Diabetes affects an increasing number of patients, and is associated with sustained and chronic inflammation. Complications arising from diabetes, including hypoxia, neuropathy, hyperglycemia, and ischemia that contribute to a delayed and reduced healing response result in chronic slow healing wounds. Here, key differences in native versus diabetic wound healing during each phase of healing are discussed, and the roles of cells and their secreted cytokines which regulate this process are outlined. Monocyte chemoattractant protein‐1 (MCP‐1) is a pro‐inflammatory mediator which plays a key role in modulating angiogenesis. Its importance in diabetic wound healing as well as recent work using MCP‐1 and similar chemokines to reduce inflammation and improve healing are reviewed. The delayed healing response observed in diabetic patients often results in the formation of slow healing wounds, commonly presenting in the lower extremities as diabetic foot ulcers (DFUs); classification systems and current treatment options for DFUs, including debridement, off‐loading, and amputation are outlined. Common dressing strategies are highlighted, and recent work developing biocompatible and bioactive hydrogels to address and hasten chronic wound healing is focused on.
High
levels of serum low-density lipoprotein (LDL) cholesterol
contribute to atherosclerosis, a key risk factor of cardiovascular
diseases. PCSK9 is a circulatory enzyme that downregulates expression
of hepatic LDL receptors, concomitantly increasing serum LDL-C. This
work investigates a small, self-assembling peptide, EPep2-8, as a
peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising
a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8,
previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly
of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular
β-sheet secondary structure. Intermolecular interactions between
nanofibers drive EPep2-8 to form a thixotropic and cytocompatible
hydrogel in aqueous and charge-neutral solutions. These properties
enable EPep2-8 to be delivered as an in situ depot for regulation
of lipoprotein homeostasis. In surface plasmon resonance studies,
EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent,
and irreversible dissociation, significantly improving the binding
affinity of Pep2-8 alone (K
D = 667 ±
48 nM). Increased binding affinity of EPep2-8 is primarily due to
the superstoichiometric interaction of the peptide with PCSK9. Promisingly,
EPep2-8 retains bioactivity in vitro, engendering
dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly
on a target site may be a simple method to improve the affinity of
peptide inhibitors.
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