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Objective:To evaluate the role of sphingosine-1-phospho-1 receptor(S1PR1)in the dorsal root ganglion in remifentanil-induced hyperalgesia in rats with incisional pain.Methods:Forty-eight male Sprague-Dawley rats with successful intrathecal and caudal vein catheterization, weighing 260-280 g, aged 2-3 months, were divided into 6 groups ( n= 8 each) using a random number table method: control group (group C), S1PR1 antagonist (FTY720) group (group F), remifentanil group (group R), remifentanil + S1PR1 antagonist (FTY720) group (group R+ F), remifentanil + incisional pain group (group R+ I), and remifentanil + incisional pain + S1PR1 antagonist (FTY720) group (group R+ I+ F). In C group, normal saline 0.1 μg·kg -1·min -1 was intravenously infused for 60 min. In R group, remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In F group, FTY720 3 nmol was intrathecally injected, and 10 min later normal saline 1.0 μg· kg -1·min -1 was infused for 60 min via the caudal vein. In R+ F group, FTY720 3 nmol was intrathecally injected, and 10 min later remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In R+ I group, remifentanil 1.0 μg·kg -1·min -1 was infused for 60 min through the caudal vein while the model of incisional pain was developed. In R+ I+ F group, FTY720 3 nmol was intrathecally injected, 10 min later the incisional pain model was prepared, and remifentanil 1.0 μg·kg -1·min -1 was injected for 60 min through the caudal vein at the same time. The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 24 h before remifentanil or normal saline infusion (T 0) and 2, 6, 24 and 48 h after stopping remifentanil or normal saline infusion (T 1-4). Rats were sacrificed after the last measurement of pain threshold, and the L 4-6 segments of dorsal root ganglion were taken for determination of the expression of S1PR1, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1β (IL-1β) and glutamate transporter-1 (GLT-1) protein and mRNA (by Western blot and quantitative polymerase chain reaction). Results:Compared with C group, the MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and the expression of GLT-1 protein and mRNA in dorsal root ganglion was down-regulated in R group ( P<0.05), and no significant change was found in the parameters mentioned above in group F ( P>0.05). Compared with R group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and GLT-1 protein and mRNA expression in dorsal root ganglion was down-regulated in R+ I group, and MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and GLT-1 protein and mRNA expression in the dorsal root ganglion was up-regulated in R+ F group ( P<0.05). Compared with R+ I group, MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and the expression of GLT-1 protein and mRNA in the dorsal root ganglion was up-regulated in R+ I+ F group( P<0.05). Conclusions:The mechanism by which remifentanil induces hyperalgesia is associated with up-regulation of S1PR1 expression, activation of inflammatory factors, and down-regulation of GLT-1 expression in the rats with incisional pain.
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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.
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Objective@#To investigate the expression of LIM domain binding 2 (LDB2) in lung cancer tissues and its correlation with sphingosine-1 phosphate receptor 1 (S1PR1). @*Methods@#Lung cancer tissues and the corresponding adjacent tissues from 52 patients in Nantong Tumor Hospital during April 2010 and May 2011 were collected as the experimental group and the control group, respectively. The expression levels of LDB2 and S1PR1 were detected by the real-time PCR (qRT-PCR). The expression results of LDB2 gene were further verified by the Oncomine database, and its correlations with clinicopathological parameters were analyzed. The ROC curve was drawn to evaluate the diagnosis value of LDB2 expression in lung cancer. The correlation of LDB2 expression with the prognosis of lung cancer was analyzed by the “Kaplan-Meier Plotter” database. In addition, the relationship between LDB2 and S1PR1 was also analyzed. @*Results@#The expression levels of LDB2 in lung cancer tissues (0.158 [0.062,0.383]) were significantly lower than that in the adjacent tissues (0.403 [0.261,0.711], U=700.0, P＜ 0.01). A total of 9 eligible studies were retrieved from the Oncomine database, and their expressions of LDB2 were also low (P＜0.01). The expressions of LDB2 in lung cancer tissues were not related to gender, age, smoking history, pathological type, tumor size, TNM staging and lymphatic metastasis (P＞0.05). The results of ROC curve showed that when the area under the ROC curve (AUC ROC ) was 0.741 (95% CI:0.643-0.839) and the cut-off value was 0.247, the sensitivity and specificity of LDB2 in the diagnosis of lung cancer were 80.8% and 61.5%, respectively. The Kaplan-Meier survival analysis showed that the 5-year overall survival time of the patients with low expression of LDB2 was shorter than that of the patients with high expression of LDB2(P＜0.01). In addition, the expression levels of S1PR1 in lung cancer tissues (0.710[0.337,1.523]) were significantly lower than that in the adjacent tissues (1.582[0.913,3.533],U=780.0, P＜0.01), and the expression levels of S1PR1 in lung cancer tissues were positively correlated with that of LDB2(r=0.827,P＜0.01). @*Conclusion@#The expressions of LDB2 and S1PR1 in lung cancer tissues are down-regulated, and have a positive correlation, and they may play an important role in the occurrence and development of lung cancer.
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Objective To study the effects of fingolimod (FTY720) on the sphingosine-1-phosphate (S1P) signaling pathway in osteoclasts.Methods Murine RAW 264.7 macrophages were induced into osteoclasts by dexamethasone and 1 α,25-(OH)2VitD3 and identified by tartrate resistant acid phosphatase Trp staining.After the osteoclasts were divided into 2 groups,the experimental group was treated with 400 ng/mL FTY720-P while the control group was not.The signal expression of extracellular signal-regulated kinase 1 (ERK1),caspase9 and protein kinase(PKC) in the downstream of S1 P pathway was detected at the gene and protein levels,and the expression of bone morphogenetic protein-2(BMP-2) and transforming growth factor-β1 (TGF-β1),which are closely related to bone reconstruction,was detected.Results The RAW264.7 cells were successfully induced into osteoclasts identified by trataric acid phosphatase staining kit (TRAP).The expression of S1PR1 in osteoclasts was higher than that in other S1PRs.After culture for 48 hours,the expression of PKC mRNA in the experimental group was significantly lower than that in the control group while the expression of BMP-2 mRNA and TGF-[β1 mRNA was significantly increased in the experimental group than in the control group (P ＜ 0.05).However,there were no significant differences in expression of ERK1 mRNA or caspase9 mRNA between the 2 groups(P ＞ 0.05).Conclusions FTY720-P can affect the expression of PKC signal in the downstream of osteoclasts by affecting S1P signaling pathway,mainly by binding to S1PR1 signal pathway,and can also promote the expression of TGF-[β1 and BMP-2 in osteoclasts,ultimately affecting the function of osteoclasts.
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Objective To investigate the effects of sphingosine-1-phosphate receptor 1 (S1PR1) changes on the proliferation of endogenous neural stem cells (NSCs) in hippocampus after traumatic brain injury (TBI).Methods Rat TBI models were constructed by the means of controlled cortical injury.A total of 72 rats were included and randomly divided into four groups:sham,TBI,TBI + SEW (TBI + S1PR1 agonist SEW2871 intervention) and TBI + VPC group (TBI + S1PR1 antagonist VPC23019 intervention),with 18 rats per group.The TBI model was induced by a control cortical injury device.The injured rats in TBI + SEW group and TBI + VPC group were respectively administrated with S1PR1 agonist SEW2871 and antagonist VPC23019 at scheduled time points after TBI.Hippocampal S1PR1 expression was detected by Western-blotting and the proliferation of NSCs was assessed by double-labeled immunofluorescence staining at days 7,14 and 21 after injury.Results At days 7,14 and 21 after TBI,the hippocampal S1PR1 levels and NSCs proliferation amounts in sham,TBI,TBI + SEW and TBI + VPC groups were evidently different (P ＜ 0.05).In particular,the outstanding changes among the four groups above occurred at 7 d after injury were as following:S1PR1 expression in TBI group significantly increased by 1.56 times compared with that in sham group,and it was respectively upregulated by 66.67％ in TBI + SEW group and down-regulated by 20.29％ in TBI + VPC group (P ＜0.05).The nmmber of NSCs proliferation in TBI group was 2.08 times more than that in sham group,and it increased by 36.75％ in TBI + SEW group and reduced by 18.77％ in TBI + VPC group (P ＜ 0.05).Conclusion The expression of S1 PRI is closely associated with the proliferation of NSCs in hippocampus after TBI,indicating that S1PR1 activation may be an effective strategy to improve the posttraumatic neurogenesis.
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Objective To investigate the effects of sphingosine-1-phosphate receptor 1 (S1PR1) changes on the proliferation of endogenous neural stem cells (NSCs) in hippocampus after traumatic brain injury (TBI).Methods Rat TBI models were constructed by the means of controlled cortical injury.A total of 72 rats were included and randomly divided into four groups:sham,TBI,TBI + SEW (TBI + S1PR1 agonist SEW2871 intervention) and TBI + VPC group (TBI + S1PR1 antagonist VPC23019 intervention),with 18 rats per group.The TBI model was induced by a control cortical injury device.The injured rats in TBI + SEW group and TBI + VPC group were respectively administrated with S1PR1 agonist SEW2871 and antagonist VPC23019 at scheduled time points after TBI.Hippocampal S1PR1 expression was detected by Western-blotting and the proliferation of NSCs was assessed by double-labeled immunofluorescence staining at days 7,14 and 21 after injury.Results At days 7,14 and 21 after TBI,the hippocampal S1PR1 levels and NSCs proliferation amounts in sham,TBI,TBI + SEW and TBI + VPC groups were evidently different (P ＜ 0.05).In particular,the outstanding changes among the four groups above occurred at 7 d after injury were as following:S1PR1 expression in TBI group significantly increased by 1.56 times compared with that in sham group,and it was respectively upregulated by 66.67％ in TBI + SEW group and down-regulated by 20.29％ in TBI + VPC group (P ＜0.05).The nmmber of NSCs proliferation in TBI group was 2.08 times more than that in sham group,and it increased by 36.75％ in TBI + SEW group and reduced by 18.77％ in TBI + VPC group (P ＜ 0.05).Conclusion The expression of S1 PRI is closely associated with the proliferation of NSCs in hippocampus after TBI,indicating that S1PR1 activation may be an effective strategy to improve the posttraumatic neurogenesis.
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Lipid second messenger sphingosine-1-phosphate (S1P) can activate sphingosine-1-phosphate receptors (S1PRs) and participate in many biological processes, such as central nervous system homeostasis, cytokine production and T cell migration. S1PR1 is the main S1PR expressed on T cell surface. The interaction between S1P and S1PR1 plays a core role in T cell migration, which is important for T cell maturation, homing and activation. The central function of S1P/S1PR1 in T cell migration made it a popular drug target in treatment research of immune diseases. This review summarizes the current knowledge of the mechanism of S1P/S1PR1 mediating T cell migration and the research progress of S1P/S1PR1 as drug target.