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)

Blood circulating in extracorporeal circuit of the apheresis sets has a contact with an artificial surface. The data on the influence of plateletpheresis on fibrinolytic activity are very limited and difficult to interpret. The aim of our study was to estimate the effect of plateletpheresis on the activation of fibrinolysis. Plateletpheresis was performed in 17 healthy blood donors using continuous-flow cell separator COM.TEC (Fresenius, Bad Homburg, Germany). Before and after plateletpheresis, blood samples were taken and markers of fibrinolysis (PAP, t-PA, PAI-1) as well as factor XII activity have been measured. We observed statistically significant decrease in t-PA and factor XII activities after plateletpheresis. There were no significant changes in concentrations of t-PA, PAI-1 and PAP as well as PAI-1 activity after plateletpheresis. Plateletpheresis performed by COM.TEC cell separator has very little, if any, effect on the activation of fibrinolysis. The mechanism of the inhibition of t-PA activity needs further investigations.
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PMID:The effect of continuous-flow automated plateletpheresis on fibrinolytic activity of donor plasma. 1610 10

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive function and early dementia or clinically probable Alzheimer's disease (AD). Oxidative stress plays a significant role in AD and is increased in the superior/middle temporal gyri of MCI subjects. Because AD involves hippocampal-resident memory dysfunction, we determined protein oxidation and identified the oxidized proteins in the hippocampi of MCI subjects. We found that protein oxidation is significantly increased in the hippocampi of MCI subjects when compared to age- and sex-matched controls. By using redox proteomics, we determined the oxidatively modified proteins in MCI hippocampus to be alpha-enolase (ENO1), glutamine synthetase (GLUL), pyruvate kinase M2 (PKM2) and peptidyl-prolyl cis/trans isomerase 1 (PIN1). The interacteome of these proteins revealed that these proteins functionally interact with SRC, hypoxia-inducible factor 1, plasminogen (PLG), MYC, tissue plasminogen activator (PLAT) and BCL2L1. Moreover, the interacteome indicates the functional involvement of energy metabolism, synaptic plasticity and mitogenesis/proliferation. Therefore, oxidative inactivation of ENO1, GLUL and PIN1 may alter these cellular processes and lead to the development of AD from MCI. We conclude that protein oxidation plays a significant role in the development of AD from MCI and that the oxidative inactivation of ENO1, GLUL, PKM2 and PIN1 is involved in the progression of AD from MCI. The current study provides a framework for future studies on the development of AD from MCI relevant to oxidative stress.
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PMID:Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. 1646 29

To improve the safety of cellular therapy products, it is necessary to establish a serum-free cell culture method that can exclude animal-derived materials in order to avoid contamination with transmissible agents. It would be optimal if the proteins necessary to a serum-free culture could be provided as recombinant proteins. In this study, the influences of recombinant artificial cell adhesive proteins on the behavior of human umbilical vein endothelial cells (HUVECs) in serum-free culture were examined in comparison with the influence of plasma fibronectin (FN). The recombinant proteins used were Pronectin F (PF), Pronectin F PLUS (PFP), Pronectin L (PL), Retronectin (RN), and Attachin (AN). HUVECs adhered more efficiently on PF or PFP than on FN. No cells adhered on PL. Regarding the VEGF or bFGF-induced cell growth, the cells on PF and PFP proliferated at a similar rate to the cells on FN. RN and AN were less effective in supporting cell growth. Since cell adhesion on PF and PFP induced phosphorylation of focal adhesion kinase, they are thought to activate integrin-mediated intracellular signaling. The cells cultured on PF or PFP were able to produce prostaglandin I(2) or tissue-plasminogen activator in response to thrombin. However, thrombin caused detachment of the cells from PF but not from PFP or FN, meaning that the cells were able to adhere more tightly on PFP or FN than on PF. These data indicate that PFP could be applicable as a substitute for plasma FN.
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PMID:Influences of the recombinant artificial cell adhesive proteins on the behavior of human umbilical vein endothelial cells in serum-free culture. 1732 Nov 46

FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress syndrome) has been considered as a serious complication of FES, the pathogenesis of ARDS associated with FES remains unclear. In the present study, we investigated the clinical manifestations, and biochemical and pathophysiological changes, in subjects associated with FES and ARDS, to elucidate the possible mechanisms involved in this disorder. A total of eight patients with FES were studied, and arterial blood pH, PaO(2) (arterial partial pressure of O(2)), PaCO(2) (arterial partial pressure of CO(2)), biochemical and pathophysiological data were obtained. These subjects suffered from crash injuries and developed FES associated with ARDS, and each died within 2 h after admission. In the subjects, chest radiography revealed that the lungs were clear on admission, and pulmonary infiltration was observed within 2 h of admission. Arterial blood pH and PaO(2) declined, whereas PaCO(2) increased. Plasma PLA(2) (phospholipase A(2)), nitrate/nitrite, methylguanidine, TNF-alpha (tumour necrosis factor-alpha), IL-1beta (interleukin-1beta) and IL-10 (interleukin-10) were significantly elevated. Pathological examinations revealed alveolar oedema and haemorrhage with multiple fat droplet depositions and fibrin thrombi. Fat droplets were also found in the arterioles and/or capillaries in the lung, kidney and brain. Immunohistochemical staining identified iNOS (inducible nitric oxide synthase) in alveolar macrophages. In conclusion, our clinical analysis suggests that PLA(2), NO, free radicals and pro-inflammatory cytokines are involved in the pathogenesis of ARDS associated with FES. The major source of NO is the alveolar macrophages.
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PMID:Clinical and pathological features of fat embolism with acute respiratory distress syndrome. 1742 99

Relative specific amino acid dependency is one of the metabolic abnormalities of melanoma cells and metabolic studies of this dependency are in their infancy. Herein, we review the current studies in this area and present new information that adds to the understanding of how tyrosine (Tyr) and phenylalanine (Phe) dependency as well as other amino acids regulate the cell behaviors of melanoma cells. Amino acid dependency of human melanoma cells is multifactorial and restricting Tyr and Phe to melanoma triggers a series of alterations in metabolic and signaling pathways in a time-ordered fashion to alter different cellular behaviors. For example, at early time points, the reduction of Tyr and Phe alters metabolic reactions quantitatively or qualitatively. The alterations include modulation of integrin/focal adhesion kinase (FAK)/G protein pathways and the plasminogen activator (PA)/PA inhibitor pathways to inhibit tumor cell invasion. At later time periods, a further drop in intracellular amino acids induces more metabolic alterations to impact the FAK/Ras/Raf and Bcl-2 pathways leading to apoptosis. The threshold effects and the targeting of multiple pathways by restriction of specific amino acids provide a connection between the metabolic alterations and signaling pathways that modulate the cellular behaviors of melanoma cells. Decoding the metabolic alterations that connect amino acid concentration to the crucial step(s) in signaling is important and an exciting area of cancer research.
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PMID:Specific amino acid dependency regulates the cellular behavior of melanoma. 1751 32

A 22-year-old woman with advanced AIDS presented with altered mental status. A brain magnetic resonance imaging and angiogram showed extensive dural sinus thromboses of the sagittal and bilateral transverse sinuses. CD4 level was low (<15/mm3) and a significant low protein S (7%; normal 54-137%) and C (41%; normal 72-147%) levels were detected. No other hypercoagulable factors were identified. Successful treatment was done with heparin and plasminogen activator catheter-directed thrombolysis were administered. A variety of haematological abnormalities have been observed in human immunodeficiency virus infection. Advanced AIDS might be considered as an acquired hypercoagulable state.
Int J STD AIDS 2008 Jan
PMID:An acute intracerebral vein thromboses in AIDS with protein C and S deficiency. 1827 52

The recombinant two kringle domain of human tissue-type plasminogen activator (TK1-2) has been shown to inhibit endothelial cell proliferation, angiogenesis, and tumor cell growth despite of sharing a low amino acid sequence homology with angiostatin. Here, we explored a possible inhibitory mechanism of action of TK1-2 by focusing on antimigratory effect. TK1-2 effectively inhibited endothelial cell migration induced by basic fibroblast growth factor or vascular endothelial growth factor in a dose-dependent manner and tube formation on Matrigel. It blocked basic fibroblast growth factor-induced or vascular endothelial growth factor-induced phosphorylation of extracellular signal-regulated kinase 1/2 and formation of actin stress fibers and focal adhesions. Interestingly, TK1-2 alone induced the weak phosphorylation of focal adhesion kinase, whereas it inhibited focal adhesion kinase phosphorylation induced by growth factors. When immobilized, TK1-2 promoted adhesion and spreading of endothelial cells compared with bovine serum albumin. However, treatment with anti-alpha(2)beta(1) blocking antibody markedly diminished endothelial cell adhesion to immobilized TK1-2 compared with anti-alpha(v)beta(3) or anti-alpha(5)beta(1) antibody. Pretreatment of soluble TK1-2 also altered the binding level of anti-alpha(2)beta(1) antibody to endothelial cells in fluorescence-activated cell sorting analysis. Indeed, a blocking antibody against integrin alpha(2)beta(1) or knocking down of integrin alpha(2) expression prevented the inhibitory effect of TK1-2 in cell migration. Therefore, these results suggest that TK1-2 inhibits endothelial cell migration through inhibition of signaling and cytoskeleton rearrangement in part by interfering with integrin alpha(2)beta(1).
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PMID:Antimigratory effect of TK1-2 is mediated in part by interfering with integrin alpha2beta1. 1864 23

Continuous recruitment and inappropriate activity of platelets in the airways may contribute to airway remodeling, a characteristic feature of inflammatory airway diseases that includes increased proliferation of the smooth muscle. The aim of the present investigation was to examine the effect of platelets on proliferation of airway smooth muscle cells (ASMC) in culture and to determine the possible role of 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) in this context. ASMC obtained from guinea pigs were cultured and co-incubated with washed platelets for 24 hours. Thereafter, the proliferation was measured with the MTS-assay; the results were also verified by using thymidine incorporation, DNA measurements and manual counting. The interaction between platelets and ASMC was visualized with fluorescence microscopy. We found that platelets bind to the ASMC and the presence of platelets caused a significant dose-dependent increase in ASMC proliferation. Co-incubation of ASMC with platelets also increased ROS-production, detected by the fluorescent probe DCFDA. Furthermore, the platelet-induced proliferation was reduced in the presence of the NADPH-oxidase inhibitors DPI and apocynin. A possible role of 5-LOX in platelet-induced proliferation and ROS-generation was evaluated by using the 5-LOX inhibitor AA-861 and the PLA(2)-inhibitor ATK. The results showed that inhibition of these enzymes significantly reduced the platelet-induced proliferation. Moreover, Western blot analysis revealed that the ASMC but not the platelets express 5-LOX. In addition, our experiments revealed that the presence of AA-861 and ATK significantly inhibited the ROS-production generated upon co-incubation of platelets and ASMC. In conclusion, we show that platelets have a marked capacity to induce ASMC proliferation. Furthermore, our study indicates that the interaction between platelets and ASMC leads to activation of 5-LOX in the ASMC followed by an increased ROS-production, events resulting in enhanced ASMC proliferation. The new findings are of importance in understanding possible mechanisms contributing to airway remodeling.
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PMID:Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species. 1897 65

Toll-like receptors (TLRs) play an important role in innate immunity. They detect pathogen-associated receptor patterns (PAMPs) and initiate subsequent immune responses. Present studies investigate the influence of TLR2 ligands on leukotrienes (LT) formation in human monocytes. LTs are proinflammatory mediators derived from arachidonic acid (AA), which is released from membranes by phospholipase A(2) (PLA(2)) enzymes. Pretreatment of MM6 cells with the TLR2 ligands LTA, FSL-1, or Pam(3)CSK(4) resulted in an up to two- to threefold enhancement of ionophore-induced LT formation in a dose- and time-dependent manner and to an augmentation of ionophore-induced AA release with similar kinetics. Also in human peripheral blood mononuclear cells (hPBMC), TLR2 activators increased LT formation. Studies with PLA(2) inhibitors indicated that the increase of AA release is a result of enhanced activity of group IV cPLA(2) in MM6 cells. TLR2 ligands elicited the time-dependent activation of p38 MAPK and ERK1/2 pathways, which led to phosphorylation of cPLA(2)alpha at Ser(505). Simultaneous inhibition of p38 MAPK and ERK1/2 pathways prevented the increase of cPLA(2)alpha phosphorylation and the augmentation of AA release. TLR2 ligand-induced increase of AA release was blocked by a neutralizing anti-hTLR2 antibody, indicating that TLR2 mediates augmented cPLA(2) activation and subsequent LT biosynthesis.
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PMID:TLR2 ligands augment cPLA2alpha activity and lead to enhanced leukotriene release in human monocytes. 1940 82

Although the introduction of t-PA (tissue plasminogen activator) was considered radical treatment for acute cerebral ischemic disease, the actual number of cases for such administration was limited in Japan for many reasons; one such reason was related to the ability of EMT (emergency medical technician) paramedics to transport patients to the proper hospital for treatment within 2 hours of onset. From this point of view, the Committee of the Prehospital Stroke Life Support (PSLS) of the Japanese Society for Emergency Medicine (JSEM) developed an original standard for prehospital treatment of stroke. In this paper, the author provides an overview of PSLS and the half-day practical course, which has been widely disseminated over a short period of time.
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PMID:Introduction of the standard prehospital stroke life support (PSLS) training of EMS paramedics for the prehospital management of cerebrovascular disease in Japan. 2022 8


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