Molecular mechanism of anti-inflammatory effects of the proteasome inhibitor MG-132 on Con A-induced acute liver injury in mice.

MG-132, an aldehyde-based peptide proteasome inhibitor (PI) that binds to the proteasome and reversibly inhibits proteasome activity, has been widely used in experimental research. However, it is not clear whether MG-132 has anti-inflammatory effects on liver injury. The molecular mechanism of the anti-inflammatory effect of the PI MG-132 on Con A-induced acute liver injury (ALI) mice was investigated by ELISA, HE, q RT-PCR, and IHC. The results showed that the serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and TNF-α and IL-6 contents of mice in the high and medium dose groups were reduced compared with those in the ALI group. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in liver tissues were significantly increased, and the malondialdehyde (MDA) content was decreased. The pathological sections of mice in the ALI group showed typical ALI manifestations such as significant central venous stasis of liver tissues, cell swelling, and inflammatory cell infiltration. The pathological damage of liver tissues was relieved significantly in the three dose groups, especially in the high-dose group. The transcriptional level of TLR4/NF-κB pathway key factors mRNA was significantly reduced, and the expression of TLR4 and NF-κB P65 protein in liver tissues was significantly and positively correlated with the contents of TNF-α and IL-1ß (p < 0.01). Our findings suggest that MG-132 can alleviate the inflammatory response to Con A-induced ALI and exert a hepatoprotective effect, and its anti-inflammatory effect is related to the inhibition of TLR4/NF-κB signaling pathway activation.

Genome sequence of Shigella flexneri 2a: insights into pathogenicity through comparison with genomes of Escherichia coli K12 and O157.

We have sequenced the genome of Shigella flexneri serotype 2a, the most prevalent species and serotype that causes bacillary dysentery or shigellosis in man. The whole genome is composed of a 4 607 203 bp chromosome and a 221 618 bp virulence plasmid, designated pCP301. While the plasmid shows minor divergence from that sequenced in serotype 5a, striking characteristics of the chromosome have been revealed. The S.flexneri chromosome has, astonishingly, 314 IS elements, more than 7-fold over those possessed by its close relatives, the non-pathogenic K12 strain and enterohemorrhagic O157:H7 strain of Escherichia coli. There are 13 translocations and inversions compared with the E.coli sequences, all involve a segment larger than 5 kb, and most are associated with deletions or acquired DNA sequences, of which several are likely to be bacteriophage-transmitted pathogenicity islands. Furthermore, S.flexneri, resembling another human-restricted enteric pathogen, Salmonella typhi, also has hundreds of pseudogenes compared with the E.coli strains. All of these could be subjected to investigations towards novel preventative and treatment strategies against shigellosis.