15d-Prostaglandin J2 inhibits noncanonical inflammasome response to ameliorate endotoxin shock.

Endotoxin shock was induced in 31 anaesthetized pigs by infusion of 5 μg/kg of Escbeicbia coli endotoxin (LPS) over 60 min into the superior mesenteric artery. Fifteen of these pigs died within 30 min of the start of LPS infusion whereas the remaining 16 survived the experimental period of 2 h. In a group of nine pigs indomethacin (2 mg/kg, i.v.)was inected 20–25 rain after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. Indomethacin immediately reversed the hypotension. In another group of five pigs, NG-nitro L-arginine-methyl ester (L-NAME, 1 and 3 mg/kg)was iniected 10 and 5 min, respectively, before the expected death without any beneficial effect on the hypotension. Three rain after the last dose of L-NAME, indomethacin (2 mg/kg, i.v.) was iniected. In three animals the hypotension was reserved by indomethacin, although this beneficial effect was delayed in comparison with the LP-Streated group not receiving L-NAME. Four pigs were pretreated with L-NAME, 3 mg/kg, i.v., 10 min prior to LPS infusion. All pretreated animals tended to die within 30 min of the start of the LPS infusion. Five rain before the expected death (20–25 rain after the start of LPS infusion) indomethacin (2 mg/kg) was inected. In three of these animals indomethacin reversed hypotenston and prevented death. Interestingly, this rise in the MABP developed very slowly. These results suggest that the beneficial effect of indomethacin in endotoxin shock might be related partially to interference with nitric oxide, which is not the only factor determining blood pressure levels during endotoxic shock.

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Studies on hemorrhagic and endotoxin shock in relation to vasomotor changes and endogenous circulating epinephrine, norepinephrine and serotonin

Plastic & Reconstructive Surgery ◽

10.1097/00006534-196202000-00036 ◽

1962 ◽

Vol 29 (2) ◽

pp. 227

Author(s):

J C Rosenbert ◽

R C Lillehei ◽

J Longerbeam ◽

B Zimmermann

Keyword(s):

Endotoxin Shock

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Troglitazone, an Insulin-Sensitizing Thiazolidinedione, Represses Combined Stimulation by LH and Insulin of de Novo Androgen Biosynthesis by Thecal Cells in Vitro

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.3.8308 ◽

2002 ◽

Vol 87 (3) ◽

pp. 1129-1133 ◽

Cited By ~ 29

Author(s):

Johannes D. Veldhuis ◽

George Zhang ◽

James C. Garmey

Keyword(s):

Gene Expression ◽

Polycystic Ovarian Syndrome ◽

De Novo ◽

Drug Concentrations ◽

Thecal Cells ◽

Cyp17 Gene ◽

Pparγ Agonist ◽

Ovarian Syndrome ◽

Prostaglandin J2

Polycystic ovarian syndrome (anovulatory hyperandrogenism) is marked by adolescent onset of systemic hyperinsulinism, oligoovulation, hirsutism, excessive LH and androgen secretion, and variable reduction in fertility. Insulin and LH are believed to act in concert to promote ovarian androgen hypersecretion in this disorder. Administration of troglitazone, an insulin-sensitizing agent and putative PPARγ agonist, can decrease hyperinsulinism, suppress T production, and ameliorate oligoovulation in some women with this endocrinopathy. The present study tests the hypothesis that troglitazone directly inhibits de novo androgen biosynthesis stimulated jointly by LH and insulin in primary cultures of (porcine) thecal cells. We show that troglitazone dose-dependently antagonizes LH/insulin’s combined stimulation of androstenedione and T production by thecal cells in vitro. Consistent steroidogenic inhibition of 80–95% was achieved at drug concentrations of 3–6.8 μm (P < 0.001). Exposure of thecal cells to the thiazolidinedione derivative also blocked bihormonally stimulated accumulation of CYP17 (cytochrome P450 17 α-hydroxylase/C17–20 lyase) gene expression, as reflected by decreased accumulation of cognate heterogeneous nuclear RNA and mRNA (by 30–65%; P < 0.05). Moreover, troglitazone suppressed LH/insulin-induced phosphorylation of the 52-kDa immunoprecipitated CYP17 enzyme by 88% (P < 0.001). A putative natural agonist of PPARγ nuclear transcription, 15-deoxy-δ-12,14-prostaglandin J2, also inhibited LH/insulin-driven androstenedione biosynthesis and CYP17 gene expression in thecal cells. In conclusion, a synthetic thiazolidinedione (troglitazone) and a natural ligand of PPARγ (15-deoxy-δ-12,14-prostaglandin J2) effectively impede the concerted stimulation by LH and insulin of in vitro thecal cell androgen production, CYP17 gene expression, and CYP17 protein phosphorylation. This ensemble of inhibitory actions on LH/insulin-stimulated steroidogenesis offers a plausible mechanistic basis for at least part of the observed clinical efficacy of troglitazone in mitigating androgen excess in women with polycystic ovarian syndrome.

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Molecular Basis for the Direct Inhibition of AP-1 DNA Binding by 15-Deoxy-Δ12,14-prostaglandin J2

Journal of Biological Chemistry ◽

10.1074/jbc.m309409200 ◽

2003 ◽

Vol 278 (51) ◽

pp. 51251-51260 ◽

Cited By ~ 105

Author(s):

Dolores Pérez-Sala ◽

Eva Cernuda-Morollón ◽

F. Javier Cañada

Keyword(s):

Dna Binding ◽

Molecular Basis ◽

Direct Inhibition ◽

Prostaglandin J2

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