Pyrrolidine dithiocarbamate attenuate shock wave induced MDCK cells injury via inhibiting nuclear factor-kappa B activation

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor- kappa B (NF kappa B)-like site has been localized to the 5′ flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.

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Inhibitors of nuclear factor kappa B cause apoptosis in cultured macrophages

Mediators of Inflammation ◽

10.1080/09629359791721 ◽

1997 ◽

Vol 6 (3) ◽

pp. 225-232 ◽

Cited By ~ 9

Author(s):

E. E. Mannick ◽

J. Mishra ◽

J. Marque ◽

M. Clavell ◽

M. J. S. Miller ◽

...

Keyword(s):

Nuclear Factor Kappa B ◽

Pyrrolidine Dithiocarbamate ◽

Nuclear Factor ◽

Chloromethyl Ketone ◽

Nuclear Factor Kappa ◽

Pharmacologic Inhibitors ◽

Precise Role ◽

Lethal Doses ◽

Transcription Factor Nuclear Factor

The precise role of the transcription factor nuclear factor kappa B (NF- κB) in the regulation of cell survival and cell death is still unresolved and may depend on cell type and position in the cell cycle. The aim of this study was to determine if three pharmacologic inhibitors of NF-κB, pyrrolidine dithiocarbamate, N-tosyl-L-lysl chloromethyl ketone and calpain I inhibitor, induce apoptosis in a murine macrophage cell line (RAW 264.7) at doses similar to those required for NF-κB inhibition. We found that each of the three inhibitors resulted in a dose- and time-dependent increase in morphologic indices of apoptosis in unstimulated, LPS-stimulated and TNF-stimulated cells. Lethal doses were consistent with those required for NF- κB inhibition. We conclude that nuclear NF-κB activation may represent an important survival mechanism in macrophages.

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Anti-angiogenic actions of pyrrolidine dithiocarbamate, a nuclear factor kappa B inhibitor

Angiogenesis ◽

10.1007/s10456-009-9158-0 ◽

2009 ◽

Vol 12 (4) ◽

pp. 365-379 ◽

Cited By ~ 15

Author(s):

Christudas Morais ◽

Glenda Gobe ◽

David W. Johnson ◽

Helen Healy

Keyword(s):

Nuclear Factor Kappa B ◽

Pyrrolidine Dithiocarbamate ◽

Nuclear Factor ◽

Nuclear Factor Kappa

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Abstract 457: Blockade of Nuclear Factor Kappa B Reverses Renal Fibrosis in Npr1 Gene-Disrupted Mice

Hypertension ◽

10.1161/hyp.60.suppl_1.a457 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Subhankar Das ◽

Ramu Periyasamy ◽

Kailash N Pandey

Keyword(s):

Natriuretic Peptide ◽

Inflammatory Cytokines ◽

Renal Fibrosis ◽

Nuclear Factor Kappa B ◽

Substantial Reduction ◽

Pyrrolidine Dithiocarbamate ◽

Nuclear Factor ◽

Null Mutant ◽

Nuclear Factor Kappa ◽

Pro Inflammatory Cytokines

Binding of atrial natriuretic peptide (ANP) to its guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) exerts diverse physiological effects by lowering the blood pressure and blood volume. The objective of the present study was to determine the effect of blockade of nuclear factor-kappa B, inhibitory kappa B kinase, and inhibitory kappa B alpha (NF-κB, IKK, IκBα) in the kidneys of Npr1 (coding for GC-A/NPRA) gene-disrupted mice. The disruption of Npr1 greatly stimulated the renal NF-κB binding activity by 6-fold (57.12 ± 3.35 vs 9.42 ± 0.92), IKK activity by 8-fold (56.05 ± 3.83 vs 6.85 ± 0.90), and IκBα phosphorylation by 11-fold (46.67 ± 1.32 vs 4.15 ±0.58), respectively, in the kidneys of null mutant (-/-; 0-copy) mice as compared with wild-type (+/+; 2-copy) mice. Interestingly, the expression levels of IκBα were reduced by 80% (5.35 ± 0.58 vs 31.64 ± 1.13) and pro-inflammatory cytokines and renal fibrosis were enhanced by 6- to 8-fold and 5-fold (32.58 ±2.06 vs 5.85 ± 0.91), respectively, in 0-copy mice than 2-copy mice. However, the treatment of 0-copy mice with NF-κB inhibitors, andrographolide, pyrrolidine dithiocarbamate, and etanercept showed a substantial reduction in renal fibrosis by 50% (14.09 ± 2.13, 18.01 ± 1.69, and 15.88 ± 0.70, respectively), attenuation of pro-inflammatory cytokines gene expression by 60-65%, IKK activity by 60% (25.37 ± 2.22, 22.67 ± 2.23, and 19.21 ± 2.50), and IkBα phosphorylation by 65-70% (19.68 ± 1.35, 24.67 ± 1.44, 16.62 ± 1.42), respectively. Our findings demonstrate that the disruption of Npr1 activates NF-κB activity, expression of various pro-inflammatory cytokines, and renal fibrosis in 0-copy mice. However, the treatments with NF-kB inhibitors suppress NF-kB activity and pro-inflammatory cytokines and repairs the fibrosis in the kidneys of Npr1 null mutant mice. The present results suggest that the blockade of NF-kB activity provides protective effects against the inflammatory and fibrotic responses in the kidney.

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