Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fractional rate of cholesterol esterification in very low density lipoprotein- and low density lipoprotein-depleted plasma (FERHDL) was studied in normolipidemic subjects and in individuals with hyperlipidemia and proven coronary artery disease (CAD). The FERHDL was significantly higher than the FER in whole plasma and was significantly higher in normal men than in normal women. In addition, men and women with primary hyperlipidemia had significantly higher FERHDL values relative to their sex-matched controls. The most significant increases in FERHDL values, however, were observed in individuals with CAD. In all patient groups, FERHDL was positively correlated with plasma triglyceride concentration. In addition, FERHDL was negatively related to plasma high density lipoprotein (HDL) cholesterol concentration in all groups except in men with CAD and in normolipidemic women. The gradient gel electrophoretic pattern of HDL from individuals with either low or high FERHDL values indicated an inverse relation between this activity and the relative amount of HDL2b particles. FERHDL likely reflects the metabolic properties of the heterogeneous population of HDL particles in the plasma and may be a function of the relative content of larger and smaller HDL particles. It appears to be a sensitive and reliable functional measure of the particle size distribution in the HDL pool and one of potential clinical value in the assessment of risk for CAD.
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PMID:Cholesterol esterification rates in very low density lipoprotein- and low density lipoprotein-depleted plasma. Relation to high density lipoprotein subspecies, sex, hyperlipidemia, and coronary artery disease. 198 5

Analytical performance of the Boehringer Mannheim/Hitachi 717 system was evaluated in a multicenter study involving seven different laboratories. Fifty-five methods including end point chemistries, enzymes, ISE, TDM, DAU, and specific protein assays were assessed over a 7 month period. Methods on the analyzer exhibited excellent precision with CVs less than 2% for within run precision, and CVs less than 3% for between day precision for most analytes; linearity, which met or exceeded manufacturer's claims; minimal sample and reagent carryover, and no significant interference from hemolysis; icterus; and lipemia. Recovery of the assigned value for 10 analytes in SRM 909 was acceptable. Comparison of methods with other BM/Hitachi analyzers resulted in slopes close to unity (0.93-1.06); comparison to other clinical chemistry analyzers yielded slopes of 0.88-1.07. Excellent performance and diverse method applications make the BM/Hitachi 717 analyzer a suitable instrument for work station consolidation.
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PMID:A multicenter evaluation of the Boehringer Mannheim/Hitachi 717 system. 228 5

Lipoprotein lipase (LPL) is important in the process of triglyceride storage in adipose tissue. Depression of LPL activity in adipose tissue is associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced wasting syndrome and may have a role in the associated serum hyperlipidemia produced by TCDD. The 3T3-L1 cell line was used as an in vitro model, independent of hormonal, nutritional, or other interfering factors associated with in vivo studies, in order to systematically examine the mechanism of action of TCDD. TCDD produced a statistically significant (P < 0.05) time- and dose-dependent decrease in LPL activity. Results of experiments with Ah-receptor blockers and structure activity studies with different polychlorinated biphenyl (PCB) and dioxin congeners were consistent with reduction of LPL activity being mediated by the Ah receptor. Culturing of 3T3-L1 cells without glucose or with cytochalasin B, a blocker of facilitative glucose transporters (GLUT), was effective in reducing LPL activity (P < 0.05). TCDD did not further reduce LPL activity in cytochalasin B pretreated 3T3-L1 cells or in 3T3-L1 cells cultured in glucose-free media. Dexamethasone pretreatment, which is known to increase GLUT expression in 3T3-L1 cells, prevented the reduction of LPL activity by TCDD. Protein tyrosine kinase activities, assayed using gamma-32P-ATP and RR-SRC, a src specific peptide substrate, were significantly increased (P < 0.05) over control levels by both TCDD and glucose deprivation. Furthermore, results of experiments treating 3T3-L1 cells with either insulin, EGF, 8-Br-cAMP, TPA, or genistein, alone or in combination with TCDD, were generally consistent with the hypothesis that lowered intracellular glucose and altered cellular kinase activities may be involved in reduction of LPL activities by TCDD. Further work is needed to confirm and better understand the role protein phosphorylation plays in TCDD-mediated alteration of glucose disposition and LPL activity. In summary, TCDD reduced LPL activity in 3T3-L1 cells as seen in vivo. Manipulation of glucose transport through a number of experimental approaches produced changes in 3T3-L1 LPL activity consistent with results of previous investigators showing glucose to be a positive regulator of LPL activity and consistent with our hypothesis that TCDD-mediated reduction of glucose transport is an important factor in the down regulation of LPL activity by TCDD.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin mechanism of action to reduce lipoprotein lipase activity in the 3T3-L1 preadipocyte cell line. 941 85

Insulin exerts wide variety of biological effects through interaction with its specific receptor, which belongs to a large family of receptor tyrosine kinases. The activated insulin receptor phosphorylates the intracellular substrate IRS protains, which then bind various signalling molecules that contain Src homology 2 domains. The first downstram molecule that was shown to associate with IRS protains is PI3-kinase. PI3-kinase contributes to a wide variety of biological actions. Both Akt(PKB), a serine-threonine kinase with a PH domain, and atypical PKC(PKC zeta, PKC lambda) have been implicated as downstream effectors of PI3-kinase. Insulin resistance contributes to the pathogenesis of NIDDM. Both primary, genetically, and secondary, environmentally factors are important for insulin resistance. The secondary factors include hyperglycemia, hyperlipidemia, obesity, TNF alpha, FFA(free fatty acid).
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PMID:[Insulin signalling system and mechanism of insulin resistance]. 1070 48

Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities.
Int J STD AIDS 2001 Sep
PMID:The metabolic toxicities of antiretroviral therapy. 1151 63

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
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PMID:Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. 1459 82

Leptin regulates energy balance and body weight by activating its receptor LEPRb and multiple downstream signaling pathways, including the STAT3 and the IRS2/PI 3-kinase pathways, in the hypothalamus. Leptin stimulates activation of LEPRb-associated JAK2, which initiates cell signaling. Here we identified SH2-B, a JAK2-interacting protein, as a key regulator of leptin sensitivity, energy balance, and body weight. SH2-B homozygous null mice were severely hyperphagic and obese and developed a metabolic syndrome characterized by hyperleptinemia, hyperinsulinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia. The expression of hypothalamic orexigenic NPY and AgRP was increased in SH2-B(-/-) mice. Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hypothalamic STAT3 and IRS2 were significantly impaired in SH2-B(-/-) mice. Moreover, overexpression of SH2-B counteracted PTP1B-mediated inhibition of leptin signaling in cultured cells. Our data suggest that SH2-B is an endogenous enhancer of leptin sensitivity and required for maintaining normal energy metabolism and body weight in mice.
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PMID:Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. 1609 27

Approximately 50% of patients on highly active antiretroviral therapy (HAART) develop lipodystrophy with central and visceral fat accumulation and/or facial and limb atrophy. Although the exact mechanisms of this are not fully understood, the facial atrophy encountered is secondary to atrophy of the subcutaneous fat, and not the deeper fat pads, as has been suggested. More recently, the above features in combination with hyperlipidaemia and insulin resistance have been described and are referred to as HIV-related fat redistribution syndrome. This review looks at treatment options available for this stigmatizing condition.
Int J STD AIDS 2006 Apr
PMID:Facial atrophy in HIV-related fat redistribution syndrome: a plastic surgical perspective on treatment options and a look to the future. 1659 41

SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.
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PMID:Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. 1723 96

Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC)in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier-protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrier-protective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rac activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection.
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PMID:Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. 1729 25


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