Purpose To investigate the role of PI3k/Akt signal pathway in the protective effects of propofol on intestinal and lung injury induced by intestinal ischemia/reperfusion(I/R). Methods Male Sprague-Dawley rats were subjected to 45 min of ischemia by occluding the superior mesenteric artery and to 2h of reperfusion to establish the model of I/R. Twenty four rats were randomly divided into four groups: Sham, intestinal I/R (II/R), propofol (P), wortmannin (W). In groups P, W, propofol was injected intravenously and continuously at the onset of reperfusion via infusion pump. PI3K inhibitor (wortmannin) was administered intravenously in group W 25 min before ischemia. Intestinal tissues and lung tissues were obtained for determination of histologic injury, wet/dry weight ratio, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Meanwhile, the expressions of caspase-3 and phosphorylated Akt (p-Akt) in intestines and lungs were detected by western blot. Results Propofol treatment alleviated intestinal and lung morphological changes which were observed in II/R group , Moreover, wet/dry weight ratio, the MDA level, MPO activity and expression of caspase-3 were significantly decreased whereas the SOD activity and p-Akt expression were significantly increased. Notably, the protections were significantly reversed by pretreatment of wortmannin. Conclusion: PI3K/Akt pathway activation play a critical role in the protective effects of propofol on intestinal and lung injury induced by ischemia/reperfusion.

Background Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and microglia pyroptosis are unknown. In this study, we investigated the promising role and underlying molecular mechanism of Erbin in the regulation of microglia pyroptosis. Methods WT and Erbin knockout mice underwent cecum ligation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Western blot and immunofluorescence were used to analyze protein expression. Flow cytometry and confocal microscopy were utilized to observe the Ca2+ changes in the cytoplasm and endoplasmic reticulum (ER). To further explore the underlying mechanism, STF083010 was administered to block the IRE1α/Xbp1s pathway. Results Erbin deletion resulted in more pronounced neuronal damage and cognitive impairment in mice that underwent CLP. Erbin knockout promoted microglial pyroptosis and inflammatory cytokines secretion in vivo and in vitro, which was mediated by activation of the IRE1α/Xbp1s. Treatment with the selective inhibitor STF083010 significantly inhibited IRE1α/Xbp1s pathway activity, decreased intracytoplasmic Ca2+, attenuated microglial pyroptosis, reduced pro-inflammatory cytokine secretion, lessened neuronal damage, and improved cognitive function. Conclusions In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca2+ influx to the cytoplasm, reducing microglial pyroptosis.

The aim of the present study was to investigate the effect of penehyclidine hydrochloride (PHc) pretreatment on mice with lipopolysaccharide (lPS)-induced acute lung injury (ali) and its possible underlying mechanisms. Mice were randomly separated into six groups: i) Sham group; ii) lPS group; iii) lPS + PHc group; iv) tumor necrosis factor a-induced protein 8-like protein 2 (TiPe2) group; v) lPS + TiPe2 group; and vi) lPS + TiPe2 + PHc group. The ali model was induced using lPS through intratracheal injection. The mice received adenovirus gene to induce the overexpression of TIPE2. After mice were sacrificed, lung injury indices were assessed, and arterial blood, bronchoalveolar lavage fluid and lung tissues were collected for subsequent assays. expression levels of related proteins were detected by using western blotting. it was found that compared with the sham group, the mice treated with lPS showed increased lung injury and dysfunctions of gas exchange. However, these trends were significantly ameliorated in the lPS + PHc group. evaluation of protein expression in lung tissues showed that the increased expression of nuclear nF-κB p65 and p-c-Jun n-terminal kinase (JnK) induced by lPS were suppressed in the lPS + PHc group and the expression of TiPe2 was increased. The mice that received adenovirus gene to induce TiPe2 overexpression could also showed protective effects compared with the mice in the lPS group. However, the expression of TiPe2 decreased rather than increased in lPS group. in the mice pretreated with PHc, the expression of TiPe2 increased in mice with lPS-induced ali. To conclude, PHc pretreatment could inhibit the occurrence of inflammation and apoptosis in LPS-induced ALI. This process may be related to the activation of TiPe2 and the inhibition of nF-κB and JnK signaling pathway in the lungs of mice.

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