Among transcriptional regulatory proteins described, NF-kappaB seems particularly important in modulating the expression of immunoregulatory genes relevant in critical illness, inflammatory diseases, apoptosis, and cancer. In particular, NF-kappaB plays a central role in regulating the transcription of cytokines, adhesion molecules, and other mediators. The biochemical basis by which diverse stimuli converge to activate or intervene this family of transcription factors is still largely unknown. The NF-kappaB transcription factor family represents an important group of regulators of a broad range of genes involved in cellular responses to inflammatory and other kinds of signals. Knockout mouse studies have also revealed a key role for this family in broad physiological processes, including immune function and metabolism. Overall, specificity seems to exist in the role of each transcriptional complex in gene transcription and physiological function. Each NF-kappaB complex displays distinct affinities for the different DNA-binding sites present in the promoters of NF-kappaB-regulated genes, and this may contribute to some of the specificity exhibited. The identification of specific components of the NF-kappaB signal transduction pathway provides an opportunity to define mechanisms at the biochemical level by which specific members of the NF-kappaB family are activated. Furthermore, this may identify specific targets for selective inhibition or promotion of NF-kappaB functions. Further studies will be required to elucidate mechanisms regulating specificity and selectivity of NF-kappaB function, as well as its role in different diseases, prior to potential clinical application.
The alternatively spliced and highly conserved EIIIA domain of fibronectin (FN) is included in most FN of the extracellular matrix in embryos. In adults, both extracellular matrix and plasma FN essentially lack EIIIA. In diverse inflammatory situations however, EIIIA is specifically included by regulated RNA splicing. In atherosclerotic lesions, FN, including the EIIIA domain (EIIIA-FN), is abundant, whereas FN in the flanking vessel wall lacks EIIIA. Lesional EIIIA-FN is localized with endothelial cells and macrophage foam cells. To directly test the function of EIIIA-FN, we generated EIIIA-null (EIIIA ؊/؊ ) mice that lack the EIIIA exon and crossed them with apolipoprotein E (ApoE)-null (ApoE ؊/؊ ) mice that develop arterial wall lesions. Compared with ApoE ؊/؊ controls, EIIIA ؊/؊ ApoE ؊/؊ mice had significantly smaller lesions throughout the aortic tree. EIIIA-FN was increased in ApoE ؊/؊ plasma, and total plasma cholesterol was reduced in EIIIA ؊/؊ ApoE ؊/؊ mice, specifically in large lipoprotein particles, suggesting a functional role for plasma EIIIA- IntroductionFibronectins (FNs) are best known as a family of ligands for the integrin family of adhesion and signaling receptors. [1][2][3][4] FNs are essential for heart and blood vessel development, 5,6 and their polymerization regulates extracellular matrix (ECM) composition and organization. 7 FN variants are generated from a single gene by alternative RNA splicing of the V, EIIIA, and EIIIB segments, which are also known as CS-1, ED-A, and ED-B segments, respectively, 8 and the (V ϩ C) region. 9 EIIIA and EIIIB are type III repeats that are included or excluded from the FN monomer. Gene targeting experiments have shown that plasma FN, which lacks EIIIA and EIIIB, but includes V/CS-1, reduces brain injury by promoting neuronal survival 10 and also functions in thrombus growth and stability. 11 EIIIA-containing fragments are present in synovial fluid in arthritis 12 and in plasma of patients with vascular 13 and pulmonary injury. 14 EIIIA peptide can induce expression of proinflammatory cytokines interleukin 1␣ (IL-1␣) and IL-1, and matrix metalloproteinases. 15 High-sequence conservation of EIIIA and EIIIB (Ͼ 95% among mammals) and regulated expression [16][17][18] suggest that they are functional. In vitro, EIIIA-FN mediates wound healing in liver by inducing stellate cells to differentiate into myofibroblasts, which promote fibrosis. 19,20 EIIIA-FN is also up-regulated during cutaneous wound healing 21 and may have a functional role. 22 Skin fibroblasts respond to EIIIA-FN in vitro by differentiating to a fibrotic phenotype. 23 EIIIA-FN is also secreted by infiltrating leukocytes and deposited in the myocardium of rejecting cardiac allografts. 24 FN alternative exons have also been shown to be binding sites for integrins. The alternative V/CS-1 segment is a binding site for leukocyte integrins ␣41 and ␣47. 25,26 Of particular interest, the alternative EIIIA domain is a ligand for leukocyte integrins: ␣91 and ␣41. 27 In the chronic inflammation tha...
Ischemic stroke is a major cause of disability and mortality worldwide, but effective restorative treatments are very limited at present. Regenerative medicine research revealed that stem cells are promising therapeutic options. Dental pulp stem cells (DPSCs) are autologously applicable cells that origin from the neural crest and exhibit neuro-ectodermal features next to multilineage differentiation potentials. DPSCs are of increasing interest since they are relatively easy to obtain, exhibit a strong proliferation ability, and can be cryopreserved for a long time without losing their multi-directional differentiation capacity. Besides, use of DPSCs can avoid fundamental problems such as immune rejection, ethical controversy, and teratogenicity. Therefore, DPSCs provide a tempting prospect for stroke treatment.
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