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Potent Activation (potent + activation)

Distribution by Scientific Domains

Medical Sciences	50%
Life Sciences	50%

Selected Abstracts

Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-, induction in plasmacytoid dendritic cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2003
Gunther Hartmann
Abstract Two different types of CpG motif-containing oligonucleotides (CpG ODN) have been described: CpG-A with high induction of IFN-, in plasmacytoid dendritic cells; and CpG-B with little induction of IFN-,, but potent activation of B cells. In this study, we demonstrate that CpG-A fail to activate B cells unless plasmacytoid dendritic cells are present. We identified a new set of CpG ODN sequences which induces high levels of IFN-, in plasmacytoid dendritic cells but remains capable of directly activating B cells. These new CpG ODN (termed CpG-C) are more potent stimulants of B cells than CpG-B due to their ability of directly and indirectly (via plasmacytoid dendritic cells) activating B cells. The sequence of CpG-C combines structural elements of both CpG-A and CpG-B. The most potent sequence, M362, contains a 5,-end ,TCGTCG-motif' and a ,GTCGTT-motif', both of which are present in CpG-B (ODN,2006); a palindromic sequence characteristic for CpG-A (ODN,2216); but no poly,G motif required for CpG-A. In conclusion, we defined the first CpG-containing sequences that potently activate both TLR9-expressing immune cell subsets in humans, the plasmacytoid dendritic cell and the B cell. CpG-C may allow for improved therapeutic immuno-modulation in vivo. [source]

A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease

AGING CELL, Issue 2 2009
María Recuero
Summary Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging , the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This paper reports that, in human neuronal cells, oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system leads to apoptotic cell death. Microarray analyses showed a potent activation of the cholesterol biosynthesis pathway following reductions in the cell cholesterol synthesis caused by the X-XOD treatment; furthermore, the apoptosis was reduced by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) expression with an interfering RNA. The potential importance of this mechanism in AD was investigated by genetic association, and it was found that HMGCR, a key gene in cholesterol metabolism and among those most strongly upregulated, was associated with AD risk. In summary, this work presents a human cell model prepared to mimic the effect of oxidative stress in neurons that might be useful in clarifying the mechanism involved in free radical-induced neurodegeneration. Gene expression analysis followed by genetic association studies indicates a possible link among oxidative stress, cholesterol metabolism and AD. [source]

Apolipoprotein E and ,-amyloid (1,42) regulation of glycogen synthase kinase-3,

JOURNAL OF NEUROCHEMISTRY, Issue 5 2003
A. Cedazo-Mínguez
Abstract Glycogen synthase kinase-3, (GSK-3,) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and ,-amyloid (A,) 1,42 on GSK-3, and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca2+ -independent and early activation of GSK-3,. ApoE4 effects were biphasic, with an early strong GSK-3, activation that was partially dependent on extracellular Ca2+, followed by a GSK-3, inactivation. ApoE4 also activated PKC-, and PKB possibly giving the subsequent GSK-3, inhibition. A,(1,42) effects were also biphasic with a strong activation dependent partially on extracellular Ca2+ followed by an inactivation. A,(1,42) induced an early and potent activation of PKC-, and a late decrease of PKB activity. ApoE4 and A,(1,42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and A,(1,42)-induced early activation of GSK-3, could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3, through activation of upstream kinases likely compensates the effects of apoE4 and A,(1,42) on GSK-3,, the unbalanced regulation of which may contribute to AD pathology. [source]

Epidermal growth factor stimulates urokinase-type plasminogen activator expression in human gingival fibroblasts.

JOURNAL OF PERIODONTAL RESEARCH, Issue 6 2004
Possible modulation by genistein, curcumin
Background:, Regulation of the extracellular matrix turnover is a crucial process in wound healing and the progress of periodontal disease. It has been proposed that urokinase-type plasminogen activator (uPA), under the control of growth factors or cytokines, provides the proteolytic potential to the accomplishment of these cellular events. Epidermal growth factor (EGF) is one of the growth factors that has been shown to be active in uPA regulation. Methods:, In this study, we have assessed the effect of EGF on uPA expression in primary cultures of human gingival fibroblasts. We also studied the signaling pathways involved in this process and the role of the dietary phytoestrogens curcumin and genistein as potential modulators of this response. Results:, Human gingival fibroblasts expressed a basal uPA activity, which was inhibited by genistein, but not by curcumin. After treatment with 10 ng/ml EGF, uPA production was strongly stimulated. Exposure to genistein and curcumin inhibited EGF-stimulated urokinase production, although only genistein showed a statistically significant inhibitory response. Using more specific inhibitors, we found that the mitogen-activated extracellular kinase and c-Jun N-terminal kinase (JNK) inhibitors PD98059 and SP600125 also blocked the EGF-dependent stimulatory effect. On the other hand, SB203580, inhibitor of the p38 member of mitogen-activated protein kinase family, did not alter this response. In accordance to these findings, EGF stimulated a potent activation of JNK and a mild activation of extracellular signal-regulated kinases 1/2. Finally, EGF stimulated the phosphorylation of its receptor and tyrphostin (AG1478), curcumin and genistein were able to inhibit this stimulatory effect. Conclusions:, These results indicate that EGF constitutes a strong stimuli on uPA expression in human gingival fibroblasts. Our data also shows that EGF-stimulated uPA production involves the activation of the extracellular signal-regulated kinases 1/2 and JNK signaling pathways and might be modulated by the natural phytoestrogens curcumin and genistein. [source]