Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study evaluated how YC-1, a guanylate cyclase activator, affects the maturation of human monocyte-derived dendritic cells. Maturation markers and intracellular signaling pathways were evaluated. YC-1 inhibited the lipopolysaccharide up-regulation of mature markers, including CD40, CD80 or CD86 in a concentration-dependent manner with IC(50) values of 4.6+/-0.4, 4.9+/-0.6 or 4.5+/-0.5 microM, respectively. YC-1, at a higher concentration, inhibited lipopolysaccharide-induced HLADR expression. These effects of YC-1 were not reversed by ODQ (10 microM), which is a soluble guanylate cyclase inhibitor, nor by KT5823 (1 microM), which is a PKG inhibitor. Additionally, YC-1 did not increase levels of cyclic nucleotides in dendritic cells, supporting the claim that YC-1 affects dendritic cells maturation in a cGMP-independent manner. YC-1, in a cGMP-independent manner, inhibited lipopolysaccharide-induced Akt activation, IkappaBalpha degradation and NF-kappaB translocation, all of which are associated with co-stimulatory molecules expression. YC-1 inhibited the capacity of dendritic cell to activate allogenic T cells with an IC(50) value of 1.2+/-0.3 microM. YC-1-treated dendritic cells have mature phenotypes that exhibit up-regulated CCR7, enhanced IL-10 release and low phagocytosis activity in the presence of lipopolysaccharide. In conclusion, YC-1 inhibited the lipopolysaccharide-induced co-stimulatory molecular expression of dendritic cells by inhibiting Akt activation, IkappaBalpha degradation and NF-kappaB translocation. These inhibitory effects on co-stimulatory molecules suppressed the capacity of dendritic cells to activate allogenic T cells. Additionally, YC-1 treated dendritic cells exhibit the up-regulation of CCR7, enhanced IL-10 release and the down-regulation of phagocytosis in the presence of lipopolysaccharide. Accordingly, YC-1 might be a useful tool for evaluation of dendritic cells on autoimmune or allergic disease.
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PMID:Modulation of human monocyte-derived dendritic cells maturation by a soluble guanylate cyclase activator, YC-1, in a cyclic nucleotide independent manner. 1767 45

Alcohol damages the developing brain and can lead to fetal alcohol syndrome. One of alcohol's most important neuropathologic effects is neuronal death. As neurons mature, they become less vulnerable to alcohol-induced death because they acquire a protective signaling pathway, mediated by nitric oxide (NO). This pathway is the NO-cGMP-cyclic GMP-dependent protein kinase G (NO-cGMP-PKG) pathway. The goal of the present studies was to determine whether nuclear factor kappa B (NF-kappaB) is the downstream effector through which the NO-cGMP-PKG pathway signals its neuroprotective effects against alcohol. An activator of NF-kappaB, tumor necrosis factor-alpha (TNF-alpha), protected immature cerebellar granule neuron cultures against alcohol-induced cell death in a dose-dependent fashion. The protective effect of TNF-alpha was similar in magnitude to the protective effects of NMDA and DETA-NONOate, both of which are NO-cGMP-PKG pathway activators. Blockade of the pathway at its first step with NAME, second step with LY83583, or third step with PKG inhibitor increased alcohol-induced cell death and the vulnerability of mature neurons to alcohol toxicity. TNF-alpha protected the neurons, even when the NO-cGMP-PKG pathway was blocked at upstream sites. NF-kappaB activation inhibitor (NFi) worsened alcohol-induced cell death and blocked the protective effects of NO-cGMP-PKG pathway activators and TNF-alpha. TNF-alpha reduced the alcohol vulnerability of immature neurons, while NFi increased the vulnerability of mature neurons. Both NMDA and TNF-alpha led to the phosphorylation and degradation of IkappaBalpha, demonstrating that both agents can activate NF-kappaB in cerebellar granule cells. Thus, NF-kappaB plays a critical role in the acquisition of alcohol resistance by maturing neurons and is a key downstream effector through which the NO-cGMP-PKG pathway signals its neuroprotective effects against alcohol.
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PMID:Nitric oxide utilizes NF-kappaB to signal its neuroprotective effect against alcohol toxicity. 1913 70