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

The activation of monocytes involves a stimulation of glycolysis, release of potent inflammatory mediators, and alterations in gene expression. All of these processes are known to be further increased under hypoxic conditions. The activated monocytes express inducible 6-phosphofructo-2-kinase (iPFK-2), which synthesizes fructose 2,6-bisphosphate, a stimulator of glycolysis. During ischemia, AMP-activated protein kinase (AMPK) activates the homologous heart 6-phosphofructo-2-kinase isoform by phosphorylating its Ser-466. Here, we studied the involvement of AMPK and iPFK-2 in the stimulation of glycolysis in activated monocytes under hypoxia. iPFK-2 was phosphorylated on the homologous serine (Ser-461) and activated by AMPK in vitro. The activation of human monocytes by lipopolysaccharide induced iPFK-2 expression and increased fructose 2,6-bisphosphate content and glycolysis. The incubation of activated monocytes with oligomycin, an inhibitor of oxidative phosphorylation, or under hypoxic conditions activated AMPK and further increased iPFK-2 activity, fructose 2,6-bisphosphate content, and glycolysis. In cultured human embryonic kidney 293 cells, the expression of a dominant-negative AMPK prevented both the activation and phosphorylation of co-transfected iPFK-2 by oligomycin. It is concluded that the stimulation of glycolysis by hypoxia in activated monocytes requires the phosphorylation and activation of iPFK-2 by AMPK.
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PMID:The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. 1206

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in the regulation of energy homeostasis and metabolic stress. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR) inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin-6) and inducible nitric oxide synthase in primary rat astrocytes, microglia, and peritoneal macrophages. AICAR attenuates the LPS-induced activation of nuclear factor kappaB via downregulation of IkappaB kinase alpha/beta activity. It also inhibits nuclear translocation of CCAAT/enhancer-binding protein (C/EBP) transcription factor by inhibiting the expression of C/EBP-delta in brain glial cells. The dominant negative form of AMPKalpha2 (D157A) and its antisense documents a possible role of AMPK in the regulation of the cellular proinflammatory process. AICAR also inhibited the production of inflammatory mediators in serum and their expression in CNS of rats injected with a sublethal dose of LPS by intraperitoneal injection. These observations in cultured cells as well as in the animal model suggest that AICAR may be of therapeutic value in treating inflammatory diseases.
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PMID:5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. 1472 46

Recent studies suggest AMP-activated protein kinase (AMPK), an enzyme involved in energy homeostasis, might be a novel signaling pathway in regulating inflammatory response, but the precise intracellular mechanisms are not fully understood. In this study, we have demonstrated that 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK, inhibited lipopolysaccharide (LPS)-induced protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in macrophages and microglial cells at the gene transcription level. Data obtained from electrophoretic mobility shift assay (EMSA) and promoter activity assay have further confirmed the ability of AICAR to block LPS-mediated NF-kappaB, AP-1, CREB, and C/EBPbeta activation. However, AICAR did not affect LPS-mediated IKK, ERK, and p38 activation. Regardless of the ability of AICAR to activate AMPK, the inhibitory effects of AICAR on iNOS and COX-2 expression were not associated with AMPK. An adenosine kinase inhibitor 5'-iodotubercidin, which effectively abolished AMPK activation caused by AICAR, did not reverse the anti-inflammatory effect of AICAR. Moreover, another AMPK activator metformin was not able to mimic the effects of AICAR. Direct addition of AICAR in EMSA assay interrupted binding of NF-kappaB, CREB, and C/EBPbeta to specific DNA elements. Taken together, this study demonstrates that the anti-inflammatory effects of AICAR against LPS-induced iNOS and COX-2 gene transcription are not associated with AMPK activation, but might be resulting from the direct interference with DNA binding to transcription factors.
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PMID:Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. 1761 55

Adiponectin stimulates cholesterol efflux in macrophages and low adiponectin may in part contribute to disturbed reverse cholesterol transport in type 2 diabetes. Monocytes express high levels of annexin A6 that could inhibit cholesterol efflux and it was investigated whether the atheroprotective effects of adiponectin are accompanied by changes in annexin A6 levels. Adiponectin reduces annexin A6 protein whereas mRNA levels are not affected. Adiponectin-mediated activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and AMP-activated protein kinase (AMPK) does not account for reduced annexin A6 expression. Further, fatty acids and lipopolysaccharide that are elevated in obesity do not influence annexin A6 protein levels. Annexin A6 in monocytes from overweight probands or type 2 diabetic patients is significantly elevated compared to monocytes of normal-weight controls. Monocytic annexin A6 positively correlates with body mass index and negatively with systemic adiponectin of the blood donors. Therefore, the current study demonstrates that adiponectin reduces annexin A6 in monocytes and thereby may enhance cholesterol efflux. In agreement with these in vitro finding an increase of monocytic annexin A6 in type 2 diabetes monocytes was observed.
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PMID:Annexin A6 is highly abundant in monocytes of obese and type 2 diabetic individuals and is downregulated by adiponectin in vitro. 1932 30

Recent reports show that 5-amino-4-imidazole carboxamide riboside (AICAR), a pharmacological activator of AMP-activated protein kinase (AMPK), inhibits the lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. MRL/MPJ-Fas(lpr) (MRL/lpr) mice show an intrinsic decreased threshold for the production of inflammatory mediators when stimulated. In our current studies, we sought to determine if AMPK activation would inhibit inflammatory mediator production in stimulated kidney mesangial cells. Cultured mesangial cells from MRL/lpr mice were treated with AICAR and stimulated with LPS/interferon (IFN)-gamma. AICAR decreased dose-dependently inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and interleukin-6 production in LPS/IFN-gamma-stimulated mesangial cells. Mechanistically, AICAR inhibited the LPS/IFN-gamma-stimulated PI3K/Akt signalling inflammatory cascade but did not affect LPS/IFN-gamma-mediated inhibitory kappa B phosphorylation or nuclear factor (NF)-kappaB (p65) nuclear translocation. Treatment with the adenosine kinase inhibitor 5'-iodotubercidin blocked the ability of AICAR to activate AMPK and prevented AICAR from inhibiting the LPS/IFN-gamma-stimulated PI3K/Akt pathway and attenuating iNOS expression. Taken together, these observations suggest that AICAR inhibits LPS/IFN-gamma-induced Akt phosphorylation through AMPK activation and may serve as a potential therapeutic target in inflammatory diseases.
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PMID:Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells. 1943 9

Toll-like receptor 4 (TLR4), a proximal signalling receptor in innate immune responses to lipopolysaccharide of gram-negative pathogens, is expressed in the heart. Accumulating evidence have consolidated the notion that TLR4 plays an essential role in the pathogenesis of cardiac dysfunction. However, the molecular mechanisms of TLR4 responsible for ischemia-induced cardiac dysfunction remain unclear. To address the signalling mechanisms of TLR4-deficiency cardioprotection against ischemic injury, in vivo regional ischemia was induced by occlusion of the left anterior descending coronary artery in wild-type (WT) C3H/HeN and TLR4-mutated C3H/HeJ mice. The results demonstrated that blunted ischemic activation of p38 mitogen-activated protein kinase and JNK signalling occurred in C3H/HeJ hearts versus C3H/HeN hearts, while ERK and AMP-activated protein kinase (AMPK) signalling pathways were augmented during ischemia in C3H/HeJ hearts versus C3H/HeN hearts. Intriguingly, ischemia-stimulated endoplasmic reticulum stress was higher in C3H/HeN hearts than that in C3H/HeJ as demonstrated by up-regulation of Grp78/BiP, Gadd153/CHOP and IRE-1alpha. Myocardial infarct, caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining demonstrated that C3H/HeN hearts suffered more damage than those of C3H/HeJ hearts during ischemia. Moreover, isolated cardiomyocytes from C3H/HeJ hearts showed resistance to hypoxia-induced contractile dysfunction compared to those from C3H/HeN hearts, which are associated with greater hypoxic activation of AMPK and ERK signalling, better intracellular Ca(2+) handling in C3H/HeJ versus C3H/HeN cardiomyocytes. These findings suggest that the cardioprotective effects against ischemic injury of hearts with deficiency in TLR4 signalling may be mediated through modulating AMPK and ERK signalling pathway during ischemia.
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PMID:Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemia. 1950 85

Adiponectin is an important antiatherogenic adipocytokine that inhibits inflammation, insulin resistance, and oxide stress. Inflammation in the vascular adventitia is a crucial factor in the pathogenesis of atherosclerosis. Adventitial fibroblasts (AFs) can proliferate, divide into myofibroblasts, and migrate to the intima to become a new component of atherosclerotic plaque under inflammation and atherosclerosis. We investigated whether adiponectin might prevent AFs from proliferating, migrating, and transforming into myofibroblasts. Cultured AFs were stimulated with lipopolysaccharide (LPS) in the presence or absence of adiponectin. Methyl thiazolyl tetrazolium assay and migration and scratch-wound assays demonstrated that adiponectin reduced the AF proliferation and migration induced by LPS, respectively, whereas treatment with AdipoR1 small interfering (si) RNA (siAdipoR1), AMP-activated protein kinase (AMPK) siRNA (siAMPK), and an AMPK inhibitor reversed the effect. Immunocytochemistry and Western blot revealed that adiponectin reduced the transition of AFs to myofibroblasts, and treatment with siAdipoR1, siAMPK, and the AMPK inhibitor increased the transition. RT-PCR, Western blotting, and nitric oxide (NO) assay showed that adiponectin reduces induced NO synthase (iNOS) and nitrotyrosine expression and NO and ONOO(-) production induced by LPS. Treatment with siAdipoR1, siAMPK, and the AMPK inhibitor significantly attenuated adiponectin-induced phosphorylation of AMPK and its downstream target acetyl-coenzyme A carboxylase and up-regulated iNOS mRNA and protein expression, which resulted in a marked increase of NO and ONOO(-) production. In apolipoprotein E-deficient mice, immunohistochemistry of treated vascular adventitia showed that both iNOS expression and ONOO(-) production could be reversed with an adenovirus-adiponectin vector. Taken together, these results suggest that adiponectin reduces LPS-induced NO production and nitrosative stress and prevents AFs from proliferating, transforming to myoflbroblasts, and migrating to the intima, thus worsening atherosclerosis, by inhibiting the AdipoR1-AMPK-iNOS pathway in AFs.
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PMID:Adiponectin inhibits lipopolysaccharide-induced adventitial fibroblast migration and transition to myofibroblasts via AdipoR1-AMPK-iNOS pathway. 1988 16

In this study, we aim to determine cellular mechanisms linking nutrient metabolism to the regulation of inflammation and insulin resistance. The nutrient sensors AMP-activated protein kinase (AMPK) and SIRT1 show striking similarities in nutrient sensing and regulation of metabolic pathways. We find that the expression, activity, and signaling of the major isoform alpha1AMPK in adipose tissue and macrophages are substantially down-regulated by inflammatory stimuli and in nutrient-rich conditions, such as exposure to lipopolysaccharide (LPS), free fatty acids (FFAs), and diet-induced obesity. Activating AMPK signaling in macrophages by 5-aminoimidazole-4-carboxamide-1-beta4-ribofuranoside or constitutively active alpha1AMPK (CA-alpha1) significantly inhibits; although inhibiting alpha1AMPK by short hairpin RNA knock-down or dominant-negative alpha1AMPK (DN-alpha1) increases LPS- and FFA-induced tumor necrosis factor alpha expression. Chromatin immunoprecipitation and luciferase reporter assays show that activation of AMPK by CA-alpha1 in macrophages significantly inhibits LPS- or FFA-induced NF-kappaB signaling. More importantly, in a macrophage-adipocyte co-culture system, we find that inactivation of macrophage AMPK signaling inhibits adipocyte insulin signaling and glucose uptake. Activation of AMPK by CA-alpha1 increases the SIRT1 activator NAD(+) content and SIRT1 expression in macrophages. Furthermore, alpha1AMPK activation mimics the effect of SIRT1 on deacetylating NF-kappaB, and the full capacity of AMPK to deacetylate NF-kappaB and inhibit its signaling requires SIRT1. In conclusion, AMPK negatively regulates lipid-induced inflammation, which acts through SIRT1, thereby contributing to the protection against obesity, inflammation, and insulin resistance. Our study defines a novel role for AMPK in bridging the signaling between nutrient metabolism and inflammation.
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PMID:Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. 2042 Dec 94

Metformin is reported to ameliorate inflammation in diabetic patients. The effect of metformin on lipopolysaccharide-induced nitric oxide production was studied by using RAW 264.7 macrophage-like cells. The action of metformin was analyzed by dividing lipopolysaccharide signaling into the MyD88-dependent and -independent pathways. Metformin significantly reduced the expression of an inducible type of nitric oxide synthase and inhibited lipopolysaccharide-induced nitric oxide production. On the other hand, metformin did not inhibit lipopolysaccharide-induced tumor necrosis factor-alpha production. The expression levels of interferon-beta protein and mRNA, which is a key molecule in MyD88-independent pathway, were significantly inhibited by metformin. Compound C, a specific AMP-activated protein kinase inhibitor, did not affect the inhibitory action of metformin. Metformin was suggested to inhibit lipopolysaccharide-induced nitric oxide production via inhibition of interferon-beta production in MyD88-independent pathway. Metformin might exhibit an anti- inflammatory action on diabetic complications as well as the antidiabetic action.
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PMID:Metformin attenuates production of nitric oxide in response to lipopolysaccharide by inhibiting MyD88-independent pathway. 2056 Jan 7

Obesity, type-2 diabetes and low-grade inflammation are becoming worldwide epidemics. In this regard, the literature provides a novel concept that we call "MicrObesity" (Microbes and Obesity), which is devoted to deciphering the specific role of dysbiosis and its impact on host metabolism and energy storage. In the present review, we discuss novel findings that may partly explain how the microbial community participates in the development of the fat mass development, insulin resistance and low-grade inflammation that characterise obesity. In recent years, numerous mechanisms have been proposed and several proteins identified. Amongst the key players involved in the control of fat mass development, Fasting induced adipose factor, AMP-activated protein kinase, G-protein coupled receptor 41 and G-protein coupled receptor 43 have been linked to gut microbiota. In addition, the discovery that low-grade inflammation might be directly linked to the gut microbiota through metabolic endotoxaemia (elevated plasma lipopolysaccharide levels) has led to the identification of novel mechanisms involved in the control of the gut barrier. Amongst these, the impacts of glucagon-like peptide-2, the endocannabinoid system and specific bacteria (e.g., Bifidobacterium spp.) have been investigated. Moreover, the advent of probiotic and prebiotic treatments appears to be a promising "pharmaco-nutritional" approach to reversing the host metabolic alterations linked to the dysbiosis observed in obesity. Although novel powerful molecular system biology approaches have offered great insight into this "small world within", more studies are needed to unravel how specific changes in the gut microbial community might affect or counteract the development of obesity and related disorders.
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PMID:The gut microbiome as therapeutic target. 2129 72


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