Background: Astrocyte over-activation and extensive neuron loss are the main characteristic pathological features of spinal cord ischemia–reperfusion injury (SCII). Prior studies have placed substantial emphasis on the role of heat shock protein family A member 8 (HSPA8) on postischemic myocardial inflammation and cardiac dysfunction. However, it has never been determined whether HSPA8 participates in astrocyte activation and thus mediated neuroinflammation associated with SCII. Methods: The left renal artery ligation-induced SCII rat models and oxygen–glucose deprivation and reoxygenation (OGD/R)-induced rat primary cultured astrocytes were established. The lentiviral vector encoding short hairpin RNA targeting HSPA8 was delivered to the spinal cord by intrathecal administration or to culture astrocytes. Then, the spinal neuron survival, gliosis, and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and its related pro-inflammatory cytokines were analyzed. Results: SCII significantly enhanced the GFAP and HSPA8 expression in the spinal cord, resulting in blood–brain barrier breakdown and the dramatical loss of spinal neuron and motor function. Moreover, injury also increased spinal nuclear factor-kappa B (NF-κB) p65 phosphorylation, NLRP3 inflammasome-mediated caspase-1 activation, and subsequent interleukin (IL)-1β as well as IL-18 secretion. Silencing the HSPA8 expression efficiently ameliorated the spinal cord tissue damage and promoted motor function recovery after SCII, through blockade of the astrocyte activation and levels of phosphorylated NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Further in vitro studies confirmed that HSPA8 knockdown protected astrocytes from OGD/R-induced injury via the blockade of NF-κB and NLRP3 inflammasome activation. Conclusion: Our findings indicate that knockdown of HSPA8 inhibits spinal astrocytic damage after SCII, which may provide a promising therapeutic strategy for SCII treatment.

Hypertensive intracerebral haemorrhage (HICH) is the most common form of haemorrhagic stroke with the highest morbidity and mortality of all stroke types. The choice of surgical or conservative treatment for patients with HICH remains controversial. In recent years, minimally invasive surgeries, such as endoscopic evacuation and stereotactic aspiration, have been attempted for haematoma removal and offer promise. However, research evidence on the benefits of endoscopic evacuation or stereotactic aspiration is still insufficient. A multicentre, randomised controlled trial will be conducted to compare the efficacy of endoscopic evacuation, stereotactic aspiration and craniotomy in the treatment of supratentorial HICH. About 1350 eligible patients from 10 neurosurgical centres will be randomly assigned to an endoscopic group, a stereotactic group and a craniotomy group at a 1:1:1 ratio. Randomisation is undertaken using a 24-h randomisation service accessed by telephone or the Internet. All patients will receive the corresponding surgery based on their grouping. They will be followed-up at 1, 3 and 6 months after surgery. The primary outcome is the modified Rankin Scale at 6-month follow-up. Secondary outcomes include: haematoma clearance rate; Glasgow Coma Scale 7 days after surgery; rebleeding rate; intracranial infection rate; hospitalisation time; mortality at 1 month and 3 months after surgery; the Barthel Index and the WHO quality of life at 3 months and 6 months after surgery. The trial aims to investigate whether endoscopic evacuation and stereotactic aspiration could improve the outcome of supratentorial HICH compared with craniotomy. The trial will help to determine the best surgical method for the treatment of supratentorial HICH. ClinicalTrials.gov, ID: NCT02811614 . Registered on 20 June 2016.

Hemorrhage shock (HS) is characterized by decreased tissue oxygenation and organ damage due to severe blood loss. Protein tyrosine phosphatase receptor type O (PTPRO) is abnormally up-regulated in the rat lungs after trauma/HS. To elucidate the regulatory mechanism of PTPRO in lung inflammation following HS, we established a rat model of HS via withdrawing blood by a catheter inserted into the femoral artery followed by resuscitation. The rats were infected with lentivirus harboring short hairpin RNA (shRNA) targeting PTPRO by intratracheal instillation. PTPRO was significantly up-regulated in rat lungs after HS. PTPRO knockdown enhanced epithelial integrity and reduced capillary leakage by up-regulating tight junction proteins zonula occludens-1 (ZO-1) and occludin (OCC) in the lungs. Besides, HS-induced myeloperoxidase activity and inflammatory cell infiltration was mitigated by PTPRO knockdown. The expression of inflammatory cytokines/chemokines (TNF-α, IL-6, MIP-2, MCP-1, and KC) in the lungs and bronchoalveolar lavage fluid was regressed after PTPRO knockdown. The nuclear factor kappa B (NF-κB) pathway was involved in HS-induced lung inflammation. PTPRO down-regulation inhibited the NF-κB pathway activation by suppressing the phosphorylation of NF-κB and its translocation from the cytoplasm into the nucleus in HS. Taken together, we demonstrated that PTPRO knockdown may contribute to attenuating inflammation in HS-induced lung injury via inhibiting NF-κB pathway activation.

Hemorrhagic shock (HS) is a common and significant cause of mortality and morbidity, often resulting in structural damage and dysfunction of the intestines. ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (Chac1) has been reported to be involved in the regulation of oxidative stress and ferroptosis in mammals. Herein, we investigate the effects of Chac1 on HS-induced intestinal injury induced by HS both in vitro and in vivo. Sprague-Dawley rat model with HS was established, and our investigations showed upregulation of the mRNA and protein levels of Chac1 in the model’s ileum tissues. Histopathological analysis revealed that knockdown of Chac1 attenuated the intestinal injury induced by HS. Depletion of Chac1 also reduced the increase in intestinal fatty acid binding protein (I-FABP) concentration. Immunofluorescence staining indicated that silencing Chac1 significantly suppressed the downregulation of occludin and zonula occludens-1 (ZO-1). HS-induced changes in lipid peroxidation (LPO), malondialdehyde (MDA), and glutathione (GSH) levels were reversed in the absence of Chac1, suggesting that downregulation of Chac1 alleviated HS-induced oxidative stress. Additionally, HS led to a decrease in glutathione peroxidase 4 (Gpx4) and ferritin heavy chain 1 (Fth1) expression, along with an increase in ferrous ion (Fe2+) concentration. Knockdown of Chac1 significantly inhibited ferroptosis by increasing Gpx4 and Fth1 expression while reducing the Fe2+ concentration. In vitro experiments using the rat small intestine crypt epithelial cells (IEC-6) demonstrated that depletion of Chac1 suppressed oxidative stress and ferroptosis induced by hypoxia/reoxygenation (H/R). In conclusion, our study provides evidence that downregulation of Chac1 mitigates HS-induced intestinal injury by inhibiting oxidative stress and ferroptosis.