O(2)-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a liver-selective nitric oxide (NO)-donating prodrug, is metabolized by hepatic enzymes to release NO within the liver. This study was undertaken to examine the effects of V-PYRRO/NO on D-galactosamine/lipopolysaccharide (GlaN/LPS)-induced liver injury in mice. Mice were given injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after GlaN/LPS (700 mg/30 microg/kg, i.p.). V-PYRRO/NO administration dramatically reduced GlaN/LPS-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase activity and improved pathology. To examine the mechanisms of the protection, cDNA microarray was performed to profile the gene expression pattern in livers of mice treated with GlaN/LPS, GlaN/LPS plus V-PYRRO/NO, or controls. V-PYRRO/NO administration greatly ameliorated GlaN/LPS-induced alterations in the expression of genes encoding the stress response, DNA damage/repair response, and drug-metabolizing enzymes in accordance with hepatoprotection. Gel shift assay and Western blot analysis supported microarray results, showing that V-PYRRO/NO suppressed GlaN/LPS-induced activation of nuclear factor-kappaB and GlaN/LPS-induced increases in caspase-1, caspase-8, tumor necrosis factor receptor 1 (TNFR1)-associated death domain, and TNF-related apoptosis-inducing ligand. Immunohistochemical analysis further revealed that GlaN/LPS-induced activation of TNFR1, caspase-3, and hepatocellular apoptosis was ameliorated by V-PYRRO/NO treatment. GlaN/LPS-induced elevation of hepatic caspase-3 activity was diminished by V-PYRRO/NO treatment. In addition, V-PYRRO/NO alone suppressed the basal expression of genes encoding inducible NO synthase and TNF-alpha-related components, as revealed by mouse 1.2 array. In summary, this study demonstrates that the liver-selective NO donor, V-PYRRO/NO, is effective in blocking GlaN/LPS-induced hepatotoxicity in mice, and that this protection appears to involve, at least in part, the suppression of the TNF-alpha-mediated cell death pathways.
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http://dx.doi.org/10.1124/jpet.300.1.18 | DOI Listing |
J Phys Chem Lett
December 2024
Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Korea.
Diazeniumdiolates spontaneously release nitric oxide (NO) in aqueous solutions. Therefore, protected diazeniumdiolates have been developed for the controlled administration of NO to specific targets. Diazeniumdiolates with photoprotecting groups are useful for spatiotemporal NO delivery.
View Article and Find Full Text PDFLife (Basel)
February 2024
Department of Pharmacology, Faculty of Medicine, 'Grigore T. Popa' University of Medicine and Pharmacy, 700115 Iasi, Romania.
Compelling evidence indicates that nitric oxide (NO) exerts a significant influence on the central nervous system, participates in the modulation of neurotransmitter release, contributes to the regulation of cognitive functions, and plays a crucial role in modulating various aspects of neural activity. We aimed to explore the influence of two NO donors, molsidomine (MSD) and V-pyrro/NO, on the innate spontaneous psychomotor abilities and short-term memory in rats. Using an actimeter test, the locomotor activity, stress-sensitive behavior, and anxiety level were investigated.
View Article and Find Full Text PDFPharmacol Rep
June 2018
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland. Electronic address:
Background: The impairment of liver sinusoidal endothelial cells (LSECs) function and diminished nitric oxide (NO) production has been regarded as an important pathogenic factor in liver steatosis. Restoring NO-dependent function was shown to counteract liver steatosis, obesity, and insulin resistance. However, it is not known whether restored liver perfusion and improvement in hepatic blood flow contributes to the anti-steatotic effects of NO.
View Article and Find Full Text PDFPharmacol Rep
June 2017
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland. Electronic address:
Purpose: To analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective NO-donors - V-PYRRO/NO and V-PROLI/NO.
Methods: C57BL/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (HFD mice). Pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of V-PYRRO/NO and V-PROLI/NO (0.
Biomed Rep
January 2016
Department of Physiology, College of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
The aim of the present study was to explore the mechanism underlying the effects of a selective liver nitric oxide (NO) donor, O-vinyl1-(pyrrolidin-1-yl)-diazen-1-ium-1,2-diolate (V-PYRRO/NO), on the gene expression of leukotriene C4 synthase (LTC4S) during hepatic ischemia/reperfusion (I/R). Adult male Sprague-Dawley rats were divided into 3 groups: Sham (control), I/R and V-PYRRO/NO + I/R groups. The liver was subjected to 1 h of partial hepatic ischemia followed by 5 h of reperfusion, saline or V-PYRRO/NO (1.
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