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Fimasartan is a newly developed angiotensin receptor blocker, which may have protective effects during myocardial infarction or atherosclerosis. In this context, we investigated the effects of long-term treatment with low-dose fimasartan on focal ischemia in rat brain. We induced focal ischemia in brain by transient intraluminal occlusion of middle cerebral artery (MCA) and administered low-dose (0.5 mg/kg) or regular doses (1 or 3 mg/kg) of fimasartan via intravenous routes. After the administration of low-dose (0.5 mg/kg) fimasartan, blood pressure did not decrease compared to the phosphate-buffered saline- (PBS-) control with MCA occlusion (MCAO) group. The infarct volume and ischemic cell death were reduced in the low-dose fimasartan-treated group (46 ± 41 mm(3) for 0.5 mg/kg and 153 ± 47 mm(3) for PBS-control with MCAO; P < 0.01) but not in the regular-dose groups. Low-dose fimasartan treatment improved functional recovery after ischemia and significantly decreased mortality. In our study, fimasartan reduced the degradation of IκB and the formation of an inflammatory end-product, COX-2. As a result, the recruitment of inflammatory cells in the peri-infarct area decreased in fimasartan-treated group. We have demonstrated that long-term, low-dose fimasartan treatment improved outcomes after focal ischemia in the brain via a reduction of inflammation. [ABSTRACT FROM AUTHOR]

The chronic low-grade inflammation in adipose tissue plays a causal role in obesity-induced insulin resistance and its associated pathophysiological consequences. In this study, we investigated the effects of extracts of Broussonetia papyrifera root bark (PRE) and its bioactive components on inflammation and insulin sensitivity. PRE inhibited TNF-α-induced NF-κB transcriptional activity in the NF-κB luciferase assay and pro-inflammatory genes' expression by blocking phosphorylation of IκB and NF-κB in 3T3-L1 adipocytes, which were mediated by activating AMPK. Ten-week-high fat diet (HFD)-fed C57BL6 male mice treated with PRE had improved glucose intolerance and decreased inflammation in adipose tissue, as indicated by reductions in NF-κB phosphorylation and pro-inflammatory genes' expression. Furthermore, PRE activated AMP-activated protein kinase (AMPK) and reduced lipogenic genes' expression in both adipose tissue and liver. Finally, we identified broussoflavonol B (BF) and kazinol J (KJ) as bioactive constituents to suppress pro-inflammatory responses via activating AMPK in 3T3-L1 adipocytes. Taken together, these results indicate the therapeutic potential of PRE, especially BF or KJ, in metabolic diseases such as obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Summary: How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-κB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-κB target genes. Furthermore, IKKα, but not IKKβ, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKα-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation. [Copyright &y& Elsevier]

TNF-related weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family that induces angiogenesis in vivo. The TWEAK receptor (TweakR) is a recently identified member of the TNF receptor (TNFR) superfamily and is expressed on smooth muscle cells (SMCs) and endothelial cells (ECs). In this report we identify the TNF receptor-associated factor (TRAF) family of signal transducers as important components of TweakR-mediated NF-κB activation. Coimmunoprecipitation experiments suggested potential interactions between the cytoplasmic tail of TweakR with TRAFs 1, 2, 3, and 5. Dominant negative forms of TRAF2 and TRAF5 substantially inhibited TweakR-mediated NF-κB activation, suggesting a role of TRAFs in regulating smooth muscle and endothelial cell function. Using alanine-scanning analysis, we defined a TRAF-binding motif, PIEET, in TweakR that mediates TRAF binding and NF-κB activation. Furthermore, TweakR mutations within the TRAF-binding motif abolished TweakR-stimulated SMC migration, revealing a role for TRAFs in TweakR-induced activation events. [Copyright &y& Elsevier]

Protein kinase C (PKC) family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. However, the role of PKC in receptor activator of NF-κB ligand (RANKL) signaling has remained elusive. We now demonstrate that PKCβ acts as a positive regulator which inactivates glycogen synthase kinase-3β (GSK-3β) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, PKCβ expression is increased by RANKL. Pharmacological inhibition of PKCβ decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-3β was decreased by PKCβ inhibition. Likewise, down-regulation of PKCβ by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-3β phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the PKCβ pathway, leading to GSK-3β inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for PKCβ's therapeutic targeting to treat inflammation-related bone diseases.

Uniform 3 nm-sized ceria nanoparticles can protect against ischemic stroke by scavenging reactive oxygen species (ROS) and reducing apoptosis. PEGylated ceria nanoparticles showed protective effects against ROS-induced cell death in vitro. Optimal doses of ceria nanoparticles reduced infarct volumes and the rate of ischemic cell death in vivo., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)