An enormous variety of primary and secondary mRNA structures are compatible with export from the nucleus to the cytoplasm. Therefore, there seems to be a mechanism for RNA export which is independent of sequence recognition. There nevertheless is likely to be some relatively uniform mechanism which allows transcripts to be packaged as ribonucleoprotein particles, to gain access to the periphery of the nucleus and ultimately to translocate across nuclear pores. To study these events, we and others have generated temperature-sensitive recessive mRNA transport (mtr) mutants of Saccharomyces cerevisiae which accumulate poly(A)؉ RNA in the nucleus at 37؇C. Several of the corresponding genes have been cloned. Upon depletion of one of these proteins, Mtr4p, conspicuous amounts of nuclear poly(A)؉ RNA accumulate in association with the nucleolus. Corresponding dense material is also seen by electron microscopy. MTR4 is essential for growth and encodes a novel nuclear protein with a size of ϳ120 kDa. Mtr4p shares characteristic motifs with DEAD-box RNA helicases and associates with RNA. It therefore may well affect RNA conformation. It shows extensive homology to a human predicted gene product and the yeast antiviral protein Ski2p. Critical residues of Mtr4p, including the mtr4-1 point mutation, have been identified. Mtr4p may serve as a chaperone which translocates or normalizes the structure of mRNAs in preparation for export.The mechanism of export of mRNA from the nucleus to the cytoplasm is remarkably accommodating in the sense that an enormous variety of primary and secondary RNA structures are compatible with export. The fact that neither the 5Ј methyl cap structure nor the 3Ј poly(A) tail appears altogether essential for export (16) suggests that there is a mechanism in the nucleus which allows for RNA recognition independent of the sequence. It is likely that during or immediately after their synthesis, transcripts are quickly packaged into ribonucleoprotein particles (RNP) which enable them to gain access to the periphery of the nucleoplasm and interact specifically with components of nuclear pores, through which they subsequently translocate (14,42). If this itinerary is relatively uniform for most mRNAs, it is reasonable to postulate that there are factors which serve as RNA chaperones and/or normalize RNA secondary structure. Single-stranded RNAs spontaneously acquire an extensive secondary structure, which is subject to proteins with annealing activity (p53 and heterogeneous nuclear RNP [hnRNP] A1 [24,25]) and melting activity (helicases [34]). Studies of the yeast Saccharomyces cerevisiae have identified several proteins which, when mutated, lead to nuclear accumulation of poly(A) ϩ RNA without inhibiting pre-mRNA splicing. Apart from nucleoporins (8), these includes components of a nucleocytoplasmic GTPase cycle [the Cnr1/2p (Gsp1/2p) GTPases, Mtr1p (Prp20p), and Rna1p (6, 35)], a cytoplasmic protein (Mtr7p [34a]), the nucleolar protein Mtr3p (19), the nuclear proteins Mtr2p (19) and Rat1p (1), and the ...

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The volatile anaesthetic isoflurane is one of the most frequently employed general anaesthetics in neonates, children and adults. Accumulating evidence demonstrated that exposure to anaesthetics is associated with widespread neurodegeneration and cognitive impairment. Thus, the identification and development of compounds capable of preventing or reducing these adverse effects is of great clinical importance. For this purpose, the present study aimed to assess the effects of a flavonoid, naringenin, on isoflurane-induced neuroapoptosis and cognitive impairment. Separate groups of neonatal rat pups were administered naringenin at 25, 50 or 100 mg/kg body weight from postnatal day 1 (P1) to P21. On P7, the pups were exposed to 6 h of isoflurane (0.75%) anaesthesia. Neuroapoptosis was examined using the TUNEL assay. The expression of cleaved caspase-3, the apoptotic pathway proteins (Bad, Bax, Bcl-2 and Bcl-xL), the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway proteins [Akt, phosphorylated (-)Akt, glycogen synthase kinase 3β (GSK‑3β), p‑GSK-3β, phosphatase and tensin homolog (PTEN)] and nuclear factor-κB (NF-κB)‑mediated signalling proteins were determined by western blot analysis. General behaviour, as well as the learning ability and memory of the pups were assessed. Naringenin significantly inhibited isoflurane‑induced neuroapoptosis and markedly decreased the protein expression of caspase-3, Bad, Bax, NF-κB, tumor necrosis factor-α, interleukin (IL)-6 and IL-1β. Furthermore, naringenin increased the expression of Bcl-xL and Bcl-2 and activated the PI3K/Akt pathway. Significant improvements in learning capacity and memory retention were observed following naringenin treatment. Naringenin effectively ameliorated cognitive dysfunction and reduced isoflurane‑induced apoptosis as well as modulating the PI3/Akt/PTEN and NF-κB signalling pathways.

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In this study, it was proved that lidocaine could dose-dependently induce the increase of intracellular calcium ion concentration, mitochondrial membrane potential and apoptosis in U87-MG glioma cell line. The up-regulation of TRPV1 enhanced cytotoxicity of lidocaine, which revealed the correlations between them. Lidocaine might have increased intracellular calcium ion concentration by activating TRPV1 gene and induced apoptosis of U87-GM glioma cell line by up-regulating mitochondrial membrane potential.