The international journal of biochemistry & cell biology
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Int. J. Biochem. Cell Biol. · Jan 2008
Caffeic acid phenethyl ester protects mice from lethal endotoxin shock and inhibits lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW 264.7 macrophages via the p38/ERK and NF-kappaB pathways.
Caffeic acid phenethyl ester has been shown to have anti-inflammatory and anti-cancer effects. We examined the effects of caffeic acid phenethyl ester on lipopolysaccharide-induced production of nitric oxide and prostaglandin E2, and expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 macrophages. We also investigated the effects of caffeic acid phenethyl ester on lipopolysaccharide-induced septic shock in mice. ⋯ Furthermore, caffeic acid phenethyl ester rescued C57BL/6 mice from lethal lipopolysaccharide-induced septic shock, while decreasing serum levels of tumor necrosis factor-alpha and interleukin-1beta. Collectively, these results suggest that caffeic acid phenethyl ester suppresses the induction of cytokines by lipopolysaccharide, as well as inducible nitric oxide synthase and cyclooxygenase-2 expression, by blocking nuclear factor-kappaB and p38/ERK activation. These findings provide mechanistic insights into the anti-inflammatory and chemopreventive actions of caffeic acid phenethyl ester in macrophages.
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Int. J. Biochem. Cell Biol. · Jan 2008
ReviewHuman H5N1 influenza: current insight into pathogenesis.
Since their emergence as avian (1996) and zoonotic human pathogens (1997), H5N1 influenza viruses have become endemic among poultry in large parts of Asia, but outbreaks have also been seen in Africa and Europe. Transmission from animals to humans remains sporadic, but mortality of human infection is high (63%). ⋯ Therefore, in the management of H5N1 disease (early) suppression of viral replication is key. The underlying biochemistry and cell biology of H5N1 pathogenesis and treatment are briefly discussed in this review.
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Int. J. Biochem. Cell Biol. · Jan 2008
Functional asymmetry of the conserved cystine loops in alphabetagamma GABA A receptors revealed by the response to GABA activation and drug potentiation.
Ligand-gated ion channels respond to specific neurotransmitters by transiently opening an integral membrane ion-selective pore, allowing ions to move down their electrochemical gradient. A distinguishing feature of all members of the ligand-gated ion channel superfamily is the presence of a 13-amino acid disulfide loop (Cys-loop) in the extracellular ligand-binding domain. Structural data derived from the acetylcholine receptor place this loop at the interface between the ligand-binding domain and the transmembrane pore-forming domain where it is ideally located to participate in coupling ligand binding to channel opening. ⋯ Currents in response to agonists were larger when mutations were carried in the alpha and beta subunits but not in the gamma subunit. In contrast, potentiation of current responses by diazepam, etomidate and pentobarbital were all enhanced when mutations were carried in the alpha and gamma subunits, but not the beta subunit. Since the disruption of interactions mediated through the ArProAl motif enhances the mutant receptor's response to both agonist and drugs we suggest that this motif in the Cys-loop of the wild-type receptor participates in interactions that create activation barriers to conformational changes during channel gating.
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Int. J. Biochem. Cell Biol. · Jan 2008
Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension.
Pulmonary arterial smooth muscle cells (PASMCs) in the medial layer of the vessel wall are responsible for vessel homeostasis, but also for pathologic vascular remodelling in diseases, such as idiopathic pulmonary arterial hypertension (IPAH). Vascular remodelling in IPAH results in vessel stiffness, occlusion, and increased vascular resistance, but its underlying mechanisms remain to be fully elucidated. In this study, we investigated the expression and function of plasminogen activator inhibitor (PAI)-1, an inhibitor of the plasminogen activator system and target gene of the transforming growth factor (TGF)-beta1 signalling cascade, in PASMC in IPAH. ⋯ PAI-1 is significantly downregulated in PASMC in IPAH, on the mRNA and protein level. PAI-1 negatively regulates PASMC proliferation, while it increases PASMC migration. Thus, its loss in IPAH may therefore contribute to pathologic vascular remodelling in IPAH.
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Int. J. Biochem. Cell Biol. · Jan 2008
SOCS 3 and PPAR-gamma ligands inhibit the expression of IL-6 and TGF-beta1 by regulating JAK2/STAT3 signaling in pancreas.
Induction of proinflammatory cytokines IL-6 and TGF-beta1 are the hallmark of human pancreatitis. Cerulein pancreatitis is similar to human edematous pancreatitis involving dysregulation of digestive enzyme production, cytoplasmic vacuolization, and increased cytokine production. We previously showed that cerulein induced IL-1beta expression through the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway in pancreatic acinar cells. ⋯ Pre-treating cerulein-stimulated AR42J cells or rats with the peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands, 15d-PGJ2 and troglitazone, induced SOCS 3 expression and inhibited JAK2/STAT3 activation. This treatment regimen also inhibited IL-6 and TGF-beta1 induction, vacuolization, and alpha-smooth muscle actin (alpha-SMA) expression. Thus, SOCS 3 expression is associated with a reduction in IL-6 and TGF-beta1 expression, edema formation, vacuolization, and alpha-SMA expression, possibly by direct regulation of JAK2/STAT3 signaling. 15d-PGJ2 and troglitazone are potentially useful pancreatitis therapies by suppressing the JAK2/STAT3 inflammatory signaling through SOCS 3 induction.