Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5684975 | Translational Research | 2017 | 13 Pages |
Abstract
Obesity-induced insulin resistance and metabolic syndrome continue to pose an important public health challenge worldwide as they significantly increase the risk of type 2 diabetes and atherosclerotic cardiovascular disease. Advances in the pathophysiologic understanding of this process has identified that chronic inflammation plays a pivotal role. In this regard, given that both animal models and human studies have demonstrated that the interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin is not only critical for normal immune response but also is upregulated in the setting of metabolic syndrome, PSGL-1/P-selectin interactions provide a novel target for preventing and treating resultant disease. Current approaches of interfering with PSGL-1/P-selectin interactions include targeted antibodies, recombinant immunoglobulins that competitively bind P-selectin, and synthetic molecular therapies. Experimental models as well as clinical trials assessing the role of these modalities in a variety of diseases have continued to contribute to the understanding of PSGL-1/P-selectin interactions and have demonstrated the difficulty in creating clinically relevant therapeutics. Most recently, however, computational simulations have further enhanced our understanding of the structural features of PSGL-1 and related glycomimetics, which are responsible for high-affinity selectin interactions. Leveraging these insights for the design of next generation agents has thus led to development of a promising synthetic method for generating PSGL-1 glycosulfopeptide mimetics for the treatment of metabolic syndrome.
Keywords
NF-κBsLeAspecialized pro-resolving mediatorSialyl Lewis ASLexTIMIPSGL-1PPAR-αVCAMICAMGSPTLR2SPMMCP-1ACE-IPLGAEGFJnkc-Jun N-terminal kinasescDNAMPOComplementary DNAsialyl Lewis Xperoxisome proliferator-activated receptor alphaAngiotensin converting enzyme inhibitorsChoChinese Hamster OvaryThrombolysis In Myocardial Infarctionshort consensus repeatEndothelial cellSialyltransferaseepidermal growth factornuclear factor-κBP-selectin glycoprotein ligand-1intracellular adhesion molecule 1myeloperoxidaseNitric oxidemonocyte chemoattractant protein 1vascular cell adhesion protein 1poly(lactic-co-glycolic acid)Toll-like receptor 2SCR
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Authors
Madhukar S. Patel, David Miranda-Nieves, Jiaxuan Chen, Carolyn A. Haller, Elliot L. Chaikof,