Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inonotus obliquus (Pers.:Fr.) Pil. is a white rot fungus that belongs to the family Hymenochaetaceae of Basidiomycetes. Extracts and fractions of this fungus have been known to have biological activities, including antimutagenic, anticancer, antioxidative, and immunostimulating effects. Recently, there have been reports that the anti-inflammatory and antinociceptive properties of the methanol extract of I. obliquus may be due to the inhibition of inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) expression via the down-regulation of nuclear factor kappaB (NF-kappaB) binding activity. However, the effects of I. obliquus on Akt and mitogen-activated protein kinase (MAPK) activation of inflammatory mediator production have not yet been elucidated. In the present study, a 70% ethanol extract of I. obliquus (IOE70) showed antioxidative effects. We also tested the ability of the I. obliquus extract to inhibit the inflammatory cascades in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells. The NO inhibition of IOE70 was better than that of other ethanol extracts from I. obliquus. To investigate the mechanism by which IOE 70 inhibits NO production and iNOS and COX-2 expression, we examined the activations of IkappaBalpha, Akt, and c-Jun NH(2) -terminal kinase (JNK) in LPS-activated macrophages. IOE70 markedly inhibited the phosphorylation of IkappaBalpha, Akt, and MAPKs in dose-dependent manners in LPS-activated macrophages. Taken together, these experiments demonstrated that IOE70 inhibition of LPS-induced expression of iNOS and COX-2 protein is mediated by Akt and JNK. Based on our findings, the most likely mechanism that can account for this biological effect of IOE70 involves the inhibition of NF-kappaB through the phosphatidylinositol 3-kinase/Akt/IkappaB pathway and the inhibition of JNK activation. Thus, IOE70 might have useful clinical applications in the management of inflammatory diseases and may also be useful as a medicinal food.
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PMID:Ethanol extract of Inonotus obliquus inhibits lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells. 1747 71

1. Cerebral vessels express oestrogen receptors (ER) in both the smooth muscle and endothelial cell layers of cerebral blood vessels. Levels of ERalpha are higher in female rats chronically exposed to oestrogen, either endogenous or exogenous. 2. Chronic exposure to oestrogen, either endogenous (normally cycling females) or exogenous (ovariectomized with oestrogen replacement), results in cerebral arteries that are more dilated than arteries from ovariectomized counterparts when studied in vitro. This effect is primarily mediated by an increase in the production of vasodilator factors, including nitric oxide (NO) and prostacylin. In contrast, oestrogen appears to suppress the production of endothelial-derived hyperpolarizing factor. Oestrogen treatment increases cerebrovascular levels of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX)-1 and prostacyclin synthase. In addition, via activation of the phosphatidylinositol 3-kinase/Akt pathway, both acute and chronic oestrogen exposure increases eNOS phosphorylation, increasing NO production. 3. Oestrogen receptors have also been localized to cerebrovascular mitochondria and exposure to oestrogen increases the efficiency of energy production while simultaneously reducing mitochondrial production of reactive oxygen species. Oestrogen increases the production of mitochondrial proteins encoded by both mitochondrial and nuclear DNA, including cytochrome c, subunits I and IV of complex IV and Mn-superoxide dismutase. Oestrogen treatment increases the activity of citrate synthase and complex IV and decreases mitochondrial production of H(2)O(2). 4. Oestrogen also has potent anti-inflammatory effects in the cerebral circulation that may have important implications for the incidence and severity of cerebrovascular disease. Administration of lipopolysaccharide or interleukin-1beta to ovariectomized female rats induces cerebrovascular COX-2 and inducible nitric oxide synthase (iNOS) protein expression and increases prostaglandin E(2) expression. Levels of COX-2 and iNOS expression vary with the stage of the oestrous cycle, and the cerebrovascular inflammatory response is suppressed in ovariectomized animals treated with oestrogen. Interleukin-1beta induction of COX-2 protein is prevented by treatment with a nuclear factor (NF)-kappaB inhibitor, and oestrogen treatment reduces cerebrovascular NF-kappaB activity. 5. Cerebrovascular dysfunction and pathology contribute to the pathogenesis of stroke, brain trauma, oedema and dementias, such as Alzheimer's disease. A better understanding of the action of oestrogen on cerebrovascular function holds promise for the development of new therapeutic entities that could be useful in preventing or treating a wide variety of cerebrovascular diseases.
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PMID:Cerebrovascular effects of oestrogen: multiplicity of action. 1760 May 62

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.
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PMID:Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. 1770 46

Anthrax lethal toxin (LeTx) is a virulence factor causing immune suppression and toxic shock of Bacillus anthracis infected host. It inhibits cytokine production and cell proliferation/differentiation in various immune cells. This study showed that a brief exposure of LeTx caused a continual MEK1 cleavage and prevented tumor necrosis factor-alpha (TNF) production in response to lipopolysaccharide (LPS) in non-proliferating cells such as human peripheral blood mononuclear cells or mouse primary peritoneal macrophages. In human monocytic cell lines U-937 and THP-1, LeTx induced cell cycle arrest in G0-G1 phase by rapid down-regulation of cyclin D1/D2 and checkpoint kinase 1 through MEK1 inhibition. However, THP-1 cells adaptively adjusted to LeTx and overrode cell cycle arrest by activating the phosphatidylinositol 3-kinase/Akt signaling pathway. Inhibitory Ser-9 phosphorylation of glycogen synthase kinase 3beta (GSK3beta) by Akt prevented proteasome-mediated cyclin D1 degradation and induced cell cycle progress in LeTx-intoxicated THP-1 cells. Recovery from cell cycle arrest was required before recovering from on-going MEK1 cleavage and suppression of TNF production. Furthermore, pretreatment with LeTx or the GSK3-specific inhibitor SB-216763, or transfection with dominant active mutant Akt or degradation-defected mutant cyclin D1 protected cells from LeTx-induced cell cycle arrest, on-going MEK1 cleavage and suppression of TNF production. These results indicate that modulation of phosphatidylinositol 3-kinase/Akt/GSK3beta signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEK1 activity for proliferation.
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PMID:Critical role of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway in recovery from anthrax lethal toxin-induced cell cycle arrest and MEK cleavage in macrophages. 1795 Dec 52

Efficient clearance of apoptotic cells is essential for tissue homeostasis, allowing for cellular turnover without inflammatory consequences. The Mer (Nyk and c-Eyk) receptor tyrosine kinase (Mertk) is involved in two aspects of apoptotic cell clearance by acting as a receptor for Gas6, a gamma-carboxylated phosphatidylserine-binding protein that bridges apoptotic and viable cells. First, Mertk acts in a bona fide engulfment pathway in concert with alphavbeta5 integrin by regulating cytoskeletal assemblages, and second, it acts as a negative regulator for inflammation by down-modulating pro-inflammatory signals mediated from bacterial lipopolysaccharide-Toll-like receptor 4 (TLR4) signaling, and hence recapitulating anti-inflammatory immune modulation by apoptotic cells. Here we describe Mertk post-receptor events that govern phagocytosis and cytoskeletal signaling are principally mediated by autophosphorylation site Tyr-867. Using the Mertk Y867F mutant and pharmacological inhibitors, we show that Tyr-867 is required for phosphatidylinositol 3-kinase and phospholipase Cgamma2 activation; their activation in turn elicits protein kinase C-dependent signals that act on the actin cytoskeleton. Although Mertk(Y867F) blocked the tyrosine phosphorylation of FAK on Tyr-861 and p130(cas) and also abrogated the phagocytosis of apoptotic cells, this mutant did not suppress lipopolysaccharide-inducible NF-kappaB transcription, nor was NF-kappaB activation dependent on the protein kinase C inhibitor, calphostin C. Finally, unlike the cytoskeletal events associated with Tyr-867 autophosphorylation, the trans-inhibition of NF-kappaB occurred in a postnuclear-dependent fashion independent of cytosolic IkappaB phosphorylation and p65/RelA sequestration. Taken together, these data suggest that Mertk has distinct and separable effects for phagocytosis and for resolving inflammation, providing a molecular rationale for how immune licensing and inflammation can be dissociated from phagocytosis in a single phagocytic receptor.
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PMID:Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation. 1803 60

Prostaglandin E2 (PGE2) is among the most important mediators involved in neuroinflammatory processes. The final step of its synthesis is regulated by enzymes termed prostaglandin E2 synthases (PGES). Three PGES are known, cytosolic (c)PGES, membrane-associated (m)PGES-1 and mPGES-2. The expression of mPGES-1 is induced by inflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha. Although some roles of mPGES-1 have already been suggested, its function in the CNS and the signaling pathways involved in its upregulation are poorly understood. In this study, we examined the regulation of mPGES-1 in primary rat microglia and the signaling pathways involved in its expression. Whereas the expression of cPGES and mPGES-2 was not stimulated by LPS, low doses of LPS (0.1-1 ng/mL) sufficiently stimulated mPGES-1 mRNA expression. A corresponding protein synthesis, however, was obtained only with higher doses (10-100 ng/mL). The LPS-induced increase of mPGES-1 was inhibited by different signaling pathway inhibitors, such as SP600125, LY294002, GF109203X, and SC-514, suggesting the involvement of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI-3K)/Akt, protein kinase C (PKC) pathways, and the nuclear factor (NF)-kappaB, respectively. In contrast to other reports, LPS-induced mPGES-1 synthesis was not invariably coupled to the synthesis of COX-2, since inhibition of PI-3K with LY294002 decreased mPGES-1 but increased COX-2 levels. This detailed view of the intracellular signaling pathways involved in mPGES-1 expression in activated microglia opens a new avenue in the search for novel potential therapeutic targets to reduce neuroinflammation, and demonstrates that mPGES-1 expression is not strictly coupled to the expression of COX-2.
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PMID:Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: evidence for uncoupled regulation of mPGES-1 and COX-2. 1838 41

Insulin is used to control pro-inflammatory hyperglycemia in critically ill patients. However, recent studies suggest that insulin-induced hypoglycemia may negate its beneficial effects in these patients. It is noteworthy that recent evidence indicates that insulin has anti-inflammatory effects that are independent of controlling hyperglycemia. To date, the mechanism by which insulin directly reduces inflammation has not been elucidated. It is well established that insulin activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling in many cell types. We and others have shown that this pathway negatively regulates LPS-induced signaling and pro-inflammatory cytokine production in monocytic cells. We hypothesized that insulin inhibits inflammation during endotoxemia by activation of the PI3K/Akt pathway. We used a nonhyperglycemic mouse model of endotoxemia to determine the effect of continuous administration of a low dose of human insulin on inflammation and survival. It is noteworthy that insulin treatment induced phosphorylation of Akt in muscle and adipose tissues but did not exacerbate lipopolysaccharide (LPS)-induced hypoglycemia. Insulin decreased plasma levels of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein 1 (MCP1)/JE, and keratinocyte chemoattractant, and decreased mortality. The PI3K inhibitor wortmannin abolished the insulin-mediated activation of Akt and the reduction of chemokine and interleukin-6 levels. We conclude that insulin reduces LPS-induced inflammation in mice in a PI3K/Akt-dependent manner without affecting blood glucose levels.
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PMID:Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. 1844 80

We here demonstrate an anti-inflammatory action of raloxifene, a selective estrogen receptor modulator, in lipopolysaccharide (LPS)-induced murine macrophage RAW264.7 cells. Treatment with raloxifene at micromolar concentrations suppressed the production of nitric oxide (NO) by down-regulating expression of the inducible nitric oxide synthase (iNOS) gene in LPS-activated cells. The decreased expression of iNOS and subsequent reduction of NO were due to inhibition of nuclear translocation of transcription factor NF-kappaB. These effects were significantly inhibited by exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, or by expression of a dominant negative mutant of PI 3-kinase. In addition, pretreatment with raloxifene reduced LPS-induced Akt phosphorylation as well as NF-kappa B DNA binding activity and NF-kappa B-dependent reporter gene activity. Thus our findings indicate that raloxifene exerts its anti-inflammatory action in LPS-stimulated macrophages by blocking the PI 3-kinase-Akt-NF-kappa B signaling cascade, and eventually reduces expression of pro-inflammatory genes such as iNOS.
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PMID:Raloxifene, a selective estrogen receptor modulator, inhibits lipopolysaccharide-induced nitric oxide production by inhibiting the phosphatidylinositol 3-kinase/Akt/nuclear factor-kappa B pathway in RAW264.7 macrophage cells. 1851 85

Reactive oxygen species (ROS) have been implicated in the regulation of NF-kappaB activation, which plays an important role in inflammation and cell survival. However, the molecular mechanisms of ROS in NF-kappaB activation remain poorly defined. We found that the non-provitamin A carotenoid, lutein, decreased intracellular H(2)O(2) accumulation by scavenging superoxide and H(2)O(2) and the NF-kappaB-regulated inflammatory genes, iNOS, TNF-alpha, IL-1beta, and cyclooxygenase-2, in lipopolysaccharide (LPS)-stimulated macrophages. Lutein inhibited LPS-induced NF-kappaB activation, which highly correlated with its inhibitory effect on LPS-induced IkappaB kinase (IKK) activation, IkappaB degradation, nuclear translocation of NF-kappaB, and binding of NF-kappaB to the kappaB motif of the iNOS promoter. This compound inhibited LPS- and H(2)O(2)-induced increases in phosphatidylinositol 3-kinase (PI3K) activity, PTEN inactivation, NF-kappaB-inducing kinase (NIK), and Akt phosphorylation, which are all upstream of IKK activation, but did not affect the interaction between Toll-like receptor 4 and MyD88 and the activation of mitogen-activated protein kinases. The NADPH oxidase inhibitor apocynin and gp91(phox) deletion reduced the LPS-induced NF-kappaB signaling pathway as lutein did. Moreover, lutein treatment and gp91(phox) deletion decreased the expressional levels of the inflammatory genes in vivo and protected mice from LPS-induced lethality. Our data suggest that H(2)O(2) modulates IKK-dependent NF-kappaB activation by promoting the redox-sensitive activation of the PI3K/PTEN/Akt and NIK/IKK pathways. These findings further provide new insights into the pathophysiological role of intracellular H(2)O(2) in the NF-kappaB signal pathway and inflammatory process.
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PMID:The non-provitamin A carotenoid, lutein, inhibits NF-kappaB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-kappaB-inducing kinase pathways: role of H(2)O(2) in NF-kappaB activation. 1862 44

The involvement of ecto-5'-nucleotidase (E-5'Nu) in the elevation of extracellular adenosine during inflammation is unclear. In the present study, the effect of lipopolysaccharide (LPS), an inflammation inducer, was investigated on E-5'Nu in human umbilical vein endothelial cells (HUVECs). E-5'Nu activity was enhanced after a 24 h exposure to LPS. This effect was dose dependent, with an EC50 of 1.66 ng/ml. At 10 microM, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 abolished the LPS-induced E-5'Nu activity. However, at 10 microM, the NF-kappaB inhibitor ammonium pyrrolidine dithiocarbamate had no effect. LPS upregulated the protein expression but not the messenger RNA expression of E-5'Nu. The inhibition of E-5'Nu by 100 microM alpha,beta-methylene adenosine-5'-diphosphate increased the LPS-induced inflammation, suggesting that E-5'Nu plays a significant role in reducing inflammation, probably through the generation of adenosine. In conclusion, the experiments indicate that LPS upregulates E-5'Nu activity in HUVECs through a PI3K-dependent increase in the abundance of E-5'Nu on cell membranes. Since adenosine is an anti-inflammatory molecule, E-5'Nu upregulation may be crucial in protecting endothelial cells against inflammatory damage.
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PMID:Stimulation of ecto-5'-nucleotidase in human umbilical vein endothelial cells by lipopolysaccharide. 1864 Dec 67


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