Biochimica et biophysica acta
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Biochim. Biophys. Acta · May 2004
The role of interleukin-10 in the regulation of the systemic inflammatory response following trauma-hemorrhage.
Pro-inflammatory cytokine release after shock is central in the development of subsequent multiple organ dysfunction syndrome. Some studies suggest that interleukin-10 (IL-10) is an immunosuppressive mediator after injury or sepsis, while others suggest that IL-10 is an important regulator of the pro-inflammatory response. We hypothesized that in a model of trauma and hemorrhagic shock (TH), IL-10 regulates pro-inflammatory cytokine activity via an autocrine effect on cytokine mRNA transcription in Kupffer cells early after TH. ⋯ Kupffer cell mRNA expression for IL-6, IL-10 and TNF-alpha was elevated in the TH group and further increased by anti-IL-10 treatment. These findings indicate that KC-dependent IL-10 regulates the early systemic inflammatory response after TH. Thus, while IL-10 is an important mediator of immunosuppression following traumatic injury, it also is beneficial with regard to its ability to counter-regulate the early inflammatory response under such conditions.
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Biochim. Biophys. Acta · Dec 2003
Low density lipoprotein induces eNOS translocation to membrane caveolae: the role of RhoA activation and stress fiber formation.
A decrease in the bioavailability of endothelium-derived nitric oxide (NO) is linked to hypercholesterolemia. However, the mechanism by which low density lipoprotein (LDL) mediates endothelial NO synthase (eNOS) dysfunction remains controversial. We investigate the effect of LDL on eNOS regulation in human endothelial cells (ECs). ⋯ Y-27632, a specific inhibitor of ROCK-1, blocked LDL-induced stress fiber formation, eNOS translocation and NO production. In conclusion, a high level of LDL increases the movement of eNOS to membrane caveolae via the increased stress fibers. The RhoA-mediated pathway may play a crucial role in this process in vascular ECs.
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Biochim. Biophys. Acta · Nov 2003
N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis.
Although oxygen free radicals (OFR) are considered to be one of the pathophysiological mechanisms involved in acute pancreatitis (AP), the contribution of acinar cells to their production is not well established. The aim of the present study was to determine the effect of N-acetylcysteine (NAC) in the course of AP induced by pancreatic duct obstruction (PDO) in rats, directly analysing by flow cytometry the quantity of OFR generated in acinar cells. NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. ⋯ This attenuation of the redox state impairment reduced cellular oxidative damage, as reflected by less severe pancreatic lesions, normal pancreatic MDA levels, as well as diminished neutrophil infiltration in pancreas. Hyperamylasemia and hemoconcentration following AP induction were ameliorated by NAC administration at early stages, when oxidative stress seems to be critical in the development of pancreatitis. In conclusion, NAC reinforces the antioxidant defences in acinar cells, preventing OFR generation therefore attenuating oxidative damage and subsequently reducing the severity of PDO-induced AP at early stages of the disease.
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Biochim. Biophys. Acta · Oct 2003
Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bbeta-chain gene.
Congenital afibrinogenemia is a rare autosomal recessive coagulation disorder characterised by hemorrhagic manifestations of variable entity and by severe plasma fibrinogen deficiency. Among the 31 afibrinogenemia-causing mutations so far reported, only 2 are missense mutations and both are located in the fibrinogen Bbeta-chain gene. Direct sequencing of the fibrinogen gene cluster in two afibrinogenemic Iranian siblings revealed a novel homozygous T>G transversion in exon 8 (nucleotide position 8025) of the fibrinogen Bbeta-chain gene. ⋯ The role of the W437G amino acid substitution on fibrinogen synthesis, folding, and secretion was assessed by in vitro expression experiments in COS-1 cells, followed by qualitative and quantitative analyses of intracellular and secreted mutant fibrinogen. Results of both pulse-chase experiments and enzyme-linked immunosorbent assays demonstrated intracellular retention of the mutant W437G fibrinogen and marked reduction of its secretion. These data, besides elucidating the pathogenetic role of the W437G mutation in afibrinogenemia, underline the importance of the Bbeta-chain D domain in fibrinogen folding and secretion.
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Biochim. Biophys. Acta · Mar 2003
ReviewLiver X receptors and the control of cholesterol homeostasis: potential therapeutic targets for the treatment of atherosclerosis.
The liver X receptors (LXRalpha and LXRbeta) are nuclear receptor transcription factors that are activated by certain oxysterol derivatives of cholesterol. As such, LXR activity may be up-regulated by cellular lipid loading or dietary cholesterol intake. Intensive research interest in the LXRs has led to the identification of an expanding list of LXR target genes. ⋯ In this review, we highlight the multiple roles of the LXRs in controlling cholesterol homeostasis via their coordinated effects on cholesterol synthesis, dietary cholesterol absorption, reverse cholesterol transport, and bile acid synthesis and excretion. We discuss the therapeutic interest of developing LXR agonists, in view of their apparent protective effects against atherosclerosis. However, we also draw attention to the possible undesirable side-effects of LXR activation, and thus the potential interest of developing target gene-specific LXR agonists, or agonists that are specific for only one LXR isoform.