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Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Heparan sulfate that occurs on cell surfaces is structurally similar to heparin, but unlike heparin it contains N-acetylated residues and is less sulfated. HS chains gain their structural variability by incomplete modification (acetylation, sulfation, epimerization), and sulfate residues are often clustered within short functional domains. HS proteoglycans (HSPGs) play a predominant role in fine-tuning the mammalian physiology because almost all molecules, present in the ECM, contain binding sites for HS. They act as co-receptors for growth factors and their receptor tyrosine kinases and transport chemokines across cells; they further activate adhesion mechanisms or enhance cell mobility (see, e.g., Bishop et al., 2007, for a review). For example, fibroblast growth factor (FGF) signaling, essential for cell proliferation, differentiation, migration, etc., requires the formation of a ternary complex where FGF and FGF receptor (FGFR) are linked by a HS chain, with the three components being present in a ratio of 2:2:2, as found by Rosenberg and his colleagues (Wu et al., 2003). Zong et al. (2017) constructed a HS microarray from 47 HS-oligosaccharides to study the binding/ligand requirements of HS-binding proteins including fibroblast growth factor 2 (FGF-2), and the chemokines CCL2, CCL5, CCL7, CCL13, CXCL8, and CXCL10.
Toxicity and occupational exposure assessment for hydroprocessed esters and fatty acids (HEFA) alternative jet fuels
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Teresa R. Sterner, Brian A. Wong, Karen L. Mumy, R. Arden James, James Reboulet, Darol E. Dodd, Richard C. Striebich, David R. Mattie
There were only minimal changes in gene expression at 200 mg/m3. The predominant changes in gene expression occurred at 2000 mg/m3 and predominantly involved chemokine genes. Overall, male and female rats displayed similar concentration response effects, both in magnitude and direction of changes in gene expression. More specifically, a single gene (IL1F6 = Interleukin 1 family member 6) was significantly upregulated at ≥200 mg/m3; fold changes were less than 2 across exposures. At 700 mg/m3 there were 32 genes with significant differential expression and 53 at 2000 mg/m3, with 29 of those common to both concentrations. The magnitude of changes in gene expression at the 200 and 700 mg/m3 was low, however, with only a single gene (SPP1, Secreted Phosphoprotein 1) demonstrating a fold change greater than 2 (2.8 at 700 mg/m3) with an elevation to 16.2 at 2000 mg/m3. There were 13 genes at 2000 mg/m3 that exhibited a fold change of greater than 2. The 13 included SPP1, integrin alpha M (ITGAM), interleukin 1 receptor type II (IL1R2), and C-C motif chemokine receptor 8 (CCR8); 9 were chemokine ligands (CCL2, CCL12 CCL22, CCL7, CCL17, CCL9, CXCL10, CXCL11 and CXCL6).