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

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two experiments were conducted with cross-bred barrows to determine the effect of somatotropin administration on liver enzyme activities. In the first experiment, pigs growing from 26 to 55 kg body weight were given two doses of pituitary porcine somatotropin (pST; 0 and 100 micrograms per kg body weight) and three levels of dietary energy (60, 80 and 100% of free choice intake). In the second experiment, pigs growing from 30 to 60 kg body weight were given two doses of recombinant porcine somatotropin (rpST; 0 and 100 micrograms per kg body weight) and five levels of dietary crude protein (110, 150, 190, 230 and 270 g crude protein/kg diet). Liver arginase (ARG, EC 3.5.3.1) and aspartate aminotransferase (AAT, EC 2.6.1.1) activities were then determined in organ samples taken at slaughter time. Dietary energy did not change liver ARG. Activities of both ARG and AAT increased as dietary crude protein increased. Both pST and rpST decreased ARG, AAT and serum utrea nitrogen. There was a lack of interaction between rpST therapy and dietary protein on either ARG or AAT activities, suggesting that set nutritional states are not required for expression of pST effects.
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PMID:Porcine somatotropin, dietary protein and energy effects on arginase and transaminase activities in pigs. 950 51

Low plasma high density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD) in adults. In the field of pediatrics, subjects with low plasma HDL-C are often found among obese or dyslipidemic children. However, it is not clear whether low HDL-C in children should be considered a risk factor for CHD. The purpose of this study was to evaluate the risk for CHD in children with low HDL-C by comparing their lipid and apolipoprotein levels and physicochemical characteristics of their HDL with those of age-matched children with normal HDL-C and CHD patients with low HDL-C. Plasma lipids and apolipoproteins were measured in 206 dyslipidemic children (dyslipidemic), 65 obese children (obese), 93 CHD patients with low HDL-C (< 40 mg/dl) and 128 children with normal HDL-C (controls). To evaluate the physicochemical characteristics of HDL, molar and fractional esterification rates of cholesterol in plasma (MER(plasma) and FER(plasma)) and HDL (MER(HDL) and FER(HDL)) were determined in 128 children with normal HDL-C, 71 dyslipidemic, 33 obese and 93 CHD who allowed second blood samples to be taken. Compared to controls, children with low HDL-C showed atherogenic profiles of lipid and apolipoprotein levels and physicochemical characteristics of HDL (lower apo A-I, lower ratio of apo A-I to apo B and higher FER(HDL)). Therefore, the differences in lipid and apolipoprotein profiles between children with low HDL-C and CHD patients with low HDL-C were examined next. The two groups of subjects based on the HDL-C level (Group I: < 30 mg/dl, Group II 30 < or = HDL-C < 40 mg/dl) were studied. Compared to CHD, Group I children showed less atherogenic apolipoprotein profiles (lower apo B and higher ratio of apo A-I to apo B). Similar findings were also found in Group II children, but the differences were less prominent than those in Group I children. FER(HDL) in children with low HDL-C were similar to those in CHD. These findings suggest that the physicochemical characteristics of HDL in children with low HDL-C are similar to those in CHD, but the abnormalities of apo B-containing lipoproteins are milder than those in CHD patients. Thus, if further changes in the nature of apo B-containing lipoproteins could be prevented, children with low HDL-C might not become high risk for CHD in later life.
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PMID:Comparison of children and coronary heart disease patients with low high density lipoprotein cholesterol levels. 962 75

Serum levels of high density lipoprotein cholesterol (HDL-C) are inversely correlated with coronary heart disease (CHD). Kinetic studies indicate that the mechanism for the variation in HDL levels associated with various pathophysiologic states includes changes in the fractional catabolic rate (FCR) and/or the synthesis rate of HDL and its major proteins apolipoprotein (apo) A-I and apo A-II. The antiatherogenic effects of HDL are thought to be mainly due to its role in reverse cholesterol transport. HDL is an assembly of heterogeneous particles. HDL enlarges when it takes up cellular cholesterol, and shrinks when HDL cholesterol ester (CE) is transfered to low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles. The functional ability of HDL (to remove cellular cholesterol) has drawn considerable attention. The fractional esterification rate of cholesterol in HDL (FER(HDL)) has been established as a functional assay of HDL, and reflects the size of HDL particles. We investigated the clinical significance of FER(HDL) and its relationship to the quantity of HDL. FER(HDL) values were inversely correlated with levels of HDL-C and large lipoprotein containing apo A-I (LpA-I). The association between FER(HDL) and CHD changed with serum HDL-C levels: increased FER(HDL) values significantly increased the risk of CHD when serum HDL-C levels were low, while there was no such relationship when HDL-C levels were high. We concluded that the combination of HDL-C levels and FER(HDL) is a stronger indicator of CHD than either the HDL-C level (quantitative measure of HDL) or FER(HDL) (functional measure of HDL) alone.
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PMID:In vivo metabolism of HDL, apo A-I, and lp A-I, and function of HDL--a clinical perspective. 1142 83

Abnormal proliferation of keratinocytes in the skin appears crucial to the pathogenesis of psoriasis, but the underlying mechanisms remain unknown. Nitric oxide (NO), released from keratinocytes at high concentrations, is considered a key inhibitor of cellular proliferation and inducer of differentiation in vitro. Although high-output NO synthesis is suggested by the expression of inducible NO synthase (iNOS) mRNA and protein in psoriasis lesions, the pronounced hyperproliferation of psoriatic keratinocytes may indicate that iNOS activity is too low to effectively deliver anti-proliferative NO concentrations. Here we show that arginase 1 (ARG1), which substantially participates in the regulation of iNOS activity by competing for the common substrate L-arginine, is highly overexpressed in the hyperproliferative psoriatic epidermis and is co-expressed with iNOS. Expression of L-arginine transporter molecules is found to be normal. Treatment of primary cultured keratinocytes with Th1-cytokines, as present in a psoriatic environment, leads to de novo expression of iNOS but concomitantly a significant down-regulation of ARG1. Persistent ARG1 overexpression in psoriasis lesions, therefore, may represent a disease-associated deviation from normal expression patterns. Furthermore, the culturing of activated keratinocytes in the presence of an ARG inhibitor results in a twofold increase in nitrite accumulation providing evidence for an L-arginine substrate competition in human keratinocytes. High-output NO synthesis is indeed associated with a significant decrease in cellular proliferation as shown by down-regulation of Ki67 expression in cultured keratinocytes but also in short-term organ cultures of normal human skin. In summary, our data demonstrate for the first time a link between a human inflammatory skin disease, limited iNOS activity, and ARG1 overexpression. This link may have substantial implications for the pathophysiology of psoriasis and the development of new treatment strategies.
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PMID:Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. 1463 38

The polyamine pathway of protozoan parasites has been successfully targeted in anti-parasitic therapies and is significantly different from that of the mammalian host. To gain knowledge into the metabolic routes by which parasites synthesize polyamines and their precursors, the arginase gene was cloned from Leishmania mexicana, and Deltaarg null mutants were created by double targeted gene replacement and characterized. The ARG sequence exhibited significant homology to ARG proteins from other organisms and predicted a peroxisomal targeting signal (PTS-1) that steers proteins to the glycosome, an organelle unique to Leishmania and related parasites. ARG was subsequently demonstrated to be present in the glycosome, whereas the polyamine biosynthetic enzymes, in contrast, were shown to be cytosolic. The Deltaarg knockouts expressed no ARG activity, lacked an intracellular ornithine pool, and were auxotrophic for ornithine or polyamines. The ability of the Deltaarg null mutants to proliferate could be restored by pharmacological supplementation, either with low putrescine or high ornithine or spermidine concentrations, or by complementation with an arginase episome. Transfection of an arg construct lacking the PTS-1 directed the synthesis of an arg that mislocalized to the cytosol and notably also complemented the genetic lesion and restored polyamine prototrophy to the Deltaarg parasites. This molecular, biochemical, and genetic dissection of ARG function in L. mexicana promastigotes establishes: (i) that the enzyme is essential for parasite viability; (ii) that Leishmania, unlike mammalian cells, expresses only one ARG activity; (iii) that the sole vital function of ARG is to provide polyamine precursors for the parasite; and (iv) that ARG is present in the glycosome, but this subcellular milieu is not essential for its role in polyamine biosynthesis.
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PMID:Arginase plays a pivotal role in polyamine precursor metabolism in Leishmania. Characterization of gene deletion mutants. 1502 92

Cellular adhesion to extracellular matrix is a central phenomenon for the maintenance of tissue integrity and cellular movement. Collectively, these processes are regulated by a fine-tuned balance between the formation and loosening of adhesive contacts, a process involving integrins, and the elevation and diminution of cytoplasmic signalling molecules. We demonstrate that prostaglandin (PG) F(2alpha) stimulation rapidly increases the capacity of Ishikawa cells stably expressing the F-prostanoid receptor (FPS) to adhere to vitronectin. Coincident with this elevation in matrix adhesion, we demonstrate a profound PGF(2alpha)-induced alteration in cytoskeletal remodelling, characterized by polymerization of the actin cytoskeleton and recruitment of focal adhesion kinase at focal adhesions and enhanced cell migration. Moreover, we show that these PGF(2alpha)-induced alterations in adhesion and morphology on vitronectin and migration could be abolished by cultivating FPS cells in the presence of integrin alphavbeta3 antibody or alphavbeta3-directed tetrapeptide arg-gly-asp-ser or inhibition of FP receptor signalling with the FP receptor antagonist, chemical disruptors of the phospholipase C-beta, protein kinase A, c-Src and epidermal growth factor receptor kinase pathways or inhibition of the monomeric G proteins Rho, Rac and CDC42. These results reveal a mechanism by which prostanoids regulate cell movement, which may be relevant to pathologies of the endometrium.
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PMID:F-prostanoid receptor alters adhesion, morphology and migration of endometrial adenocarcinoma cells. 1796 20

Microglial activation and adaptive immunity have been implicated in the neurodegenerative processes in Parkinson disease. It has been proposed that these responses may be triggered by modified forms of alpha-synuclein (alpha-SYN), particularly nitrated species, which are released as a consequence of dopaminergic neurodegeneration. To examine the relationship between alpha-SYN, microglial activation, and adaptive immunity, we used a mouse model of Parkinson disease in which human alpha-SYN is overexpressed by a recombinant adeno-associated virus vector, serotype 2 (AAV2-SYN); this overexpression leads to slow degeneration of dopaminergic neurons. Microglial activation and components of the adaptive immune response were assessed using immunohistochemistry; quantitative polymerase chain reaction was used to examine cytokine expression. Four weeks after injection, there was a marked increase in CD68-positive microglia and greater infiltration of B and T lymphocytes in the substantia nigra pars compacta of the AAV2-SYN group than in controls. At 12 weeks, CD68 staining declined, but B- and T-cell infiltration persisted. Expression of proinflammatory cytokines was enhanced, whereas markers of alternative activation (i.e. arginase I and interleukins 4 and 13) were not altered. Increased immunoreactivity for mouse immunoglobulin was detected at all time points in the AAV2-SYN animals. These data show that overexpression of alpha-SYN alone, in the absence of overt neurodegeneration, is sufficient to trigger neuroinflammation with both microglial activation and stimulation of adaptive immunity.
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PMID:Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. 1901 46

The tumor microenvironment is heterogeneous for the expansion and infiltration by myeloid derived suppressor cells (MDSCs) which has been hypothesized to be dependent on tumor burden. We report a relationships between tumor size, MDSCs and T-cells; using four murine mammary tumors to assess tumor growth, infiltration and gene expression. Our analysis of cellular infiltration into tumors and gene expression used collagenase dissociated tumors and density gradient isolation of non-parenchymal cells (NPCs). The frequency of splenic and peripheral blood (PB) MDSCs was tumor dependent resulting in a significantly increased number of MDSCs. The MDSC frequency inversely correlated with the frequency of CD3+ lymphocytes in the spleen, independent of the tumor studied and directly correlated with tumor burden. Tumor growth up-regulated cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), granulocyte (G-) and granulocyte-monocyte-colony stimulating factor (GM-CSF), arginase-1 (ARG-1), and nitric oxide synthase-2 (NOS-2) transcription in the tumor and spleens (not VEGF-A). The frequency of splenic MDSCs directly correlated with splenic COX-2, NOS-2, and ARG-1 message levels, while COX-2 and NOS-2 transcript levels inversely correlated with splenic CD3+ cell frequency. COX-2 mRNA levels also directly correlated with the ARG-1 and NOS-2 transcript levels from tumor-infiltrating leukocytic cells, supporting prostaglandin E2 as a regulator of ARG-1 and NOS-2 transcription. In summary, MDSC numbers in the spleen and tumor microenvironment are tumor dependent, directly correlating with tumor size and inversely correlating with T-cell number. MDSCs are also directly associated with VEGF-A and G-CSF transcript levels suggesting multiple mechanisms for MDSC regulation and COX-2, NOS-2 and ARG-1 supporting multiple mechanisms of T-cell suppression.
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PMID:Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. 1936 67

ATP-binding cassette transporter A1 (ABCA1) is a cell membrane protein that exports excess cholesterol from cells to apolipoprotein (apo) A-I, the major protein in high density lipoproteins. Genetic studies have shown that ABCA1 protects against cardiovascular disease. The interaction of apoA-I with ABCA1 promotes cholesterol removal and activates signaling molecules, such as Janus kinase 2 (JAK2), that optimize the lipid export activity of ABCA1. Here we show that the ABCA1-mediated activation of JAK2 also activates STAT3, which is independent of the lipid transport function of ABCA1. ABCA1 contains two candidate STAT3 docking sites that are required for the apoA-I/ABCA1/JAK2 activation of STAT3. The interaction of apoA-I with ABCA1-expressing macrophages suppressed the ability of lysopolysaccaride to induce the inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, which was reversed by silencing STAT3 or ABCA1. Thus, the apoA-I/ABCA1 pathway in macrophages functions as an anti-inflammatory receptor through activation of JAK2/STAT3. These findings implicate ABCA1 as a direct molecular link between the cardioprotective effects of cholesterol export from arterial macrophages and suppressed inflammation.
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PMID:The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. 1978 54

Arginase catalyses the last step of the urea cycle. At least two isoenzymes of arginase are known; cytosolic ARG I and mitochondrial ARG II. ARG I is predominantly expressed in liver cytosol, as a part of urea cycle in ureotelic animals. The second isoform ARG II is primarily responsible for non-ureogenic functions, expressed in mitochondria of both hepatic and non-hepatic tissues in most vertebrates. Most micro-organisms and invertebrates are known to have only one type of arginase, whose function is unrelated to ornithine-urea cycle (OUC). However, in ureo-osmotic marine elasmobranchs arginase is localized in liver mitochondria as a part of OUC to synthesize urea for osmoregulation. An evolutionary transition occurred in arginase enzyme in terrestrial ureotelic vertebrates, with the evolution of ARG I from a pre-existing ancestral mitochondrial ARG II. This cytosolic ARG I activity is supposed to have first appeared in lung fishes, but the 40% and 60% distribution of arginase I and II activity in liver and kidney tissue of Heteropneustes fossilis indicates reconsideration of the above fact.
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PMID:Does fish represent an intermediate stage in the evolution of ureotelic cytosolic arginase I? 1990 Apr 9


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