Publications by authors named "Yali Hong"

5 Publications

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Indoleamine-2,3-Dioxygenase Activates Wnt/β-Catenin Inducing Kidney Fibrosis after Acute Kidney Injury.

Gerontology 2021 Jun 15:1-9. Epub 2021 Jun 15.

Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.

Introduction: As disorder of tryptophan metabolism is common in CKD, the rate-limiting enzyme of tryptophan, indoleamine-2,3-dioxygenase (IDO), has been reported to be involved in CKD, while the accurate mechanism remains unknown. This study was designed to explore correlations between IDO and kidney fibrosis after ischemia-reperfusion injury (IRI).

Methods: Wild-type (WT) mice and IDO knockout (IDO-/-) mice were divided into the sham group and acute kidney injury (AKI) group. Mice in the sham group underwent dorsal incision and exposure of renal pedicle without clamping renal artery, while mice in the AKI group received unique renal artery IRI, and the contralateral kidney was removed at day 13 after IRI. Blood and IRI kidneys were collected at day 14. Kidney function was analyzed by measuring serum Cr and BUN. Morphology was analyzed by tissue periodic acid-Schiff (PAS) staining and Masson staining. Further, fibrosis markers and Wnt/β-catenin pathway proteins were determined by Western blot. Prostaglandin E2 (PGE2) was administrated for 2 weeks after the IRI mice model was established to observe whether it ameliorates kidney fibrosis after IRI.

Results: WT AKI mice revealed elevated expression of IDO compared with WT sham mice. Kidney function of IDO-/- AKI mice showed better than that of WT AKI mice. PAS staining exhibited less loss of tubular epithelial cells and atrophy tubules in IDO-/- AKI mice. Furthermore, kidney fibrosis areas and the expressions of fibrosis markers, including α-SMA, fibronectin, and vimentin, were increased in WT AKI mice. In addition, GSK-3β and β-catenin were significantly declined in IDO-/- AKI mice. On top of that, PGE2 administration revealed inhibited IDO expression and that reducing GSK-3β and β-catenin resulting in lower expressions of α-SMA, fibronectin, and vimentin in WT AKI mice.

Conclusions: IRI could increase IDO expression to activate Wnt/β-catenin pathway resulting kidney fibrosis. PGE2 could ameliorate kidney fibrosis via inhibiting IDO expression.
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http://dx.doi.org/10.1159/000515041DOI Listing
June 2021

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

CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis.

Mol Carcinog 2017 Nov 13;56(11):2434-2445. Epub 2017 Jul 13.

Department of Pharmacology, Nanjing Medical University, Nanjing, China.

Corticotrophin-releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis-associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH-treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin-6 (IL-6) and vascular endothelial growth factor (VEGF) through activating nuclear factor-kappa B (NF-κB). The CRH-induced IL-6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH-induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF-κB/IL-6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF-κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer.
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http://dx.doi.org/10.1002/mc.22691DOI Listing
November 2017

The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs.

Toxicol Appl Pharmacol 2017 05 22;323:44-52. Epub 2017 Mar 22.

Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular intervention, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, PR China. Electronic address:

Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is mainly formed as a byproduct of glycolysis. Elevated MGO level is known to induce apoptosis of vascular endothelial cells, which is implicated with progression of atherosclerosis and diabetic complications. However, the underlying mechanisms have not been exhaustively investigated yet. Here, we further characterized the mechanisms how MGO induced apoptosis in human umbilical vein endothelial cells (HUVECs). Our data revealed that cytosolic phospholipase A2 (cPLA2) played an important role in MGO-induced cell apoptosis. It was found that MGO could increase both the activity and expression of cPLA2. Inhibition of cPLA2 by Pyrrophenone (PYR) or siRNA significantly attenuated the MGO-induced apoptosis. Additionally, MGO time-dependently decreased the phosphorylation of nuclear factor κB (NF-κB). Pretreatment of the cells with NF-κB inhibitor, BAY11-7082, further increased MGO-induced apoptosis of HUVECs, indicating that NF-κB played a survival role in this MGO-induced apoptosis. Furthermore, in the presence of si-cPLA2 or PYR, MGO no longer decreased NF-κB phosphorylation. Beyond that, the antioxidant N-acetyl cysteine (NAC) could reverse the changes of both cPLA2 and NF-κB caused by MGO. p38, the upstream of cPLA2, was also significantly phosphorylated by MGO. However, p38 inhibitor failed to reverse the apoptosis induced by MGO. This study gives an important insight into the downstream signaling mechanisms of MGO, cPLA2-NF-κB, in endothelial apoptosis.
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http://dx.doi.org/10.1016/j.taap.2017.03.020DOI Listing
May 2017
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