Efficacy and Safety of Dl-3-n-Butylphthalide Combined With Human Urinary Kallidinogenase in the Treatment of Acute Ischemic Stroke.

OBJECTIVES: Intravenous thrombolysis and mechanical endovascular thrombectomy are recommended for patients whose stroke onsets are within the first 6 hours; however, patients beyond this time window have very limited options. Dl-3-n-butylphthalide (NBP) and human urinary kallidinogenase (HUK) have shown potential clinical benefits in the treatment of acute ischemic stroke (AIS) patients. This research aims to investigate the efficacy and safety of NBP combined with HUK in the treatment of ischemic stroke patients. PATIENTS AND METHODS: We reviewed the 215 AIS patients registered in the database of the Fifth Affiliated Hospital of Sun Yat-sen University from April 2019 to October 2020. Among them, 65 patients received NBP sodium chloride injection treatment, 55 patients received HUK treatment, and 95 patients received NBP sodium chloride injection combined with HUK treatment. The recovery of neural function was evaluated by the National Institutes of Health Stroke Scale (NIHSS), and the recovery of daily function was evaluated by the modified Rankin Scale (mRS). The NIHSS and mRS scores after the 7-day treatment, 6-month independency rate (6-month mRS score ≤1), and related factors were compared among the 3 groups. The safety was monitored by recording adverse events. RESULTS: The NIHSS and mRS scores of 7-day and 6-month treatment in the NBP combined with HUK group were lower than the monotherapy ( P < 0.05). In addition, the NBP combined with HUK treatment achieved an independency rate of 82.1%, whereas NBP and HUK treatments achieved only 53.8% and 63.6%, respectively ( P < 0.001). Binary logistic regression showed that NBP combined with HUK therapy treatment could lead to a 5.28 times higher rate of patients' 6-month independency after AIS occurrence. No serious adverse events occurred in both the combined therapy and monotherapy. CONCLUSIONS: Dl-3-n-butylphthalide combined with HUK is safe to treat AIS patients. It can significantly improve the neural function and the 6-month recovery of AIS patients.

Eicosapentaenoic acid prevents inflammation induced by acute cerebral infarction through inhibition of NLRP3 inflammasome activation.

OBJECTIVE: Acute cerebral infarction (ACI) is the most common type of acute cerebrovascular diseases resulting in high rate of death and disability. Numerous evidences show that inflammation is the leading cause of ischemic brain injury, thus anti-inflammatory therapy is an attractive candidate for ischemic brain damage. Eicosapentaenoic acid (EPA) exerts anti-inflammatory activity in lots of human inflammatory diseases, whereas its effect in ACI is left to elucidate. METHOD: Nlpr3-/- mice, Gpr40-/-; Gpr120-/- mice and mice with right middle cerebral artery occlusion (MCAO) were used to detect NLR family pyrin domain containing 3 (NLRP3) inflammasome activation by Western Blot and the release of proinflammatory cytokines by ELISA. To estimate the acute ischemic condition in vitro, oxygen-glucose deprivation (OGD) was induced in BV2 microglia cells. Transfection of the shRNA targeting GPR40 and GPR120 mRNA into BV2 cells was also assessed. Apoptosis in ischemic cerebral tissues and BV2 cells was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry. RESULT: Here we show that EPA suppresses ACI-induced inflammatory responses through blocking NLRP3 inflammasome activation. In addition, EPA inhibits NLRP3 inflammasome activation through G protein-coupled receptor 40 (GPR40) and GPR120. Importantly, EPA ameliorates ACI-induced apoptosis. CONCLUSION: EPA exerts beneficial effect on ACI-induced inflammation through blocking NLRP3 inflammasome activation by GPR40 and GPR120. Our findings suggest the potential clinical use of EPA in ACI.

Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription.

The effective therapeutic approach of cerebral infarction is limited because of its underlying complexity. Recently, multiple long noncoding RNAs (lncRNAs) have been identified in the pathogenesis of cerebral infarction. Here, the current study aims to explore the interaction among lncRNA cyclin-dependent kinase inhibitor-2B-antisense RNA 1 (CDKN2B-AS1), transcription factor B-cell lymphoma/leukemia 11A (BCL11A), and MAPKK kinase kinase 1 (MAP4K1) and further investigate whether they affect cerebral infarction progression. The expression of CDKN2B-AS1, BCL11A, and MAP4K1 was altered in lymphocytes extracted from patients with cerebral infarction. In order to identify their roles in regulatory T (Treg) cells, the proliferation and apoptosis of the CD4+CD25+ Treg cells were examined, and levels of IL-4, IL-10, and TGF-ß were determined. Also, the RNA crosstalk among CDKN2B-AS1, BCL11A, and MAP4K1 was validated. Finally, we established a rat model of middle cerebral arterial occlusion to evaluate the neurologic impairment and cerebral infarction volume. The results revealed that lymphocytes in patients with cerebral infarction presented with the up-regulated expression of CDKN2B-AS1. Moreover, BCL11A could specifically bind to CDKN2B-AS1 and MAP4K1 promoter so as to inhibit MAP4K1. Moreover, it was observed that down-regulated CDKN2B-AS1 inhibited CD4+CD25+ Treg-cell proliferation, reduced levels of IL-4, IL-10, and TGF-ß and cerebral infarction volume, and elevated MAP4K1 expression. Collectively, our study provides evidence that CDKN2B-AS1 silencing could increase MAP4K1 expression to inhibit the CD4+CD25+ Treg-cell proliferation by reducing enrichment of transcription factor BCL11A, thereby protecting against cerebral infarction progression, highlighting a promising therapeutic strategy for treating cerebral infarction.-Lei, J.-J., Li, H.-Q., Mo, Z.-H., Liu, K.-J., Zhu, L.-J., Li, C.-Y., Chen, W.-L., Zhang, L. Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription.

Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway.

This study aimed to explore potential new drugs in the treatment of ischemic stroke by Connectivity Map (CMap) and to determine the role of luteolin on ischemic stroke according to its effects on matrix metalloproteinase-9 (MMP9) and PI3K/Akt signaling pathway. Based on published gene expression data, differentially expressed genes were obtained by microarray analysis. Potential compounds for ischemic stroke therapy were obtained by CMap analysis. Cytoscape and gene set enrichment analysis (GSEA) were used to discover signaling pathways connected to ischemic stroke. Cell apoptosis and viability were, respectively, evaluated by flow cytometry and an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were used to test the expression of MMP9 and the PI3K/Akt signaling pathway-related proteins in human brain microvascular endothelial cells (HBMECs) and tissues. Additionally, the infarct volume after middle cerebral artery occlusion (MCAO) was determined by a TTC (2,3,5-triphenyltetrazolium chloride) assay. The microarray and CMap analyses identified luteolin as a promising compound for future therapies for ischemic stroke. Cytoscape and GSEA showed that the PI3K/Akt signaling pathway was crucial in ischemic stroke. Cell experiments revealed that luteolin enhanced cell viability and downregulated apoptosis via inhibiting MMP9 and activating the PI3K/Akt signaling pathway. Experiments performed in vivo also demonstrated that luteolin reduced the infarct volume. These results suggest that luteolin has potential in the treatment of ischemic stroke through inhibiting MMP9 and activating PI3K/Akt signaling pathway.

Application of Doctor-Nurse-Patient Integration Management Mode in Patients with Endometriosis.

BACKGROUND: To investigate the effect of applying doctor-nurse-patient integration management mode to patients with endometriosis (EMT). METHODS: A total of 160 patients with EMT from the Department of Neurology of The Fifth Affiliated Hospital Sun Yat-Sen University from January 2017 to October 2017 were selected. They were divided into control group and experimental group according to the time sequence of hospitalization, with 80 patients in each group. The traditional nursing management mode was implemented in the control group, and doctor-nurse-patient integration mode was implemented in the experimental group. The psychological status, quality of life, and satisfaction of the 2 groups of patients were compared one year after surgery. RESULTS: The anxiety and depression scores in the observation group were (41.89±7.50) and (42.40±7.40) points, respectively, and those in the control group were (57.55±9.68) and (55.00±9.35) points, respectively. The differences between the two groups were statistically significant (t=-11.44, -9.42, P<0.05). The improvement rate of quality of life (sleep, work and sexual life) in the observation group was 87.5%, which was higher than that in the control group (63.8%). The difference between the 2 groups was statistically significant (U=583, P<0.01). The satisfaction rate in the observation group was 90.00%, which was higher than that in the control group (78.75%) (U=592.00, P< 0.01). CONCLUSION: The doctor-nurse-patient integration management mode can effectively improve the negative psychological status and quality of life of patients with EMT and improve patient satisfaction, which is worth popularizing.

Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

BACKGROUND AND OBJECTIVES: Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. MATERIALS AND METHODS: 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. RESULTS: Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. CONCLUSION: Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment.