Search results for "enzyme activation"
showing 10 items of 304 documents
The Unfolded Protein Response Plays a Predominant Homeostatic Role in Response to Mitochondrial Stress in Pancreatic Stellate Cells.
2016
Activated pancreatic stellate cells (PaSC) are key participants in the stroma of pancreatic cancer, secreting extracellular matrix proteins and inflammatory mediators. Tumors are poorly vascularized, creating metabolic stress conditions in cancer and stromal cells that necessitate adaptive homeostatic cellular programs. Activation of autophagy and the endoplasmic reticulum unfolded protein response (UPR) have been described in hepatic stellate cells, but the role of these processes in PaSC responses to metabolic stress is unknown. We reported that the PI3K/mTOR pathway, which AMPK can regulate through multiple inputs, modulates PaSC activation and fibrogenic potential. Here, using primary a…
Statins and the squalene synthase inhibitor zaragozic acid stimulate the non-amyloidogenic pathway of amyloid-beta protein precursor processing by su…
2010
Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (AbetaPP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates alpha-secretase activity. Treatment of human n…
Alpha-secretase as a therapeutic target.
2007
In the non-amyloidogenic pathway the alpha-secretase cleaves the amyloid precursor protein (APP) within the sequence of Abeta-peptides and precludes their formation. In addition, alpha-secretase cleavage releases an N-terminal extracellular domain with neurotrophic and neuroprotective properties. The disintegrin metalloproteinase ADAM10 has been shown to act as alpha-secretase in vivo, to prevent amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. An increase in alpha-secretase activity therefore is an attractive strategy for treatment of AD and may be achieved by modulating selective signalling pathways. Functional characterization of the human ADAM10 prom…
Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on rac proteins
2006
Abstract We have shown recently that the azathioprine metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes. In the present study, we describe a new molecular mechanism by which 6-Thio-GTP blocks GTPase activation. Although 6-Thio-GTP could bind to various small GTPases, it specifically blocked activation of Rac1 and Rac2 but not of closely related Rho family members such as Cdc42 and RhoA in primary T cells upon stimulation with αCD28 or fibronectin. Binding of 6-Thio-GTP to Rac1 did not suppress Rac effector coupling directly but blocked Vav1 exchange activity upon 6-Thio-GTP hydrolysis, suggesting that 6-Thio-GTP loading leads to accumulation of…
Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-beta activity
2010
At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of r…
Characterization of collagenase 3 (matrix metalloproteinase 13) messenger RNA expression in the synovial membrane and synovial fibroblasts of patient…
1999
Objective To study the localization and cell type–specific expression of collagenase 3 messenger RNA (mRNA) in the synovial membrane, its regulation in primary synovial fibroblasts, and the correlation with systemic markers of inflammation and radiographic damage in rheumatoid arthritis (RA). Methods The expression of collagenase 3 mRNA was characterized by Northern blot analysis, reverse transcriptase–polymerase chain reaction, and in situ hybridization. Immunohistochemical detection of cell type–specific antigens was used in combination with in situ hybridization of collagenase 3 mRNA to characterize the cellular origin of collagenase 3 mRNA expression. Results Collagenase 3 mRNA was dete…
Kallikrein–kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys
2009
In a subgroup of hereditary angioedema (HAE) patients with normal C1-esterase inhibitor levels, HAE is caused by a Thr309Lys mutation in the coagulation factor XII (F12) gene. The aim of this study was to examine elements of the kallikrein-kinin system ('contact system') and the downstream-linked coagulation, complement and fibrinolytic systems in the plasma of six patients with HAE caused by the Thr309Lys mutation and healthy probands. Blood samples were taken from participants during the symptom-free interval between attacks. Samples were analyzed for activity and concentrations of components of the kallikrein-kinin system and linked enzyme systems. The mean FXII clotting activity was 90%…
Sulfatide excreting heterozygous carrier of juvenile metachromatic leukodystrophy or asymptomatic patient of adult metachromatic leukodystrophy.
1975
In a family with juvenile metachromatic leukodystrophy (sulfatide lipidosis) 2 patients showed residual arysulfatase A activities of 5--6%. The patients' healthy father was characterized biochemically by a 39% normal activity of leukocyte plus plasma arylsulfatase A. The father was further characterized by a high sulfatide excretion (0.2--0.5 mg/I urine) and, paradoxically, by a normal sulfatide degrading enzyme activity in vitro. This special carrier is suspected to be heterozygous for a) arylsulfatase A deficiency and b) arylsulfatase A (sulfatidase) lability. This presumed additional genetic defect could be the cause of the sulfatide excretion which, in turn, would be a sign of the precl…
Identification of glyoxalase 1 polymorphisms associated with enzyme activity.
2013
The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glycation end products (AGEs), such as methylglyoxal (MG) and other reactive dicarbonyls, the formation of which is increased in diabetes patients as a result of excessive glycolysis. MG is partly responsible for harmful protein alterations in living cells, notably in neurons, leading to their dysfunction, and recent studies have shown a negative correlation between GLO1 expression and tissue damage. Neuronal dysfunction is a common diabetes complication due to elevated blood sugar levels, leading to high levels of AGEs. The aim of our study was to determine whether single nucleotide polymorphisms (S…
β-Amyloid-induced activation of Caspase-3 in primary cultures of rat neurons
2000
It is known that beta-amyloid peptide (Abeta) contributes to the neurodegeneration in Alzheimer's disease (AD) and operates through activation of an apoptotic pathway. Apoptotic signal is driven by a family of cysteine proteases called caspases. The beta-amyloid precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated beta-amyloid peptide formation. Cerebellar neurons from rat pups were treated with the aged Abeta(25-35) at 1 and 5 microM and fluorescence assays of caspase activity performed over 4 days. We observed an increase in caspase activity after 48 h treatment in both 1 and 5 microM treated cells, then (72-96 h) caspase activity…