Mdivi-1 ameliorates early brain injury after subarachnoid hemorrhage via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.

Aberrant modulation of mitochondrial dynamic network, which shifts the balance of fusion and fission towards fission, is involved in brain damage of various neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage, however, the underlying molecular mechanisms have remained to be elucidated. This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1 (Drp1, a dominator of mitochondrial fission) on blood-brain barrier (BBB) disruption and neuronal apoptosis following SAH and the potential mechanisms. The endovascular perforation model of SAH was performed in adult male Sprague Dawley rats. The results indicated Mdivi-1(a selective Drp1 inhibitor) reversed the morphologic changes of mitochondria and Drp1 translocation, reduced ROS levels, ameliorated the BBB disruption and brain edema remarkably, decreased the expression of MMP-9 and prevented degradation of tight junction proteins-occludin, claudin-5 and ZO-1. Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB), leading to decreased expressions of TNF-ɑ, IL-6 and IL-1ß. Moreover, Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome. To investigate the underlying mechanisms further, we determined that Mdivi-1 reduced p-PERK, p-eIF2α, CHOP, cleaved caspase-3 and Bax expression as well as increased Bcl-2 expression. Rotenone (a selective inhibitor of mitochondrial complexes I) abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1. In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.

Mutation of iceA in Helicobacter pylori compromised IL-8 induction from human gastric epithelial cells.

IceA of Helicobacter pylori (H. pylori) has been suggested as a virulence factor for the bacteria, but its pathogenic role remains unelucidated. Here, we examined the effect of iceA mutation on the secretion of IL-8 by human gastric epithelial cells. We also investigated whether the changes in IL-8 production caused by iceA mutation were associated with impaired adherence of H. pylori to the epithelial cells or with impaired apoptosis of these cells. The iceA mutant strain was constructed from wildtype H. pylori strain by insertional mutagenesis of iceA. The human gastric epithelial cells SGC7901 were infected with wildtype or mutant H. pylori for appropriate lengths of time. The adherence of the bacteria to the epithelial cells was examined by fluorescent microscopy using an anti-H. pylori antibody and flow cytometry. The apoptosis of the epithelial cells was studied by annexin-V staining and flow cytometry. The production of IL-8 by SGC 7901 cells was determined by ELISA. We found that iceA mutation was associated with significantly impaired production of IL-8 from the epithelial cells, which was not due to impaired adherence by the bacteria to the epithelial cells as wildtype and mutant H. pylori exhibited similar levels of binding to the epithelial cells. Furthermore, inactivation of iceA did not affect the apoptotic cell death of SGC7901. Our findings indicate that iceA may contribute to the pathogenicity of H. pylori by modulating the production of IL-8 by host epithelial cells.