Anti-inflammatory effects of spermidine in lipopolysaccharide-stimulated BV2 microglial cells

<p>Abstract</p> <p>Background</p> <p>Spermidine, a naturally occurring polyamine, displays a wide variety of internal biological activities including cell growth and proliferation. However, the molecular mechanisms responsible for its anti-inflammatory activity have not yet been elucidated.</p> <p>Methods</p> <p>The anti-inflammatory properties of spermidine were studied using lipopolysaccharide (LPS)-stimulated murine BV2 microglia model. As inflammatory parameters, the production of nitric oxide (NO), prostaglandin E₂(PGE₂), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were evaluated. We also examined the spermidine's effect on the activity of nuclear factor-kappaB (NF-κB), and the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) pathways.</p> <p>Results</p> <p>Pretreatment with spermidine prior to LPS treatment significantly inhibited excessive production of NO and PGE₂in a dose-dependent manner, and was associated with down-regulation of expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Spermidine treatment also attenuated the production of pro-inflammatory cytokines, including IL-6 and TNF-α, by suppressing their mRNA expressions. The mechanism underlying spermidine-mediated attenuation of inflammation in BV2 cells appeared to involve the suppression of translocation of NF-κB p65 subunit into the nucleus, and the phosphorylation of Akt and MAPKs.</p> <p>Conclusions</p> <p>The results indicate that spermidine appears to inhibit inflammation stimulated by LPS by blocking the NF-κB, PI3K/Akt and MAPKs signaling pathways in microglia.</p

Investigations into the relationship between feedback loops and functional importance of a signal transduction network based on Boolean network modeling

<p>Abstract</p> <p>Background</p> <p>A number of studies on biological networks have been carried out to unravel the topological characteristics that can explain the functional importance of network nodes. For instance, connectivity, clustering coefficient, and shortest path length were previously proposed for this purpose. However, there is still a pressing need to investigate another topological measure that can better describe the functional importance of network nodes. In this respect, we considered a feedback loop which is ubiquitously found in various biological networks.</p> <p>Results</p> <p>We discovered that the number of feedback loops (NuFBL) is a crucial measure for evaluating the importance of a network node and verified this through a signal transduction network in the hippocampal CA1 neuron of mice as well as through generalized biological network models represented by Boolean networks. In particular, we observed that the proteins with a larger NuFBL are more likely to be essential and to evolve slowly in the hippocampal CA1 neuronal signal transduction network. Then, from extensive simulations based on the Boolean network models, we proved that a network node with the larger NuFBL is likely to be more important as the mutations of the initial state or the update rule of such a node made the network converge to a different attractor. These results led us to infer that such a strong positive correlation between the NuFBL and the importance of a network node might be an intrinsic principle of biological networks in view of network dynamics.</p> <p>Conclusion</p> <p>The presented analysis on topological characteristics of biological networks showed that the number of feedback loops is positively correlated with the functional importance of network nodes. This result also suggests the existence of unknown feedback loops around functionally important nodes in biological networks.</p

Protective effects of Scutellaria baicalensis Georgi against hydrogen peroxide-induced DNA damage and apoptosis in HaCaT human skin keratinocytes

Oxidative stress due to excessive accumulation of reactive oxygen species (ROS) is one of the risk factors for the development of several chronic diseases. In this study, we investigated the protective effects of Scutellaria bai- calensis rhizome ethanol extract (SBRE) against oxidative stress-induced cellular damage and elucidated the un- derlying mechanisms in the HaCaT human skin keratinocyte cell line. Our results revealed that treatment with SBRE prior to hydrogen peroxide (H2O2) exposure significantly increased viability of aCaT cells. SBRE also effectively attenuated H2O2-induced comet tail formation and inhibited the H2O2-induced phosphorylation levels of the histone γH2AX, as well as the number of apoptotic bodies and Annexin V-positive cells. In addition, SBRE exhibited scavenging activity against intracellular ROS generation and restored the mitochondrial membrane po- tential loss by H2O2. Moreover, H2O2 enhanced the cleavage of caspase-3 and degradation of poly (ADP-ribose)- polymerase, a typical substrate protein of activated caspase-3, as well as DNA fragmentation; however, these events were almost totally reversed by pretreatment with SBRE. Furthermore, SBRE increased the levels of heme oxygenase-1 (HO-1), which is a potent antioxidant enzyme, associated with the induction of nuclear fac- tor-erythroid 2-related factor 2 (Nrf2). According to our data, SBRE is able to protect HaCaT cells from H2O2- induced DNA damage and apoptosis through blocking cellular damage related to oxidative stress through a mech-anism that would affect ROS elimination and activating the Nrf2/HO-1 signaling pathway

Platelet-derived growth factor induces p21/WAF1 promoter in vascular smooth muscle cells via activation of an Sp1 site

AbstractMany studies suggested that cyclin-dependent kinase inhibitor (CDKI) p21 acts as a universal inhibitor of cyclin/CDK catalytic activity. This protein has also been shown to be a component of active cyclin/CDK complexes. In addition, it has recently been suggested that p21 serves as an assembly factor in platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMC). However, little is known concerning the molecular mechanisms by which PDGF induces p21 gene expression in VSMC. In this report we demonstrate that PDGF induces the p21 expression at both the mRNA and protein levels. This increase in p21 gene expression was due to activation of the p21 promoter by PDGF. Through both deletion and mutation analysis of the p21 promoter, we defined a 10-bp sequence that is required for the activation of the p21 promoter by PDGF. In addition, gel shift and supershift assays demonstrated that this PDGF-responsive element binds specifically to the transcription factor Sp1. These results demonstrate that Sp1 mediates PDGF-induced p21 gene expression in VSMC. Moreover, immunoblot and immonoprecipitation analysis showed that the level of hyperphosphorylated retinoblastoma protein (Rb) is increased and the protein is physically associated with Sp1 in PDGF-treated cells, indicating that phosphorylated Rb may play a role in regulating Sp1 to activate p21 expression

Agaricus blazei Extract Induces Apoptosis through ROS-Dependent JNK Activation Involving the Mitochondrial Pathway and Suppression of Constitutive NF-κB in THP-1 Cells

Agaricus blazei is widely accepted as a traditional medicinal mushroom, and it has been known to exhibit immunostimulatory and anti-cancer activity. However, the apoptotic mechanism in cancer cells is poorly understood. In this study, we have investigated whether A. blazei extract (ABE) exerts antiproliferative and apoptotic effects in human leukemic THP-1 cells. We observed that ABE-induced apoptosis is associated with the mitochondrial pathway, which is mediated by reactive oxygen species (ROS) generation and prolonged c-Jun N-terminal kinase (JNK) activation. In addition, the ABE treatment resulted in the accumulation of cytochrome c in the cytoplasm, an increase in caspase activity, and an upregulation of Bax and Bad. With those results in mind, we found that ABE decreases constitutive NF-κB activation and NF-κB-regulated gene products such as IAP-1 and -2. We concluded that ABE induces apoptosis with ROS-dependent JNK activation and constitutive activated NF-κB inhibition in THP-1 cells

Schisandrae Fructus ethanol extract ameliorates inflammatory responses and articular cartilage damage in monosodium iodoacetate-induced osteoarthritis in rats

Schisandrae Fructus, the fruit of Schisandra chinensis (Turcz.) Baill., is widely used in traditional medicine for the treatment of a number of chronic diseases. Although, Schisandrae Fructus was recently reported to attenuate the interleukin (IL)-1β-induced inflammatory response in chondrocytes in vitro, its protective and therapeutic potential against osteoarthritis (OA) in an animal model remains unclear. Therefore, we investigated the effects of the ethanol extract of Schisandrae Fructus (SF) on inflammatory responses and cartilage degradation in a monosodium iodoacetate (MIA)-induced OA rat model. Our results demonstrated that administration with SF had a tendency to attenuate MIA-induced damage of articular cartilage as determined by a histological grade of OA. SF significantly suppressed the production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in MIA-induced OA rats. SF also effectively inhibited expression of inducible nitric oxide (NO) synthase and cyclooxygenase-2, thereby inhibiting the release of NO and prostaglandin E2. In addition, the elevated levels of matrix metalloproteinases-13 and two biomarkers for diagnosis and progression of OA, such as cartilage oligomeric matrix protein and C-telopeptide of type II collagen, were markedly ameliorated by SF administration. These findings indicate that SF could be a potential candidate for the treatment of OA

Schisandrae Fructus ethanol extract ameliorates inflammatory responses and articular cartilage damage in monosodium iodoacetate-induced osteoarthritis in rats

Schisandrae Fructus, the fruit of Schisandra chinensis (Turcz.) Baill., is widely used in traditional medicine for the treatment of a number of chronic diseases. Although, Schisandrae Fructus was recently reported to attenuate the interleukin (IL)-1β-induced inflammatory response in chondrocytes in vitro, its protective and therapeutic potential against osteoarthritis (OA) in an animal model remains unclear. Therefore, we investigated the effects of the ethanol extract of Schisandrae Fructus (SF) on inflammatory responses and cartilage degradation in a monosodium iodoacetate (MIA)-induced OA rat model. Our results demonstrated that administration with SF had a tendency to attenuate MIA-induced damage of articular cartilage as determined by a histological grade of OA. SF significantly suppressed the production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in MIA-induced OA rats. SF also effectively inhibited expression of inducible nitric oxide (NO) synthase and cyclooxygenase-2, thereby inhibiting the release of NO and prostaglandin E2. In addition, the elevated levels of matrix metalloproteinases-13 and two biomarkers for diagnosis and progression of OA, such as cartilage oligomeric matrix protein and C-telopeptide of type II collagen, were markedly ameliorated by SF administration. These findings indicate that SF could be a potential candidate for the treatment of OA