The pathological manifestations of fatal cases of human hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) are characterized by inflammatory damage to the central nervous system (CNS). Here, the dynamic distribution of EV71 in the CNS and the subsequent pathological characteristics within different regions of neonatal rhesus macaque brain tissue were studied using a chimeric EV71 expressing green fluorescence protein. The results were compared with brain tissue obtained from the autopsies of deceased EV71-infected HFMD patients. These observations suggested that the virus was prevalent in areas around the blood vessels and nerve nuclei in the brain stem and showed a preference for astrocytes in the CNS. Interestingly, infected astrocytes within the in vivo and in vitro human and macaque systems exhibited increased expression of excitatory neurotransmitters and cytokines that also stimulated the neuronal secretion of the excitatory neurotransmitters noradrenalin and adrenalin, and this process most likely plays a role in the pathophysiological events that occur during EV71 infection.

Abstract. All-trans retinoic acid (ATRA) is a derivative of vitamin A that can induce differentiation and apoptosis, as well as inhibit proliferation, in glioma cells. However, the effect of ATRA on the migration and invasiveness of glioma remains poorly understood. In addition, although it is universally accepted that ATRA can induce apoptosis and inhibit proliferation in glioma cells, the association between the concentration and effects of ATRA remain unclear. Therefore, the present study investigated the effects of ATRA treatment on the migration, invasion, apoptosis and proliferation of glioma cells. The U87 and SHG44 glioma cell lines were treated with various concentrations of ATRA, consisting of 0, 5, 10, 20 and 40 µmol/l. A scratch wound healing assay and a Matrigel invasion assay were used to investigate cell migration and invasion, respectively. Flow cytometry was performed to investigate apoptosis and cell cycle distribution. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to investigate the expression of matrix metalloproteinase (MMP)-2 and -9 in each cell treatment group. Following treatment with ATRA, the migration, invasion and proliferation of the glioma cells were significantly inhibited, and the apoptosis rate was significantly increased compared with that of the blank control group. Furthermore, a dose-effect association was identified between each effects and ATRA treatment. The mRNA and protein expression of MMP-2 in U87 glioma cells was not significantly affected following treatment with low concentrations of ATRA, consisting of 5 and 10 µmol/l ATRA, compared with the expression in the control group (P>0.05). However, treatment with high concentrations of ATRA, consisting of 20 and 40 µmol/l ATRA, significantly downregulated the expression levels of MMP-2 in U87 cells. In contrast to U87 cells, the administration of ATRA treatment to SHG44 glioma cells resulted in a significant and dose-dependent downregulation in MMP-2 mRNA and protein expression (P<0.01). In addition, significant downregulation of MMP-9 expression was identified in the two glioma cell lines (P<0.01). The results of the present study indicate that treatment with ATRA may inhibit migration, invasion and proliferation, and promote apoptosis in glioma cells. Furthermore, the current study indicates that the inhibition of glioma cell invasion by ATRA may be partially associated with its effect ability to downregulate MMP expression.

Gliomas are the most common primary malignant brain tumor with poor prognosis, characterized by a highly heterogeneous cell population, extensive proliferation, and migration. A lot of molecular mechanisms regulate gliomas development and invasion, including abnormal expression of oncogenes and variation of epigenetic modification. MicroRNAs could affect cell growth and functions. Several reports have demonstrated that miR-139 plays multifunctions in kinds of solid tumors through different pathways. However, the antitumor mechanisms of this miR-139 are not unveiled in detail. In this study, we not only validated the low expression level of miR-139 in glioma tissues and cell lines but also detected the effect of miR-139 on modulating gliomas proliferation and invasion both in vitro and in vivo. We identified insulin-like growth factor 1 receptor, associate of Myc 1, and peroxisome proliferator-activated receptor γ coactivator 1β as direct targets of miR-139 and the levels of them were all inversely correlated with miR-139 in gliomas. Insulin like growth factor 1 receptor promoted gliomas invasion through Akt signaling and increased proliferation in the peroxisome proliferator-activated receptor γ coactivator 1β-dependent way. Associate of Myc 1 also facilitated gliomas progression by activating c-Myc pathway. Overexpression of the target genes could retrieve the antitumor function of miR-139, respectively, in different degrees. The nude mice transplantation tumor experiment displayed that glioma cells stably expressed miR-139 growth much slower in vivo than the negative control cells. Taken together, these findings suggested miR-139 acted as a favorable factor against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new evidenced prognostic marker and therapeutic target for gliomas.

These results suggest that the T allele of rs10249788 located in the promoter of the AHR gene is associated with a protective effect on vitiligo in Han Chinese populations.