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Spinal cord injury (SCI) leads to severe and long-lasting neurological disability. Presently, the lack of effective therapies for SCI is largely attributable to an incomplete understanding of its pathogenesis. F-box and WD repeat domain-containing protein 7 (FBW7, also known as FBXW7) is a type of E3 ubiquitin ligase complex, and plays essential roles in regulating different pathological and physiological processes. In this study, we attempted to explore the effects of FBW7 on SCI progression by the in vivo and in vitro experiments. SCI mice showed significantly reduced expression of FBW7 in spinal cord tissues. Promoting FBW7 expression via intrathecal injection of AAV9/FBW7 effectively improved locomotor function in SCI mice. Neuronal death in spinal cords of SCI mice was obviously ameliorated by FBW7 over-expression, along with greatly decreased expression of cleaved Caspase-3. In addition, microglial activation in spinal cord specimens was detected in SCI mice through increasing Iba-1 expression levels, which was, however, attenuated in SCI mice injected with AAV9/FBW7. Additionally, FBW7 over-expression dramatically restrained inflammatory response in spinal cord tissues of SCI mice, as evidenced by the down-regulated expression of tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) through blocking the activation of nuclear factor-κB (NF-κB) signaling. These anti-inflammatory effects of FBW7 were confirmed in LPS-stimulated mouse microglial BV2 cells. Finally, our in vitro studies showed that conditional medium (CM) collected from LPS-incubated BV2 cells markedly induced apoptosis in the isolated primary spinal neurons; However, this effect was overtly ameliorated by CM from LPS-exposed BV2 cells over-expressing FBW7. Thus, FBW7-regulated inflammation in microglial cells was involved in the amelioration of neuronal apoptosis during SCI development. Collectively, these findings illustrated that FBW7 expression was down-regulated in spinal cords of SCI mice, and promoting its expression could effectively mitigate SCI progression by repressing microglial inflammation and neuronal death. • FBW7 protects mice against SCI in mice. • FBW7 up-regulation alleviates inflammation in SCI mice and in LPS-treated microglial cells. • FBW7 increase alleviates neuronal apoptosis stimulated by LPS. [ABSTRACT FROM AUTHOR]

Abstract: Increased lymphocyte apoptosis has been suggested to contribute to the development of systemic lupus erythematosus (SLE), but the critical factors involved in the apoptotic pathways are still unknown. By long serial analysis of gene expression (LongSAGE) profiles and microarray analyses, a novel apoptosis-related gene BclGL expression was found significantly increased in peripheral blood CD4+ T cells of SLE patients, which was correlated with the enhanced CD4+ T cells apoptosis, anti-nuclear antibody (ANA) titer and proteinuria. In vitro, BclGL expression could be specially upregulated by SLE serum stimulation and positively correlated with induced CD4+ T cell apoptosis. Enforcing BclGL overexpression by lentivirus could directly enhance CD4+ T cell apoptosis, but these apoptosis-inducing effects could be partially inhibited by knockdown of BclGL expression. Collectively, these results indicate that increased BclGL expression may contribute to the aberrant CD4+ T cell apoptosis which causes an inappropriate immune response and impaired homeostasis in SLE. [Copyright &y& Elsevier]

Abstract: Hepatitis B virus (HBV) is a major causative agent of hepatocellular carcinoma (HCC) but the pathogenesis remains poorly understood. To provide novel insights into the pathogenesis of HBV, we examined the expression profile of HBV-positive HepG2.2.15 and -negative HepG2 cells. Genes that were markedly up- or down-regulated in the presence of HBV are involved in signal transduction, apoptosis, transcriptional regulation, protein degradation and oncogenesis. Among the analyzed co-signaling molecules CD40, CD80, CD86, B7-H1, B7-DC, OX40, and B7RP-1, CD40 was the only one up-regulated. Following establishment of stable HepG2 cell lines transfected with HBV genes, we found that HBxAg up-regulated the expression of CD40. We also found that CD40 activation by CD40L could promote the expression of negative co-signaling molecule B7-H1, rather than induce the apoptosis of HepG2HBx cell as expected. These results suggest that CD40 up-regulation by HBxAg may play a facilitating role in the pathogenesis causing HCC. [Copyright &y& Elsevier]