of NSCs that is mediated via JNK signaling. It is speculated that this might be one of possible mechanisms contributing to the increased incidence of neurological disorders caused by elevation of FFAs. In light of this, lowering plasma FFA level to normal level, through adjustment of diets and/or application of some BLZ945 potential drugs, may be beneficial to avoid unnecessary neuropsychopathic symptoms and brain abnormalities. The following are the supplementary data related to this article.
    Introduction HMGA2 is a non-histone chromosomal high-mobility group A (HMGA) family protein that binds to the minor groove of AT-rich DNA sequences (Fusco and Fedele, 2007; Grosschedl et al., 1994). The HMGA2 protein does not have direct transcriptional activity but rather transforms the chromatin structure through its DNA binding (Thanos and Maniatis, 1992); these changes in chromatin architecture can alter the local transcription. In general, HMGA2 is highly expressed during embryogenesis and is nearly undetectable in adult tissues (Chiappetta et al., 1996). In many cases, HMGA2 is up-regulated in tumor cells in adult tissues (Fedele et al., 2010; Young and Narita, 2007); overexpression studies have generally shown that HMGA2 induces oncogenesis (Fedele et al., 2010). However, there are some exceptions, particularly in adult stem cells. Recent studies have proposed the possibility that HMGA2 is intimately involved in the regulation of adult stem cells. HMGA2 was highly expressed in neural stem cells (NSCs) and regulated the stemness of NSCs in young mice (Nishino et al., 2008). In humans, normal CD34-positive hematopoietic stem cells (HSCs) express HMGA2, and the proliferation and differentiation of HSCs are governed by HMGA2 (Rommel et al., 1997). These data suggest that HMGA2 may have critical roles in regulating stemness in NSCs or HSCs and also in hUCBSCs. Our previous study showed that the expression of HMGA2, p16INK4A, p21CIP1/WAF1 and p27KIP1 was strongly affected by the aging of hUCBSCs (Lee et al., 2011). These results indicate that HMGA2 has crucial roles in adult stem cells, especially hUCBSCs, and can regulate stem cell aging in addition to proliferation and differentiation. Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that are involved in the control of stem cell proliferation (Welham et al., 2011). Previously, we reported that the PI3K signaling pathway determines the proliferation and differentiation potential of hUCBSCs (Yu et al., 2012). PI3K is one component of an intracellular signaling cascade that also involves AKT and mammalian target of rapamycin (mTOR). The PI3K/AKT/mTOR pathway regulates several cellular functions, such as proliferation, growth, survival, mobility and tumorigenesis, and several studies have investigated the PI3K/AKT/mTOR pathway within the context of adult stem cell regulation (Mantovani et al., 1998; Martelli et al., 2011). However, the interactions between PI3K/AKT/mTOR and HMGA2 in adult stem cells remain uncharacterized. p16Ink4a and p19Arf, also known as cyclin-dependent kinase inhibitors, are well-known tumor suppressor genes. There is considerable evidence that p16Ink4a and p19Arf promote cellular aging (Bennecke et al., 2010; Collado et al., 2007), and previous studies have shown that HMGA2 modulates stemness and aging by reducing p16Ink4a and p19Arf expression in adult stem cells (Nishino et al., 2008). However, it remains unknown whether HMGA2 regulates p16Ink4a and p19Arf directly or indirectly in adult stem cells. In this study, we elucidate the mechanistic relationship among p16Ink4a, p19Arf and HMGA2 within the context of the PI3K/AKT/mTOR/p70S6K pathway. Moreover, our results confirm that HMGA2 regulates the proliferation and aging of hUCBSCs.