von Willebrand factor is a useful predictor and prognostic measure for TA-TMA, which may help clinicians identify and manage this life-threatening disease earlier.
Antimicrobial peptides (AMPs) play pivotal roles in the innate defense of vertebrates. A novel AMP (cathelicidin-PY) has been identified from the skin secretions of the frog Paa yunnanensis . Cathelicidin-PY has an amino acid sequence of RKCNFLCKLKEKLRTVITSHIDKVLRPQG. Nuclear magnetic resonance (NMR) spectroscopy analysis revealed that cathelicidin-PY adopts a tertiary structure with a mostly positively charged surface containing a helix (Thr15-Ser19). It possesses strong antimicrobial activity, low hemolytic activity, low cytotoxicity against RAW 264.7 cells, and strong anti-inflammatory activity. The action of antimicrobial activity of cathelicidin-PY is through the destruction of the cell membrane. Moreover, cathelicidin-PY exerts anti-inflammatory activity by inhibiting the production of nitric oxide (NO) and inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Cathelicidin-PY inhibits the activation of Toll-like receptor 4 (TLR4) inflammatory response pathways induced by lipopolysaccharide (LPS). The NMR titration experiments indicated that cathelicidin-PY can bind to LPS. In conclusion, we have identified a novel potent peptide antibiotic with both antimicrobial and anti-inflammatory activities and laid the groundwork for future research and development.
Abstract Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia . Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.
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