Neuroprotective effects of neural stem cells pretreated with neuregulin1ß on PC12 cells exposed to oxygen-glucose deprivation/reoxygenation.

Studies on ischemia/reperfusion (I/R) injury suggest that exogenous neural stem cells (NSCs) are ideal candidates for stem cell therapy reperfusion injury. However, NSCs are difficult to obtain owing to ethical limitations. In addition, the survival, differentiation, and proliferation rates of transplanted exogenous NSCs are low, which limit their clinical application. Our previous study showed that neuregulin1ß (NRG1ß) alleviated cerebral I/R injury in rats. In this study, we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1ß on PC12 cells injured by oxygen-glucose deprivation/reoxygenation (OGD/R). Our results found that 5 and 10 nM NRG1ß promoted the generation and proliferation of NSCs. Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1ß improved the level of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, nicotinamide adenine dinucleotide phosphate, and nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial damage in injured PC12 cells; these indexes are related to ferroptosis. Research has reported that p53 and solute carrier family 7 member 11 (SLC7A11) play vital roles in ferroptosis caused by cerebral I/R injury. Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4 (GPX4) was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells, but this change was alleviated after co-culturing NSCs with damaged PC12 cells. These findings suggest that NSCs pretreated with NRG1ß exhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway.

Transplantation of Human Umbilical Cord Mesenchymal Stem Cells-Derived Neural Stem Cells Pretreated with Neuregulin1ß Ameliorate Cerebral Ischemic Reperfusion Injury in Rats.

Ischemic stroke is a common cerebrovascular disease and recovering blood flow as early as possible is essential to reduce ischemic damage and maintain neuronal viability, but the reperfusion process usually causes additional damage to the brain tissue in the ischemic area, namely ischemia reperfusion injury. The accumulated studies have revealed that transplantation of exogenous neural stem cells (NSCs) is an ideal choice for the treatment of ischemia reperfusion injury. At present, the source and efficacy of exogenous NSCs after transplantation is still one of the key issues that need to be resolved. In this study, human umbilical cord mesenchymal stem cells (hUC-MSCs) were obtained and induced into NSCs byadding growth factor and neuregulin1ß (NRG1ß) was introduced during the differentiation process of NSCs. Then, the rat middle cerebral artery occlusion/reperfusion (MCAO/R) models were established, and the therapeutic effects were evaluated among groups treated by NRG1ß, NSCs and NSCs pretreated with 10 nM NRG1ß (NSCs-10 nM NRG1ß) achieved through intra-arterial injection. Our data show that the NSCs-10 nM NRG1ß group significantly improves neurobehavioral function and infarct volume after MCAO/R, as well as cerebral cortical neuron injury, ferroptosis-related indexes and mitochondrial injury. Additionally, NSCs-10 nM NRG1ß intervention may function through regulating the p53/GPX4/SLC7A11 pathway, and reducing the level of ferroptosis in cells, further enhance the neuroprotective effect on injured cells.

High-Volume Hemofiltration in Critically Ill Patients With Secondary Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Prospective Study in the PICU.

OBJECTIVES: Hemophagocytic lymphohistiocytosis, which includes primary (familial) and secondary hemophagocytic lymphohistiocytosis, is a fatal disease in children. Macrophage activation syndrome was defined in patients who met secondary hemophagocytic lymphohistiocytosis criteria with an underlying autoimmune disease. High-volume hemofiltration has shown beneficial effects in severe sepsis and multiple organ dysfunction syndrome. Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome shares many pathophysiologic similarities with sepsis. The present study assessed the effects of high-volume hemofiltration in children with secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. DESIGN: A single-center nonrandomized concurrent control trial. SETTING: The PICU of Shanghai Children's Hospital, Shanghai Jiao Tong University. PATIENTS: Thirty-three critically ill secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome patients treated between January 2010 and December 2014. INTERVENTIONS: Thirty-three patients were divided into two groups: high-volume hemofiltration + hemophagocytic lymphohistiocytosis-2004 group (17 cases) or hemophagocytic lymphohistiocytosis-2004 group (16 cases). High-volume hemofiltration was defined as an ultrafiltrate flow rate of 50-70 mL/kg/hr. Clinical and biological variables were assessed before initiation and after 48 and 72 hours of high-volume hemofiltration therapy. MEASUREMENTS AND MAIN RESULTS: The total mortality rate was 42.4% (14/33), but mortality at 28 days was not significantly different between the two groups (high-volume hemofiltration + hemophagocytic lymphohistiocytosis-2004 group: five deaths, 29.4%; hemophagocytic lymphohistiocytosis-2004 group: nine deaths, 56.3%; chi-square, 2.431; p = 0.119). Children received high-volume hemofiltration for 60.2 ± 42.0 hours. After 48 and 72 hours respectively, a significant decrease in serum ferritin (p < 0.001), aspartate aminotransferase (p = 0.037 and p < 0.001), total bilirubin (p = 0.041 and p = 0.037), and serum creatinine (p = 0.006 and p = 0.004) levels were observed. Furthermore, the natural killer-cell activity up-regulated (p = 0.047) after 72 hours. Furthermore, significantly decreased levels of serum tumor necrosis factor-α (from 91.5 ± 44.7 ng/L at 48 hr to 36.7 ± 24.9 ng/L at 72 hr; p = 0.007)) and interleukin-6 (from 46.9 ± 21.1 ng/L at 48 hr to 27.7 ± 14.5 ng/L at 72 hr; p < 0.0001) were observed. After 7 days, patients receiving high-volume hemofiltration had significantly lower bilirubin, creatinine, ferritin, procalcitonin, lactate dehydrogenase level, tumor necrosis factor-α, and interleukin-6 levels, and needed less mechanical ventilation compared with hemophagocytic lymphohistiocytosis-2004 group patients. No serious adverse events were observed. CONCLUSIONS: High-volume hemofiltration may improve organ function by decreasing cytokine levels (tumor necrosis factor-α and interleukin-6). High-volume hemofiltration may be an effective adjunctive treatment in secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome.