Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.11.2 (prolyl hydroxylase)
 1,814 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcription factor which controls growth, differentiation, and inflammation in different tissues. Roles of PPAR-gamma activation in PSCs are poorly characterized. Here we examined the effects of PPAR-gamma ligands on the key parameters of PSC activation. PSCs were isolated from rat pancreas tissue, and used in their culture-activated, myofibroblast-like phenotype. Activation of PPAR-gamma was induced with 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) or with troglitazone. Expression of PPAR-gamma was predominantly localized in the nuclei, and PPAR-gamma was transcriptionally active after ligand stimulation. PPAR-gamma ligands inhibited platelet-derived growth factor-induced proliferation. This effect was associated with inhibition of cell cycle progression beyond the G1 phase. PPAR-gamma ligands decreased alpha-smooth muscle actin protein expression and alpha1(I) procollagen and prolyl 4-hydroxylase(alpha) mRNA levels. Activation of PPAR-gamma also resulted in the inhibition of inducible monocyte chemoattractant protein-1 expression. 15d-PGJ2, but not troglitazone, inhibited the degradation of IkappaB-alpha and consequent NF-kappaB activation. In conclusion, activation of PPAR-gamma inhibited profibrogenic and proinflammatory actions in activated PSCs, suggesting a potential application of PPAR-gamma ligands in the treatment of pancreatic fibrosis and inflammation.
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PMID:Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells. 1160 85

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. However, the signal transduction pathways in PSCs remain largely unknown. We examined the role of p38 mitogen-activated protein (MAP) kinase in the activation of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype. Activation of p38 MAP kinase was determined by Western blotting using anti-phosphospecific antibody. The effects of two p38 MAP kinase inhibitors, 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) and 4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole (SB202190), on the parameters of PSC activation, including proliferation, expression of alpha-smooth muscle actin, alpha1(I) procollagen, and prolyl 4-hydroxylase (alpha) genes, and monocyte chemoattractant protein-1 production were evaluated. Interleukin-1beta and platelet-derived growth factor-BB activated p38 MAP kinase. Platelet-derived growth factor-induced PSC proliferation was inhibited by SB203580 and SB202190. These reagents decreased alpha-smooth muscle actin protein expression, and alpha1(I) procollagen and prolyl 4-hydroxylase (alpha) mRNA levels. Treatment with these p38 MAP kinase inhibitors also resulted in inhibition of monocyte chemoattractant protein-1 expression. In addition, SB203580 inhibited spontaneous activation of freshly isolated PSCs in culture on plastic. Thus, inhibition of p38 MAP kinase modulated profibrogenic and proinflammatory actions in PSCs, implying a potential application of p38 MAP kinase inhibitors for the treatment of pancreatic fibrosis and inflammation.
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PMID:Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells. 1249 May 69