Glucagon-like Peptide-1 Receptor Agonist Liraglutide Inhibits Endothelin-1 in Endothelial Cell by Repressing Nuclear Factor-Kappa B Activation

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP).Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment.Results and Limitations. Membranous expression of NEP (P<0.001), cytoplasmic ET-1 (P=0.002), and cytoplasmic NFκB (P<0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P<0.001) and NFκB (P<0.001). ET-1 was also correlated with NFκB (P<0.001). NEP expression (P=0.017), pT stage (P=0.013), and SMs (P=0.036) were independent predictors of time to PSA recurrence.Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

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Exendin-4 Preserves Blood-Brain Barrier Integrity via Glucagon-Like Peptide 1 Receptor/Activated Protein Kinase-Dependent Nuclear Factor-Kappa B/Matrix Metalloproteinase-9 Inhibition After Subarachnoid Hemorrhage in Rat

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.750726 ◽

2021 ◽

Vol 14 ◽

Author(s):

Zhiyi Xie ◽

Budbazar Enkhjargal ◽

Matei Nathanael ◽

Lingyun Wu ◽

Qiquan Zhu ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Protein Kinase ◽

Matrix Metalloproteinase ◽

Blood Brain Barrier ◽

Nuclear Factor Kappa B ◽

Brain Barrier ◽

Nuclear Factor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Metalloproteinase 9

In this study, we investigated the role of Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, in blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH) in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats. Ex-4 was intraperitoneally injected 1 h after SAH induction. To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and Dorsomorphin, a specific inhibitor of adenosine monophosphate-activated protein kinase (AMPK), were intracerebroventricularly injected 48 h before induction of SAH correspondingly. Immunofluorescence results supported GLP-1R expressed on the endothelial cells of microvessels in the brain after SAH. Administration of Ex-4 significantly reduced brain water content and Evans blue extravasation in both hemispheres, which improved neurological scores at 24 h after SAH. In the mechanism study, Ex-4 treatment significantly increased the expression of GLP-1R, p-AMPK, IκB-α, Occludin, and Claudin-5, while the expression of p-nuclear factor-kappa B (NF-κB) p65, matrix metalloproteinase-9 (MMP-9), and albumin was significantly decreased. The effects of Ex-4 were reversed by the intervention of GLP-1R siRNA or Dorsomorphin, respectively. In conclusion, Ex-4 could preserve the BBB integrity through GLP-1R/AMPK-dependent NF-κB/MMP-9 inhibition after SAH, which should be further investigated as a potential therapeutic target in SAH.

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