Search

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to rutinoid. steroid and thyroid hormone receptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin (PG)[sub2] metabolite, l5-deoxy-Δ[sup12.14] PGJ[sub2] (l5d-PGJ[sub2] are two PPAR-γ ligands, which modulate the transcription of target genes. 2 The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ[sub2] on the tissue injury caused by ischaemia/ reperfusion (I/ R) of the gut. 3 I /R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45min. followed by release of the chimp allowing reperfusion for 2 or 4h. This procedure results in splanchnic artery occlusion (SAO) shock. 4 Rats subjected to SAO developed a significant fall in mean arterial blood pressure and only 10% of the animals survived for the entire 4h reperfusion period. Surviving animals were killed for histological examination and biochemical studies Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumour necrosis factor (TNF)-α and interleukin (IL)-1β levels and marked injury to the distal ileum. 5 Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-l) antibody resulted in diffuse staining. 6 Administration at 30min prior to the onset of gut ischaemia of the two PPAR-γ agonists (rosiglitazone (0.3mg kg[sup-1] i.v.) and 15d-PGJ[sub2] (0.3mg kg[sup-1] i.v.)) significantly reduced the (i) fall in mean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity) (iv) lipid peroxidation (MDA levels), (v) production of proinflammatory cytokines (TNF-α and IL-lβ) and (vi) histological evidence of gut injury. Administration of rosiglitazone and 15d-PGJ[sub2] also markedly reduced the nitrotyrosine formation and the upregulation of ICAM-I during reperfusion. 7 In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2 are related to the activation of the PPAR-γ receptor, we also investigated the effect of a PPAR-γ antagonist, bisphenol A diglycidyl ether (BADGE). on the protective effects of rosiglitazone and 15d-PGJ[sub2]. BADGE.(1 mgkg[sup-1] administered i.v. 30min prior to the treatment of rosiglitazone or 15d-PGJ[sub2] significantly antagonised the effect of the two PPAR-γ agonists and thus abolished the protective effect against gut I/R. 8 These results demonstrate that the two PPAR- γ agonists, rosiglitazone and 15d-PGJ[sub2] significantly reduce I/R injury of the intestine. [ABSTRACT FROM AUTHOR]

The nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a pivotal role in the induction of genes involved in physiological processes, as well as in the response to inflammation. In this study, we used a selective nonpeptidyl superoxide dismutase mimetic, M40403, to investigate the role of superoxide anion in NF-kappaB activation during acute inflammation in mice. Injection of carrageenan into the pleural cavity of mice induced an acute inflammatory response characterized by fluid accumulation in the pleural cavity that contained a large number of neutrophils, as well as an increased production of tumor necrosis factor-alpha and interleukin-1beta. All parameters of inflammation were attenuated by M40403 (10 mg/kg i. p., 30 min prior to carrageenan administration). These inflammatory events were associated with the activation of NF-kappaB in the lung. In particular, the appearance of inhibitory protein kappaB-alpha (IkappaB-alpha) in homogenates of lung tissues was investigated by immunoblot analysis at 4 h after carrageenan administration. IkappaB-alpha levels were substantially reduced in the lung tissue from carrageenan-treated mice in comparison with sham-treated mice. Furthermore, to detect NF-kappaB/DNA binding activity, whole extracts from lung tissue of each mouse were analyzed by electrophoretic mobility-shift assay. The DNA binding activity significantly increased in whole extracts obtained from lung tissues of vehicle-treated mice 4 h after carrageenan administration. Treatment of mice with M40403 caused a significant inhibition of carrageenan-induced IkappaB-alpha degradation and NF-kappaB/DNA binding activity. These data confirm that M40403 exerts a potent antiinflammatory activity and clearly demonstrate that the reduction of the inflammatory process is associated with modification of the activation of signal transduction pathways.

Objective: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. Rosiglitazone (Avandia) is a PPAR-gamma agonist (the most potent PPAR-gamma agonist of the thiazolidinedione antidiabetics). In the present study, we investigated the effects of rosiglitazone on the development of nonseptic shock caused by zymosan in mice., Design: Experimental study., Setting: University laboratory., Subjects: Male CD mice., Interventions: We investigated the effects of rosiglitazone (3 mg/kg) on the development of nonseptic shock caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in mice., Measurements and Main Results: Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of zymosan and/or rosiglitazone and monitored for 12 days (for loss of body weight and mortality rate). Treatment of mice with rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, and poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, and poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from zymosan-treated mice that received rosiglitazone. To elucidate whether the protective effects of rosiglitazone are related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, GW 9662, on the protective effects of rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with rosiglitazone) significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the protective effect., Conclusions: This study provides evidence, for the first time, that rosiglitazone attenuates the degree of zymosan-induced nonseptic shock in mice.

Simplakidine A, a unique 4-alkyl-substituted pyridiunium alkaloid, has been isolated from the Caribbean sponge Plakortis simplex. The stereostructure of simplakidine A has been determined using MS and NMR data, molecular mechanics, and an extension of the J-based configuration analysis. Data about the growth-inhibition activity of simplakidine A are reported.

1. Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy-delta(12,14)-PGJ(2) (15d- PGJ(2)) functions as an early anti-inflammatory signal. 2. The aim of the present paper is to investigate the effects of 15d-PGJ(2) in rats subjected to experimental colitis. 3. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d-PGJ(2) was administered daily as intraperitoneal injection (20 or 40 microg kg(-1)). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. 4. 15d-PGJ(2) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d-PGJ(2) also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 5. Furthermore, 15d-PGJ(2) reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP-ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM-1 caused by DNBS in the colon. 6. Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d- PGJ(2) also caused a substantial reduction of the activation of nuclear factor-kappaB (NF-kappaB). Furthermore, 15d-PGJ(2) stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis. 7. In conclusion, 15d-PGJ(2) reduces the development of experimental colitis.

Glycoglycerolipid analogues, characterized by a glycerol aglicone beta-linked in position 2 to a glucose or galactose residue, and by a lipophilic C6 acyl chain on the glycerol unit, significantly inhibit proliferation of activated T cells. The inhibitory activity displayed by such synthetic compounds is comparable to the immunosuppressive properties shown by the natural glycolipids simplexides, to which they are structurally related. Vice versa, when the acyl chain is located on the sugar unit, no immunomodulating activity is observed, suggesting a strict relationship between the activity and the location of the acyl chain.