Edaravone improves the post-traumatic brain injury dysfunction in learning and memory by modulating Nrf2/are signal pathway

OBJECTIVES: To investigate the molecular mechanism of edaravone (EDA) in improving the post-traumatic brain injury (TBI) dysfunction in learning and memory. METHODS: In vitro and in vivo TBI models were established using hydrogen peroxide (H2O2) treatment for hippocampal nerve stem cells (NSCs) and surgery for rats, followed by EDA treatment. WST 1 measurement, methylthiazol tetrazolium assay, and flow cytometry were performed to determine the activity, proliferation, and apoptosis of NSCs, and malondialdehyde (MDA), lactic dehydrogenase (LDH), and reactive oxygen species (ROS) detection kits were used to analyze the oxides in NSCs. RESULTS: Following EDA pretreatment, NSCs presented with promising resistance to H2O2-induced oxidative stress, whereas NSCs manifested significant increases in activity and proliferation and a decrease in apoptosis. Meanwhile, for NSCs, EDA pretreatment reduced the levels of MDA, LDH, and ROS, with a significant upregulation of Nrf2/antioxidant response element (ARE) signaling pathway, whereas for EDA-treated TBI rats, a significant reduction was observed in the trauma area and injury to the hippocampus, with improvement in memory and learning performance and upregulation of Nrf2/ARE signaling pathway. CONCLUSIONS: EDA, by regulating the activity of Nrf2/ARE signal pathway, can improve the TBI-induced injury to NSCs and learning and memory dysfunction in rats.

Effect of Duzhong Butiansu Capsule on improving spermatogenesis obstacle in mice induced by cyclophosphamide / 中草药

Objective: To investigate the reproductive protective effect of Duzhong Butiansu Capsule (DBC) by using cyclophosphamide induced spermatogenic disorder model, and explore its mechanism. Methods: The model of spermatogenic disorder was established by intraperitoneal injection of cyclophosphamide (60 mg/kg) for 5 d. Drug intervention at high and low doses (1.388 g/kg and 0.694 g/kg) was given for 4 weeks from the 8th day. The body weight and organ index of each group were measured. The pathological structure of testis was detected by HE staining. ELISA method was used to detect the levels of T, FSH, LH, MDA, SOD, GSH-Px. Western blotting and immunohistochemistry were used to analyze the expression of Nrf2/ARE signaling pathway related factors Nrf2, HO-1, NQO1, HDAC2, and p-PKC in testicular tissue. Results: Compared with the model group, DBC significantly reduced the weight of mice, increased the index of testis, epididymis and kidney, improved the pathological morphology of testis, increased the number of spermatozoa, increased the motility of sperm, decreased the rate of abnormal sperm, increased the level of T and decreasd the level of LH and FSH, increased the content of MDA, decreased the content of SOD and GSH-Px, increased the expression of Nrf2, HO-1, NQO1, HDAC2, and p-PKC protein, and increased the area of positive expression of Nrf2, HO-1 protein (P < 0.05 or P < 0.01). Conclusion: DBC can obviously improve the spermatogenic disorder induced by cyclophosphamide, and the mechanism may be related to the regulation of Nrf2/ARE signal pathway associated with oxidative stress.

Lipoic acid protects the lungs of rats against acute injury induced by paraquat poisoning through Nrf2-ARE signaling pathway / 中华急诊医学杂志

Objective To investigate the nuclear factor-erythroid 2-related factor (Nrf-2),and heme oxidase 1 (HO-1) expression in acute lung injury induced by paraquat poisoning in rats and explore the mechanism of lipoic acid acting on protection of lung from paraquat poisoning.Methods Seventy-two adult healthy male Sprague Dawley (SD) rats were randomly divided into three groups with different treatments designated as:control group (control group,n =12),paraquat group (PQ group,n =30) and paraquat + lipoic acid group (LA group,n =30).PQ group and LA group were randomly divided into five subgroups (n =6 in each) according to 6 h,12 h,24 h,48 h and 72 h after modeling and treatment.The rats in PQ group and PQ + LA group were treated with intra-peritoneal injection (ip) of PQ (25 mg/kg),while the rats in control group were treated with the equal volume of saline instead.Half an hours after intra-peritoneal injection of PQ,lipoic acid (100 mg/kg) was injected into caudal vein of rats once a day until they were sacrificed.The body weight was measured everyday.The rats of each group were sacrificed at the given intervals,and lung tissues were harvested to measure lung coefficient of rats.The same part of left lung of rats in each group was taken for HE staining and immunohistochemistry in order to detect the expressions of Nrf2 and HO-1.The right lung of rats in each group was taken for the detection of GSH-Px and SOD activity.All data were analyzed by using the One-way analysis of variance (ANOVA) and SNK-q test.Results The body weight reduction in LA group (191.02 ± 0.82) g,(183.37 ± 7.74) g was significantly less than that in PQ group (183.85 ± 2.07) g,(173.13 ± 4.34) g at 48 h and 72 h after PQ poisoning,respectively (P ＜ 0.01,P ＜ 0.05).The lung coefficient in LA group (6.83 ± 0.48) mg/g,(7.61 ±0.28) mg/g,(8.29 ±0.36) mg/g was less compared with PQ group (7.39 ±0.53) mg/g,(8.48±0.23) mg/g,(9.06±0.10) mg/g at 24 h,48 h,and 72 h,respectively (P＜0.01,P＜ 0.05).The immunohistochemical expressions of Nrf-2 in LA group (3.99 ±0.50),(3.51 ±0.12) were higher than those in PQ group (1.33 ±0.22),(1.62 ±0.41) at 48 h and 72 h.The immunohistochemical expression of HO-1 in LA group (1.76 ±0.17) was higher than that in PQ group (1.31 ±0.15) at 72 h.The levels of GSH-Px activity in LA group were significantly higher in comparison with PQ group at 24h,48h,and 72h (P ＜0.01,P ＜0.05).The levels of SOD activity in the LA group were significantly higher in comparison with PQ group at 6 h,12 h,24 h,48 h,and 72 h after PQ administration (P ＜ 0.01).Conclusions Nrf2-ARE (antioxidant response element) signaling pathway is involved in the pathogenesis of acute lung injury induced by paraquat poisoning,and lipoic acid may protect acute lung injury in rats induced by paraquat poisoning through Nrf2-ARE signaling pathway.

Research progress of Nrf2/ARE pathway regulating mechanism / 天津医药

Nuclear factor E2 related factor Nrf2 is a nuclear transcription factors involved in a variety of protein expression. As a center of oxidative stress regulation, it combines with antioxidant components (antioxidant responsive element, ARE) and activates downstream multiple anti-oxidation, anti-inflammatory and detoxifying enzyme protein expression. This signaling pathway is involved in the development of inflammation, tumor and other pathological process. This review describes the basic structure, biological effects and signaling pathways of Nrf2, summarizes the latest progress about mechanisms of factors, which are involved in the positive and negative regulations of signal pathway, providing a new target for anti-inflammatory, antioxidant, and antitumor biochemical treatment. Based on these, the paper also looks forward to applicating bioinformatics technology and providing better prospects for the development of target intervention.