Thromboxane A2 receptor (TXA2R) activation is thought to be involved in thrombosis/hemostasis and inflammation responses. We have previously shown that TXA2R antagonist SQ29548 attenuates BV2 microglia activation by suppression of ERK pathway, but its effect is not tested in vivo. The present study aims to explore the role of TXA2R on microglia/macrophages activation after ischemia/reperfusion brain injury in mice. Adult male ICR mice underwent 90-min transient middle cerebral artery occlusion (tMCAO). Immediately and 24 h after reperfusion, SQ29548 was administered twice to the ipsilateral ventricle (10 μl, 2.6 μmol/ml, per dose). Cerebral infarction volume, inflammatory cytokines release and microglia/macrophages activation were measured using the cresyl violet method, quantitative polymerase chain reaction (qPCR), and immunofluorescence double staining, respectively. Expression of TXA2R was significantly increased in the ipsilateral brain tissue after ischemia/reperfusion, which was also found to co-localize with activated microglia/macrophages in the infarct area. Administration of SQ29548 inhibited microglia/macrophages activation and enrichment, including both M1 and M2 phenotypes, and attenuated ischemia-induced IL-1ß, IL-6, and TNF-α up-regulation and iNOS release. TXA2R antagonist SQ29548 inhibited ischemia-induced inflammatory response and furthermore reduced microglia/macrophages activation and ischemic/reperfusion brain injury.
BackgroundTransplantation of neural stem cells (NSCs) has been proposed as a promising therapeutic strategy for the treatment of ischemia/reperfusion (I/R)-induced brain injury. However, existing evidence has also challenged this therapy on its limitations, such as the difficulty for stem cells to survive after transplantation due to the unfavorable microenvironment in the ischemic brain. Herein, we have investigated whether preconditioning of NSCs with adjudin, a small molecule compound, could enhance their survivability and further improve the therapeutic effect for NSC-based stroke therapy.MethodWe aimed to examine the effect of adjudin pretreatment on NSCs by measuring a panel of parameters after their transplantation into the infarct area of ipsilateral striatum 24 hours after I/R in mice.ResultsWe found that pretreatment of NSCs with adjudin could enhance the viability of NSCs after their transplantation into the stroke-induced infarct area. Compared with the untreated NSC group, the adjudin-preconditioned group showed decreased infarct volume and neurobehavioral deficiency through ameliorating blood–brain barrier disruption and promoting the expression and secretion of brain-derived neurotrophic factor. We also employed H2O2-induced cell death model in vitro and found that adjudin preconditioning could promote NSC survival through inhibition of oxidative stress and activation of Akt signaling pathway.ConclusionThis study showed that adjudin could be used to precondition NSCs to enhance their survivability and improve recovery in the stroke model, unveiling the value of adjudin for stem cell-based stroke therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0677-0) contains supplementary material, which is available to authorized users.
Aging, marked by the physical and functional decline in numerous biological processes, is associated with multiple pathologies including cancer, neurodegenerative diseases and cardiocerebral vascular diseases. The accumulation of reactive oxygen species (ROS) production is considered one of the major causes of aging-associated diseases and a major therapeutic target. Hydroxyurea has been widely used for cellular senescence model. The expression level of cell cycle-related protein, ROS production and senescence-associated β-galactosidase are considered to be markers of cellular senescence. Strategies to slow senescence may be beneficial for various aging-associated diseases. The results of the current study indicated that adjudin, a multi-functional small molecule compound, delayed hydroxyurea-induced senescence in mouse embryo fibroblasts (MEFs). Adjudin reduced the proportion of senescence-associated β-galactosidase-positive cells and decreased the expression levels of senescence-associated markers, p16 and p21. Mechanistically, adjudin exerted its anti-senescence effect by elevating the expression level of sirtuin 3 (Sirt3), which attenuated ROS production through the regulation of forkhead box O3a and manganese superoxide dismutase expression. Furthermore, by comparing wild-type and Sirt3-knockout MEFs, it was demonstrated that Sirt3 mediated the anti-senescence effect of adjudin. Taken together, the findings indicated that adjudin has anti-aging properties that may be exploited to treat aging-associated diseases.
Background Robotic-assisted minimally invasive surgery is associated with worse oncologic outcomes for some but not other types of cancers. We conducted a propensity score-matched analysis to compare oncologic outcomes of robotic-assisted laparoscopic (RPD) vs. open pancreatoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDAC). Methods Treatment-naïve PDAC patients undergoing either RPD or OPD at our hospital between January 2013 and December 2017 were included. Propensity score matching was conducted at a ratio of 1:2. The primary outcome was disease-free survival (DFS) and overall survival (OS). Results A total of 672 cases were identified. The propensity score-matched cohort included 105 patients receiving RPD and 210 patients receiving OPD. The 2 groups did not differ in the number of retrieved lymph nodes [11 (7-16) vs. 11 (6-17), P = 0.622] and R0 resection rate (88.6% vs. 89.0%, P = 0.899). There was no statistically significant difference in median DFS (14 [95% CI 11-22] vs. 12 [95% CI 10-14] months (HR 0.94; 95% CI 0.87-1.50; log-rank P = 0.345) and median OS (27 [95% CI 22-35] vs. 20 [95% CI 18-24] months (HR 0.77; 95% CI 0.57-1.04; log-rank P = 0.087) between the two groups. Multivariate COX analysis showed that RPD was not an independent predictor of DFS (HR 0.90; 95% CI 0.68-1.19, P = 0.456) or OS (HR 0.77; 95% CI 0.57-1.05, P = 0.094). Conclusion Comparable DFS and OS were observed between patients receiving RPD and OPD. This preliminary finding requires further confirmation with prospective randomized controlled trials. Keywords Pancreatic ductal adenocarcinoma • Robotic-assisted pancreatoduodenectomy • Open pancreatoduodenectomy • Propensity score matching Open pancreatoduodenectomy (OPD) is the cornerstone in the treatment of pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head or uncinate process, but is associated with significant morbidities [1-4]. Minimally invasive surgery was introduced in 1994 for PDAC patients [5], followed by robotic-assisted pancreatoduodenectomy (RPD) in 2003 [6]. Though technically challenging, RPD has a variety of advantages, including less blood loss, faster recovery, and less postoperative complications [4, 7-12]. However, the long-term oncological outcomes of RPD remain undefined [13-17]. Propensity score matching is a statistical method to minimize bias in retrospective studies [18]. We conducted a retrospective analysis to compare the long-term oncological outcomes between RPD and OPD using propensity scorematching. The primary end point of the study was diseasefree survival (DFS) and overall survival (OS).
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