Publications by authors named "Junyu Mu"

3 Publications

  • Page 1 of 1

Urocortin participates in LPS-induced apoptosis of THP-1 macrophages via S1P-cPLA2 signaling pathway.

Eur J Pharmacol 2020 Nov 16;887:173559. Epub 2020 Sep 16.

Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, PR China. Electronic address:

There is little literature showing the effect of urocortin (UCN) on macrophage apoptosis. The underlying mechanism is also unclear. This work was to investigate the involvement of UCN in the regulation of LPS-induced macrophage apoptosis and hence in the prevention from the atherosclerotic lesion development through targeting PLA2. Flow cytometry analysis showed that cell apoptosis was increased by more than 50% after LPS treatment in human THP-1 macrophage. Lp-PLA2 and cPLA2 were found to mediate LPS-induced macrophage apoptosis and NF-κB differentially influenced the expression of Lp-PLA2 and cPLA2. However, the reverse regulation of the expression of Lp-PLA2 and cPLA2 by NF-κB suggested that NF-κB may not be a key target for regulating macrophage apoptosis. Interestingly, we found that the approximate three folds upregulation of cPLA2 was in line with the induction of S1P formation and cell apoptosis by LPS. Inversely, LPS obviously decreased UCN expression by about 50% and secretion by about 25%. Both the enzyme inhibitor and knockdown expression of cPLA2 could completely abolish LPS-induced cell apoptosis. In addition, suppression of S1P synthesis by Sphk1 inhibitor PF-543 reduced the expression of cPLA2 and cell apoptosis but at the same time restored the normal level of UCN in cell culture supernatant. Furthermore, addition of exogenous UCN also reversed LPS-induced expression of cPLA2 and apoptosis. Taken together, UCN may be the reverse regulator of LPS-S1P-cPLA2-apoptosis pathway, thereby contributing to the prevention from the formation of unstable plaques.
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http://dx.doi.org/10.1016/j.ejphar.2020.173559DOI Listing
November 2020

Activation of CRHR1 contributes to cerebral endothelial barrier impairment via cPLA phosphorylation in experimental ischemic stroke.

Cell Signal 2020 02 9;66:109467. Epub 2019 Nov 9.

Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, China. Electronic address:

The activation of corticotrophin-releasing hormone receptor (CRHR) 1 is implicated in neuronal injury in experimental stroke. However, little is known about the relationship between CRHR1 activation and brain endothelial barrier impairment after ischemia and reperfusion (I/R). Recently we have demonstrated that the activation of extracellular signal-regulated kinase (Erk) 1/2 as well as p38 is required for hydrogen peroxide (HO)-increased cytosolic phospholipase A (cPLA) phosphorylation in bEnd3 cells. Using this in vitro ischemic-like model, we found that both blockade and interference of CRHR1 inhibited HO-enhancd p38, Erk1/2 and cPLA phosphorylation and in turn suppressed monolayer hyperpermeability and ZO-1 redistribution. Then using the transient middle cerebral artery occlusion (tMCAO) mouse model, we revealed that CRHR1 antagonist NBI27914 pretreatment attenuated cPLA phosphorylation, Evans blue dye (EBD) extravasation, tight junction disruption and mitochondrial cytochrome c release. CRHR1 interference also inhibited cortical vascular hyperpermeability. Furthermore, NBI27914 administration attenuated neurovascular injury. After 30 min MCAO with 7 days reperfusion CRHR1 interference alleviated hippocampal blood-brain barrier (BBB) leakage and improved spatial cognitive dysfunction. Thus, our study demonstrates that during ischemic stroke the activation of endothelial CRHR1 contributes to BBB impairment via cPLA phosphorylation.
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http://dx.doi.org/10.1016/j.cellsig.2019.109467DOI Listing
February 2020

S1PR2 antagonist alleviates oxidative stress-enhanced brain endothelial permeability by attenuating p38 and Erk1/2-dependent cPLA phosphorylation.

Cell Signal 2019 01 2;53:151-161. Epub 2018 Oct 2.

Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211116, Jiangsu, China. Electronic address:

Both sphingosine-1-phosphate receptor-2 (S1PR2) and cytosolic phospholipase A (cPLA) are implicated in the disruption of cerebrovascular integrity in experimental stroke. However, the role of S1PR2 in induction of cPLA phosphorylation during cerebral ischemia-induced endothelial dysfunction remains unknown. This study investigated the effect of S1PR2 blockade on oxidative stress-induced cerebrovascular endothelial barrier impairment and explored the possible mechanisms. In bEnd3 cells, cPLA inhibitor CAY10502 as well as S1PR2 antagonist JTE013 profoundly suppressed hydrogen peroxide (HO)-induced changes of paracellular permeability and ZO-1 localization. Besides p38, extracellular signal-regulated kinase (Erk) 1/2 is required for HO-increased cPLA phosphorylation and endothelial permeability. Pharmacological and genetic inhibition of S1PR2 significantly suppressed their phosphorylation in response to HO. Especially lentivirus-mediated knockdown of S1PR2 inhibited HO-induced ZO-1 redistribution and paracellular hyperpermeability. Using the permanent middle cerebral artery occlusion (pMCAO) mouse model, we found JTE013 pretreatment markedly reduced Evans blue dye (EBD) extravasation and reversed the decrease in VE-cadherin, occludin, claudin-5 and CD31 expression in infarcted hemisphere. Lentivirus-mediated S1PR2 knockdown also attenuated EBD extravasation. Furthermore, JTE013 pretreatment attenuated neurological deficit, brain edema and infarction volume. Therefore, our findings suggest the protective effect of JTE013 on brain endothelial barrier integrity is likely mediated by suppressing p38 and Erk1/2-dependent cPLA phosphorylation under oxidative stress.
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http://dx.doi.org/10.1016/j.cellsig.2018.09.019DOI Listing
January 2019
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