Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin is an antiatherogenic adipokine that inhibits inflammation by mechanisms that are not completely understood. We explored the effect of adiponectin on endothelial synthesis of interleukin-8 (IL-8), a pro-inflammatory chemokine that plays a role in atherogenesis. Adiponectin decreased the secretion of IL-8 from human aortic endothelial cells (HAEC) stimulated with tumor necrosis factor-alpha (TNF-alpha). Adiponectin also inhibited IL-8 mRNA expression induced by TNF-alpha. Phosphorylation of IkappaB-alpha was decreased by adiponectin, but phosphorylation of ERK, SAPK/JNK, and p38MAPK were unaffected. Adiponectin increased intra-cellular cAMP levels in HAEC in a dose-dependent manner; PKA activity was also increased. The inhibitory effect of adiponectin on TNF-alpha-induced IL-8 synthesis was inhibited by pretreatment with Rp-cAMP, a PKA inhibitor. These observations suggest that adiponectin inhibits IL-8 synthesis through inhibition of a PKA dependent NF-kappaB signaling pathway. We also showed that adiponectin enhances Akt phosphorylation. The inhibitory effect of adiponectin on TNF-alpha-induced IL-8 synthesis was abrogated in part by pretreatment with the PI3 kinase inhibitor LY294002 or by Akt siRNA transfection, suggesting that Akt activation might inhibit IL-8 synthesis induced by TNF-alpha. We conclude that inhibition of NF-kappaB and activation of Akt phosphorylation may mediate adiponectin inhibition of atherosclerosis.
...
PMID:Adiponectin inhibits endothelial synthesis of interleukin-8. 1633 93

Adiponectin (APM) is an adipocyte-derived adipokine with immunosuppressive, antidiabetic, and antiatherosclerotic properties. Low molecular weight (LMW)- and higher molecular weight (HMW)-APM circulate in the serum and activate different signaling pathways. We were interested to see whether LMW-APM exerts different effects on monocytic cells compared with the HMW isoform. Therefore, the effects of recombinant LMW-APM produced in insect cells and the APM from higher eukaryotic cells containing HMW forms on monocytic cells were investigated with respect to apoptosis and inflammation. LMW- and HMW-APM induce apoptosis in nondifferentiated THP-1 cells, reduce macrophage scavenger receptor (MSR) A mRNA expression, and stimulate phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). However, HMW-APM induces the secretion of interleukin (IL)-6 in human monocytes and THP-1 cells but does not suppress lipopolysaccharide (LPS)-induced IL-6 secretion. In contrast, LMW-APM reduces LPS-mediated IL-6 release and furthermore, stimulates IL-10 secretion, most likely by reducing the abundance of inhibitor of nuclear factor (NF)-kappaB kinase beta, leading to a diminished nuclear translocation of NF-kappaB p65. Our data indicate that the different APM isoforms do share common effects on monocytic cells but also induce isoform-specific responses. Although apoptosis, the activation of AMPK, and the reduction of MSR are mediated by all APM isoforms, only LMW-APM displays anti-inflammatory properties.
...
PMID:Different effects of adiponectin isoforms in human monocytic cells. 1643 92

Adiponectin is a recently described adipokine that has been recognized as a key regulator of insulin sensitivity and tissue inflammation. It is produced by adipose tissue (white and brown) and circulates in the blood at very high concentrations. It has direct actions in liver, skeletal muscle and the vasculature, with prominent roles to improve hepatic insulin sensitivity, increase fuel oxidation [via up-regulation of adenosine monophosphate-activated protein kinase (AMPK) activity] and decrease vascular inflammation. Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in the liver. In contrast to other adipokines, adiponectin secretion and circulating levels are inversely proportional to body fat content. Levels are further reduced in subjects with diabetes and coronary artery disease. Adiponectin antagonizes many effects of tumour necrosis factor-alpha(TNF-alpha) and this, in turn, suppresses adiponectin production. Furthermore, adiponectin secretion from adipocytes is enhanced by thiazolidinediones (which also act to antagonize TNF-alpha effects). Thus, adiponectin may be the common mechanism by which TNF-alpha promotes, and the thiazolidinediones suppress, insulin resistance and inflammation. Two adiponectin receptors, termed AdipoR1 and AdipoR2, have been identified and these are ubiquitously expressed. AdipoR1 is most highly expressed in skeletal muscle and has a prominent action to activate AMPK, and hence promote lipid oxidation. AdipoR2 is most highly expressed in liver, where it enhances insulin sensitivity and reduces steatosis via activation of AMPK and increased peroxisome-proliferator-activated receptor alpha ligand activity. T-cadherin, which is expressed in endothelium and smooth muscle, has been identified as an adiponectin-binding protein with preference for HMW adiponectin multimers. Given the low levels of adiponectin in subjects with the metabolic syndrome, and the beneficial effect of the adipokine in animal studies, there is exciting potential for adiponectin replacement therapy in insulin resistance and related disorders.
...
PMID:Adiponectin--a key adipokine in the metabolic syndrome. 1663 86

Compensatory beta cell growth occurs in accordance to overweight and increasing insulin demands. The proliferative actions of insulin and insulin-like growth factors are mediated via the IRS-2-PI(3)K-Akt pathway of pleiotropic insulin signaling. However, sustained activation leads to negative feedback via the mTOR-induced proteasomal degradation of IRS-2. The proliferative actions of incretins and adipokines are mediated via other pathways that ultimately converge with the IRS-2-PI(3)K-Akt axis. The incretins GIP and GLP-1 increase IRS-2 levels in beta cells by acting via the cAMP-PKA pathway, whereas leptin inhibits PTEN activity via CK2-dependent pathways. By increasing PIP(3) availability the adipokine amplifies the magnitude as well as duration of factors acting via the IRS-2-PI(3)K-Akt pathway. Considering that AMPK prevents mTOR-induced degradation of IRS-2, we propose that adiponectin and leptin cooperatively achieve compensatory beta cell growth in accordance to adiposity. In conditions of overt obesity, when adiponectin levels are too low to provide sufficient IRS-2 levels, loss of compensatory beta cell growth may occur.
...
PMID:Leptin and adiponectin regulate compensatory beta cell growth in accordance to overweight. 1709 72

Recently, the insulin-sensitizing adipokine adiponectin and the insulin resistance-inducing adipokine tumor necrosis factor-alpha (TNF-alpha) were reported to inhibit each other's production in adipocytes. We investigated the effects of two beta(3)-adrenoceptor agonists, 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316,243) and (+/-)-(R(*),R(*))-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid (BRL37344), on the gene expression of adiponectin, two adiponectin receptors, and TNF-alpha in adipose tissues of C57BL/6J mice. CL-316,243 and BRL37344 downregulated adiponectin, but upregulated adiponectin receptor 2 (not receptor 1) in epididymal or/and subcutaneous white adipose tissues and in brown adipose tissue. TNF-alpha expression was upregulated only in epididymal adipose tissue. To further explore these effects, we treated differentiated 3T3-L1 adipocytes with the non-selective beta-adrenoceptor agonist isoproterenol. As a result, adiponectin receptor 2 (but not receptor 1) gene expression and TNF-alpha protein expression increased, but gene expression and secretion of adiponectin decreased. The upregulation of adiponectin receptor 2 by isoproterenol is most likely via beta(2),beta(3)-adrenoceptors, adenylyl cyclases, and protein kinase A (PKA). However, the accompanying activation of AMP-activated protein kinase (AMPK) may inhibit this upregulation. Our results suggest that upregulation of TNF-alpha and downregulation of adiponectin by beta-adrenoceptor activation may contribute to the pathogenesis of catecholamine-induced insulin resistance, and that upregulation of adiponectin receptor 2 may be a feedback result of reduced adiponectin.
...
PMID:beta-adrenoceptor agonists downregulate adiponectin, but upregulate adiponectin receptor 2 and tumor necrosis factor-alpha expression in adipocytes. 1757 33

Adiponectin, an adipokine predominantly secreted from adipose tissue, has potent anti-inflammatory properties. Although the mechanisms for the anti-inflammatory properties of adiponectin are not well understood, recent evidence suggests that increased production of interleukin-10 (IL-10), a potent immunomodulatory cytokine, is involved in the anti-inflammatory actions of adiponectin. Globular adiponectin (gAcrp) increased IL-10 promoter activity and IL-10 mRNA accumulation in RAW 264.7 macrophages. Deletion of the sequences from -416 and -369 in the IL-10 promoter, containing a cyclic AMP-response element (CRE), decreased gAcrp-induced IL-10 promoter activation. Treatment of RAW 264.7 macrophages with gAcrp increased the phosphorylation of cyclic AMP response element binding protein (CREB) at Ser(133), as well as enhanced the DNA binding activity of CREB. Further, overexpression of a dominant negative form of CREB suppressed gAcrp-induced transcriptional activation of IL-10. gAcrp-stimulated CREB phosphorylation was mediated by the activation of both ERK1/2- and cAMP-dependent protein kinase (PKA)-dependent pathways. Inhibition of either ERK1/2 or PKA activity prevented gAcrp-stimulated CREB phosphorylation, as well as gAcrp-stimulated IL-10 promoter activation. Taken together, these data identify gAcrp-stimulated phospho-CREB as a key transcription factor responsible for gAcrp-induced IL-10 promoter activation.
...
PMID:Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264.7 macrophages. 1826 67

It is recognized that obesity contributes to cardiovascular and metabolic disorders through alterations in the levels of adipocyte-derived cytokines (adipokines). Adiponectin is an adipokine that is downregulated in obese individuals. It has beneficial actions on the cardiovascular system by directly acting on the heart and blood vessels, and acute administration of adiponectin can minimize the tissue damage resulting from myocardial infarction. More recent research has been aimed at identifying novel adiponectin-like factors involved in metabolic and cardiovascular regulation. Activation of Akt, a protein kinase involved in cell signaling, has been implicated in the control of skeletal muscle hypertrophy. An experimental mouse model demonstrates that substantial increases in muscle fiber hypertrophy, weight and strength occur upon induction of Akt signaling in skeletal muscle. In a mouse model of obesity, the increase in muscle mass caused by myogenic Akt induction results in diminished fat deposition and improvements in whole body metabolism. Based on these findings a protocol to identify novel muscle-secreted proteins (myokines) that confer the phenotypic changes brought on by myogenic Akt induction has been devised. One of these newly discovered factors, referred to as follistatin-like 1, is able to promote revascularization in ischemic limbs and protect the heart from ischemic stress.
...
PMID:Adipokines, myokines and cardiovascular disease. 1904 26

Obesity is one of the most prevalent medical conditions, often associated with several negative stereotypes. Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years. Further, the body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function. When RNA interference (RNAi) was used to specifically silence adipokine gene expression in various in vitro models, this led to increases in cell death, modification of the expression of key signaling genes (i.e. suppressor of cytokine signaling-3; SOCS-3), and modulation of the activation of cellular energy sensors (i.e. adenosine monophosphate-activated protein kinase; AMPK). Subsequently, when RNAi was used to inhibit the expression of brain-derived leptin in adult rats this resulted in minor increases in weight gain in addition to modifying the expression of other adipokine genes (eg. resistin). In summary, although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain.
...
PMID:Could there be a fine-tuning role for brain-derived adipokines in the regulation of bodyweight and prevention of obesity? 1914 19

Adiponectin is an adipokine with anti-atherogenic, anti-diabetic and insulin sensitizing properties. Its effects on energy homeostasis, glucose and lipid metabolism are mediated by two ubiquitously expressed seven-transmembrane receptors, AdipoR1 and -R2. With the exception of APPL1 and RACK1, no intracellular binding partners of adiponectin receptors are reported and thus signaling pathways downstream of these receptors remain largely unknown. To incorporate adiponectins protective potential in drug development it is essential to understand adiponectin signaling cascades in detail. A yeast two-hybrid approach employing AdipoR1s cytoplasmatic N-terminus led to the identification of the regulatory subunit of protein kinase CK2. We confirmed the interaction in co-immunoprecipitation, ELISA experiments and co-localization analysis in mammalian cells. Furthermore we could localize the interaction site in an N-terminal basic region close to the transmembrane domain. In adiponectin stimulation experiments of C2C12 mouse myotubes and MCF7 cells incorporating CK2 inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benz-imidazole (DMAT) we found a modulator role of CK2 in adiponectin signaling. Accordingly we identified the regulatory subunit of protein kinase CK2 as a novel intracellular partner of AdipoR1 and have strong evidence of CK2 as an effector molecule in adiponectin signaling. Since CK2 is involved in signaling cascades of other adipokines and hormones, e.g. leptin and insulin, our findings suggest a possible key function in crosstalk between adiponectin and insulin signaling pathways and could provide further insight into the anti-diabetic effects of adiponectin.
...
PMID:Protein kinase CK2 interacts with adiponectin receptor 1 and participates in adiponectin signaling. 1923 63

This review summarizes recent advances in our understanding of the pre- and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMP-activated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5'- and 3'-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production.
...
PMID:Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. 1931 13


1 2 3 4 5 6 7 Next >>

---