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  • br Conclusion The present study is


    Conclusion The present study is the first to provide in vivo evidence that the σ1R deficiency can cause age-related increases in aggregation and phosphorylation of αSyn in dopaminergic neurons of SNpc. The σ1R has been reported to be decreased in the INT-777 region of the nigrostriatal dopaminergic pathway, in patients in the early stage of Parkinson's disease (Mishina et al., 2008, Toyohara et al., 2009). Therefore, the lowered level of σ1R in the brain of PD patients may enhance the aggregation and phosphorylation of αSyn that eventually may lead to the loss of dopaminergic neurons and the decline of motor coordination. Thus, σ1R and associated ligands may represent new therapeutic targets for the treatment of Parkinsonism.
    Disclosure statement
    Introduction Persistent liver injury and progressive fibrosis can result in cirrhosis, which markedly increases the risk of developing liver failure and cancer [1]. Hepatic stellate cells (HSC), which are also called Ito cells, are identified as the major profibrogenic cells in the liver [2]. During liver injury, HSCs are transformed into myofibroblasts (MFBs) that produce most of the collagen matrix in injured livers [2]. Accordingly, reducing activated HSCs is logical with respect to attenuating or reversing fibrogenesis. MFBs apoptosis plays a critical role during regression of liver fibrosis [3], suggesting that induction of apoptosis in activated HSCs represents a therapeutic antifibrogenic strategy in liver fibrosis. In recent years, antifibrotic drug research which focused on the promotion of apoptosis in activated HSCs has achieved a great progress; a lot of agents such as sorafenib, HS-173, and dihydroartemisinin induce HSCs apoptosis and reduce liver fibrosis [4], [5], [6]. Hedgehog (Hh) signaling controls tissue morphogenesis during embryogenesis [7]. It is activated when Hh ligands bind to patched (Ptc) receptors, subsequently releasing the Ptc-mediated repression of smoothened (Smo), and resulting in the activation of Gli transcription factors. Hh signaling plays a pivotal role in the homeostasis maintaining and modulates wound healing responses in a number of adult tissues, including the liver [8]. Aberrant activation of Hh signaling has been reported to be implicated in the pathogenesis of hepatic fibrosis [1], [8], and Hh signaling inhibition safely reverses liver fibrosis [9]. However, the underlying mechanisms involved in the anti-fibrotic effects of Hh pathway antagonist have not been completely characterized. Hh helps to orchestrate cell fate-regulation of HSCs, of particular note is that Hh has been identified as an autocrine viability factor for myofibroblastic HSCs, thus blocking Hh signaling increases apoptosis in HSCs [10], [11]. This may contribute to the antifibrotic effects of Hh pathway inhibitors in liver fibrosis. GANT61, a novel Hh signaling inhibitor which directly blocks Gli-mediated transcription, can effectively reduce lung fibrosis and kidney fibrosis [12], [13], [14]. Furthermore, a recent study has demonstrated that GANT61 markedly alleviate HCV-induced fibrogenesis [15], indicating that GANT61 may be beneficial in liver fibrosis treatment. GANT61 induces extensive cell death in certain types of malignant hepatocytes [7], but it is still unknown whether GANT61 affects the apoptosis of HSCs. GANT61 activates autophagy, which then induces cell apoptosis or impedes cell proliferation in a variety of cancer cells [7], [16], [17]. On the contrary, autophagy also promotes viability of certain cells after GANT61 treatment [18]. Therefore, whether GANT61-induced autophagy is salutary or detrimental is context dependent. In addition, previous studies have demonstrated that the endoplasmic reticulum (ER) stress sensor protein PERK and its downstream phosphorylation-eIF2a are implicated in the process of Hh-dependent autophagy inhibition [19], suggesting that ER stress may be involved in GANT61-induced autophagy. However, there is still a lack of evidence for the role of autophagy in GANT61-treated HSCs and the underlying mechanism remains unclarified. Therefore, the present study describes the role of GANT61-induced autophagy in HSCs, and reports that inhibition of Hh pathway induces ER stress, which regulates autophagy and suppresses apoptosis in HSCs.