Autophagy‐lysosome dysfunction is involved in gastric ischemia‑reperfusion injury by promoting microglial activation in the paraventricular nucleus

Abstract

The hypothalamic paraventricular nucleus (PVN) is a specific center in the brain that regulates gastric mucosal injury following gastric ischemia-reperfusion (GI-R) injury.This study aimed to investigate whether autophagy-lysosome dysfunction in the PVN tissues of GI-R rats is involved in the gastric injury, and the underlying molecular mechanisms. The rat model of GI-R was established by clamping the celiac artery for 30 min and reperfusion for different hours (1, 3, and 6 h). The gastric injury was evaluated by hematoxylin and eosin staining of the stomach and the gastric mucosal index. The autophagy-lysosome dysfunction in the PVN was evaluated by the protein levels of LC3 II and Beclin-1 (markers for autophagosome activity) and the activity of acid phosphatase (a representative lysosomal enzyme). Immunohistochemical staining of ionized calcium-binding adaptor molecule 1 in the PVN was performed to evaluate microglial activation. Reactive oxygen species (ROS) content and phosphorylated γ-aminobutyric acid B receptor (p-GABA B R) expression in the PVN were also examined. The results revealed that, in GI-R rats, the shorter the reperfusion duration, the more severe the gastric mucosal damage. The autophagy-lysosome dysfunction exhibited by GI-R rats further enhanced microglial activation, ROS production, p-GABA B R expression, and gastric injury. In addition, activating microglial cells increased ROS production, p-GABA B R expression, and gastric injury in GI-R rats, while inhibiting microglial activation resulted in the opposite results. Taken together, autophagy-lysosome dysfunction induced by GI-R aggravated the gastric injury by inducing microglia activation.

Combination of polythyleneimine regulating autophagy prodrug and Mdr1 siRNA for tumor multidrug resistance

“…Subsequently, the GFP-LC3 puncta were observed to dramatic increases under CLSM (F i g. 4 I and J). Our previous research shows that the abilities of lysosomal acidity and blocking autophagic flux would reflect in the decreased activity of acid phosphatase (ACP) [ 55 ]. As shown in Fig.…”