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- Johansson, Maria E, 1977, et al.
(författare)
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Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice
- 2014
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 44:10, s. 3081-3092
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-kappa B-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.
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- Ackloo, S, et al.
(författare)
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Target 2035 - an update on private sector contributions
- 2023
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Ingår i: RSC medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 14:6, s. 1002-1011
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging ‘open’ principles to develop a pharmacological tool for every human protein.
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- Bu, D. X., et al.
(författare)
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Nuclear factor {kappa}B-mediated transactivation of telomerase prevents intimal smooth muscle cell from replicative senescence during vascular repair
- 2010
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Ingår i: Arterioscler Thromb Vasc Biol. - 1524-4636 .- 1079-5642. ; 30:12, s. 2604-10
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To gain insights into mechanisms by which intimal hyperplasia interferes with the repair process by investigating expression and function of the catalytic telomerase reverse transcriptase (TERT) subunit after vascular injury. METHODS AND RESULTS: Functional telomerase is essential to the replicative longevity of vascular cells. We found that TERT was de novo activated in the intima of injured arteries, involving activation of the nuclear factor kappaB pathway. Stimulation of the isolated intimal smooth muscle cell (SMC) by basic fibroblast growth factor or tumor necrosis factor alpha resulted in increased TERT activity. This depends on the activation of c-Myc signaling because mutation of the E-box in the promoter or overexpression of mitotic arrest deficient 1 (MAD1), a c-Myc competitor, abrogated the transcriptional activity. Inhibition of nuclear factor kappaB in both intimal SMCs and the injured artery attenuated TERT transcriptional activity through reduction of c-Myc expression. Pharmacological blockade of TERT led to SMC senescence. Finally, depletion of telomerase function in mice resulted in severe intimal SMC senescence after vascular injury. CONCLUSIONS: These results support a model in which vascular injury induces de novo expression of TERT in intimal SMCs via activation of nuclear factor kappaB and upregulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia.
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- Muller, S, et al.
(författare)
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Target 2035 - update on the quest for a probe for every protein
- 2022
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Ingår i: RSC medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 13:1, s. 13-21
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. Target 2035 aims to develop a pharmacological modulator for every protein in the human proteome to fill this gap.
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