Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin is an adipokine with potent anti-inflammatory properties. The development of alcoholic liver disease is thought to involve increased pro-inflammatory activity, mediated in part by the activation of hepatic macrophages (Kupffer cells). Chronic ethanol feeding sensitizes hepatic macrophages to activation by lipopolysaccharide (LPS), leading to increased production of reactive oxygen species and tumor necrosis factor-alpha (TNF-alpha). Adiponectin can normalize Toll-like receptor-4 (TLR-4) mediated signaling in hepatic macrophages after ethanol feeding, likely contributing to the hepatoprotective effect of adiponectin in the progression of alcoholic liver disease. However, the mechanisms by which adiponectin suppress TLR-4 mediated responses are not well understood. Using the macrophage-like cell line, RAW264.7, we have investigated the molecular mechanisms by which adiponectin suppresses LPS-stimulated TNF-alpha production. Globular adiponectin (gAcrp)-mediated desensitization of LPS-stimulated responses in RAW264.7 macrophages was dependent on the production of the anti-inflammatory cytokine interleukin (IL)-10. gAcrp initially increased TNF-alpha expression in RAW264.7 macrophages; this TNF-alpha then contributed to increased expression of IL-10. This initial gAcrp-mediated increase in TNF-alpha production by macrophages was mediated via activation of ERK1/2-->Egr-1 and nuclear factor (NF)-kappaB-dependent mechanisms. gAcrp-stimulated IL-10 expression was also dependent on the phosphorylation of cAMP response element-binding protein and the cAMP response element in the IL-10 promoter. In summary, these studies reveal a complex, integrated response of macrophages to gAcrp. gAcrp initially activated signaling pathways considered to be pro-inflammatory, with a subsequent increase in the expression of the potent, anti-inflammatory cytokine, IL-10. Increased IL-10 expression was ultimately required for the suppression of TLR4-mediated signaling by gAcrp.
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PMID:Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. 1833 64

Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.
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PMID:Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice. 1837 60

The abundance of the adiponectin receptors, AdipoR1 and AdipoR2, and the effects of the antidiabetic adipokine adiponectin in monocytes of normal-weight and overweight controls and type 2 diabetic patients (T2D) were analyzed. AdipoR1 and AdipoR2 mRNAs were increased in monocytes of obese controls and T2D patients when compared to normal-weight controls, and AdipoR1 mRNA positively correlated to AdipoR2 mRNA, the waist to hip ratio and systemic adiponectin. However, AdipoR1 and AdipoR2 proteins were lower in monocytes of T2D compared to normal-weight donors. Induction of IL-6 and IL-8 by adiponectin, an effect involving p38 MAPK, was also reduced in T2D monocytes.
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PMID:Reduced response to adiponectin and lower abundance of adiponectin receptor proteins in type 2 diabetic monocytes. 1844 81

Adiponectin, an adipocyte-derived cytokine, affects a number of physiological processes, including immune function and inflammation. We investigated whether globular adiponectin (gAd) affects the expression of inflammation-related genes in murine macrophages (RAW264 cells). DNA microarray analysis indicated that granulocyte colony-stimulating factor (G-CSF) showed the largest increase in expression in gAd-stimulated RAW264 cells. The gAd-induced secretion of G-CSF increased in a time- and dose-dependent manner. U0126 (MEK1/2 inhibitor) and PD98059 (MEK1 inhibitor) reduced the gAd-induced G-CSF mRNA expression and G-CSF protein production. gAd induced the phosphorylation of MEK1/2 and ERK1/2 in RAW264 cells. In addition, the gAd-induced phosphorylation of MEK1/2 and ERK1/2 was dramatically reduced by PD98059 and U0126, respectively. Collectively, these results suggest that MEK1/2-ERK1/2 signaling is involved in the adiponectin-induced secretion of G-CSF.
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PMID:Induction of granulocyte colony-stimulating factor by globular adiponectin via the MEK-ERK pathway. 1855 87

Recent studies have shown that factors from adipose tissue influence and regulate the reproductive system. Hormones such as leptin and resistin are now known to regulate several reproductive processes. Adiponectin is the most abundant protein secreted by adipose tissue, and its circulating concentration is inversely related to adiposity and body mass index. Little is known about the involvement of adiponectin in reproduction. In the present study, the effect of recombinant adiponectin on the meiotic maturation and early embryo development in vitro was investigated, using porcine oocytes. Adiponectin receptors, AdipoR1 and AdipoR2, were found to be expressed in porcine oocytes and cumulus cells of both small and large follicles. Both AdipoR1 and AdipoR2 were immunolocalized to cumulus-oocyte complexes (COCs), oocytes, and early developing embryos. When included in oocyte maturation medium for 46 h, adiponectin significantly decreased the frequency of meiotic immature oocytes derived from large follicles (3-6 mm) but not from small follicles (<3mm). From studies of oocytes matured in the presence of adiponectin and mitogen-activated protein kinase (MAPK) pathway inhibitors MEK1 (PD98059), MEK1/2 (U0126), and p38MAPK (SB203580) it was concluded that adiponectin enhances oocyte maturation thought the p38MAPK pathway. Finally, a superior rate of embryo development to the blastocyst stage was achieved by embryos cultured in the presence of adiponectin. These results indicate that adiponectin has a positive effect on the meiotic maturation and in vitro embryo development of porcine oocytes and suggests a physiological role for this adipokine in early development in mammals.
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PMID:Adiponectin enhances in vitro development of swine embryos. 1863 63

Knowledge of the regulatory factors associated with down-regulation of adiponectin gene expression and up-regulation of PAI-1 gene expression is crucial to understand the pathophysiological basis of obesity and metabolic diseases, and could establish new treatment strategies for these conditions. We showed that expression of 5-HT(2A) receptors was up-regulated in hypertrophic 3T3-L1 adipocytes, which exhibited decreased expression of adiponectin and increased expression of PAI-1. 5-HT(2A) receptor antagonists and suppression of 5-HT(2A) receptor gene expression enhanced adiponectin expression. Activation of Gq negatively regulated adiponectin expression, and inhibition of mitogen-activated protein kinase reversed the Gq-induced effect. Moreover, the 5-HT(2A) receptor blockade reduced PAI-1 expression. These findings indicate that antagonism of 5-HT(2A) receptors in adipocytes could improve the obesity-linked decreases in adiponectin expression and increases in PAI-1 expression.
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PMID:5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue. 1867 14

Adiponectin is an adipokine with potent anti-inflammatory properties. Treatment of macrophages with adiponectin results in a suppression of lipopolysaccharide (LPS)-stimulated cytokine production. Here we investigated the transcriptional and post-transcriptional mechanisms by which adiponectin suppresses LPS-stimulated tumor necrosis factor (TNF)-alpha production. Treatment of RAW 264.7 macrophages with LPS increased TNF-alpha promoter-driven luciferase activity (TNF-alpha promoter/Luc activity) by 20-fold over basal. After culture with 1 mug/ml globular adiponectin (gAcrp) for 18 h, TNF-alpha promoter/Luc activity was increased even in the absence of LPS; further challenge with LPS only increased TNF-alpha promoter/Luc activity by 1.4-fold. Treatment with gAcrp decreased LPS-stimulated ERK1/2 phosphorylation and IkappaB degradation and suppressed the ability of LPS to increase the DNA binding activity of Egr-1 and p65. gAcrp also suppressed LPS-mediated stabilization of TNF-alpha mRNA. In controls cells, the half-life of TNF-alpha mRNA was increased from approximately 30 min at base line to approximately 80 min in response to LPS. After treatment with gAcrp for 18 h, LPS failed to increase TNF-alpha mRNA stability. This gAcrp-mediated loss of stimulus-induced stabilization of TNF-alpha mRNA required the presence of the TNF-alpha 3'-untranslated region and was associated with an increase in expression and RNA binding activity of tristetraprolin, an mRNA-binding protein that destabilizes TNF-alpha mRNA. In summary, these data characterize the complex transcriptional and post-transcriptional effects of gAcrp on LPS-stimulated TNF-alpha expression in macrophages. gAcrp treatment profoundly suppressed the ability of LPS to increase TNF-alpha transcription and reduced the stimulus-induced stabilization of TNF-alpha mRNA in response to LPS.
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PMID:Suppression of lipopolysaccharide-stimulated tumor necrosis factor-alpha production by adiponectin is mediated by transcriptional and post-transcriptional mechanisms. 1867 74

Tissue factor (TF) plays a pivotal role in thrombus formation and atherogenesis in acute coronary syndrome. Tissue factor pathway inhibitor (TFPI) is a specific physiological inhibitor of TF/FVIIa complex that regulates TF-induced coagulation. Adiponectin (Adp) is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties. Adp inhibits inflammatory cytokine and adhesion molecules expression, and it can prevent endothelial dysfunction. In this study, we investigated the effects of Adp on tumor necrosis factor-alpha (TNF-alpha)-induced expression of TF and TFPI in human umbilical vein endothelial cells (HUVECs), and the signaling transduction pathways involved. It was found that Adp significantly inhibited both TF protein expression and activity in TNF-alpha-stimulated HUVECs. In the meanwhile, it increased TFPI protein expression and activity for about two folds. Adp also inhibited TF mRNA expression induced by TNF-alpha, but had no effect on TFPI mRNA expression. The inhibitory effect of Adp on TNF-alpha-induced TF expression was prevented by pretreatment with Rp-cAMPs, a PKA inhibitor. Adp increased intracellular cAMP content and PKA activity levels in a dose-dependent manner. Phosphorylation of IkappaB-alpha was decreased by Adp, but phosphorylation of p44/42 MAPK, SAPK/JNK, and p38 MAPK were not affected. These results suggested that Adp inhibits TF expression through inhibition of a PKA dependent nuclear factor-kappaB (NF-kappaB) signaling pathway. It was also found that adiponectin promoted Akt and AMP-activated protein kinase phosphorylation. The inhibitory effect of Adp on TNF-alpha-induced TF synthesis was abrogated in part by pretreatment with the PI3kinase inhibitor LY294002, suggesting that Akt activation might inhibit TF expression induced by TNF-alpha. The inhibitory effect of Adp is almost completely abrogated by inhibition of both the cAMP/PKA pathway and PI3K/Akt pathway. In conclusion, our data indicated that inhibition of NF-kappaB through stabilization of IkappaB-alpha and activation of Akt phosphorylation may mediate the inhibitory effect of Adp on TF expression; but the enhancement effect of Adp on the TFPI production might occur via translational rather than transcriptional regulation.
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PMID:Adiponectin inhibits tissue factor expression and enhances tissue factor pathway inhibitor expression in human endothelial cells. 1869 Mar 50

The insulin-sensitizing hormone, adiponectin, belongs to the expanding C1q/TNF (tumour necrosis factor) family of proteins. We recently identified a family of adiponectin paralogues designated as CTRP (C1q/TNF-related protein) 1-7, and in the present study describe CTRP10. In the present study, we show that CTRP1, CTRP2, CTRP3, CTRP5 and CTRP7 transcripts are expressed predominantly by adipose tissue. In contrast, placenta and eye expressed the highest levels of CTRP6 and CTRP10 transcripts respectively. Expression levels of CTRP1, CTRP2, CTRP3, CTRP6 and CTRP7 transcripts are up-regulated in 8-week-old obese (ob/ob) mice relative to lean controls. Treatment of mice with a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, rosiglitazone, increased the expression of CTRP1 and decreased CTRP6 transcript levels. All CTRPs are secreted glycoproteins when expressed in mammalian cells. CTRP1, CTRP2, CTRP3, CTRP5 and CTRP6 circulate in the blood and are potential endocrine hormones; their serum levels vary according to the sex and genetic background of mice. Importantly, serum levels of CTRP1 and CTRP6 are increased in adiponectin-null mice. Like adiponectin, all secreted CTRP proteins form trimers as their basic structural units. CTRP3, CTRP5, CTRP6 and CTRP10 trimers are further assembled into higher-order oligomeric complexes via disulfide bonding mediated by their N-terminal cysteine residues. Besides forming homo-oligomers, CTRP1/CTRP6, CTRP2/CTRP7 and adiponectin/CTRP2 are secreted as heterotrimers, thus providing a mechanism to potentially generate functionally distinct ligands. Functional characterization of one such family member, CTRP1, showed that it specifically activates Akt and p44/42-MAPK (mitogen-activated protein kinase) signalling pathways in differentiated mouse myotubes. Moreover, injection of recombinant CTRP1 into mice significantly reduced their serum glucose levels. Thus at least CTRP1 may be considered a novel adipokine. In summary, these molecular, biochemical and functional data provide an important framework to further address the physiological functions and mechanisms of the action of this family of secreted glycoproteins in normal and disease states.
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PMID:Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. 1899 88

Adiponectin is a major insulin-sensitizing, multimeric hormone derived from adipose tissue that acts on muscle and liver to regulate whole-body glucose and lipid metabolism. Here, we describe a novel and highly conserved paralog of adiponectin designated as C1q/TNF-related protein (CTRP) 9. Of all the CTRP paralogs, CTRP9 shows the highest degree of amino acid identity to adiponectin in its globular C1q domain. CTRP9 is expressed predominantly in adipose tissue and females expresses higher levels of the transcript than males. Moreover, its expression levels in ob/ob mice changed in an age-dependent manner, with significant up-regulation in younger mice. CTRP9 is a secreted glycoprotein with multiple post-translational modifications in its collagen domain that include hydroxylated prolines and hydroxylated and glycosylated lysines. It is secreted as multimers (predominantly trimers) from transfected cells and circulates in the mouse serum with levels varying according to sex and metabolic state of mice. Furthermore, CTRP9 and adiponectin can be secreted as heterooligomers when cotransfected into mammalian cells, and in vivo, adiponectin/CTRP9 complexes can be reciprocally coimmunoprecipitated from the serum of adiponectin and CTRP9 transgenic mice. Biochemical analysis demonstrates that adiponectin and CTRP9 associate via their globular C1q domain, and this interaction does not require their conserved N-terminal cysteines or their collagen domains. Furthermore, we show that adiponectin and CTRP9 form heterotrimers. In cultured myotubes, CTRP9 specifically activates AMPK, Akt, and p44/42 MAPK signaling pathways. Adenovirus-mediated overexpression of CTRP9 in obese (ob/ob) mice significantly lowered serum glucose levels. Collectively, these results suggest that CTRP9 is a novel adipokine, and further study of CTRP9 will yield novel mechanistic insights into its physiological and metabolic function.
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PMID:Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. 1878 8


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