A highly efficient hybrid peptide ameliorates intestinal inflammation and mucosal barrier damage by neutralizing lipopolysaccharides and antagonizing the lipopolysaccharide‐receptor interaction
| Autor: | Lulu Zhang, Paul Mozdziak, James N. Petitte, Henan Guo, Rujuan Wu, Baseer Ahmad, Dayong Si, Xubiao Wei, Manyi Zhang, Zhongxuan Li, Rijun Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine Lipopolysaccharide Anti-Inflammatory Agents Peptide Biochemistry Cell Line Proinflammatory cytokine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics Animals Intestinal Mucosa Receptor Cytotoxicity Molecular Biology Inflammation chemistry.chemical_classification Toll-like receptor Mucous Membrane Interleukin-6 Tumor Necrosis Factor-alpha Chemistry NF-kappa B Cell biology Mice Inbred C57BL Toll-Like Receptor 4 RAW 264.7 Cells 030104 developmental biology TLR4 Tumor necrosis factor alpha Peptides 030217 neurology & neurosurgery Antimicrobial Cationic Peptides Signal Transduction Biotechnology |
| Zdroj: | The FASEB Journal. 34:16049-16072 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | Intestinal inflammatory disorders, such as inflammatory bowel disease, are major contributors to mortality and morbidity in humans and animals worldwide. While some native peptides have great potential as therapeutic agents against intestinal inflammation, potential cytotoxicity, anti-inciting action, and suppression of anti-inflammatory activity may limit their development as anti-inflammatory agents. Peptide hybridization is an effective approach for the design and engineering of novel functional peptides because hybrid peptides combine the advantages and benefits of various native peptides. In the present study, a novel hybrid anti-inflammatory peptide that combines the active center of Cecropin A (C) and the core functional region of LL-37 (L) was designed [C-L peptide; C (1-8)-L (17-30)] through in silico analysis to reduce cytotoxicity and improve the anti-inflammatory activity of the parental peptides. The resulting C-L peptide exhibited lower cytotoxicity than either C or L peptides alone. C-L also exerted a protective effect against lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages and in the intestines of a mouse model. The hybrid peptide exhibited increased anti-inflammatory activity compared to the parental peptides. C-L plays a role in protecting intestinal tissue from damage, LPS-induced weight loss, and leukocyte infiltration. In addition, C-L reduces the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and interferon-gamma (IFN-γ), as well as reduces cell apoptosis. It also reduced mucosal barrier damage caused by LPS. The anti-inflammatory effects of the hybrid peptide were mainly attributed to its LPS-neutralizing activity and antagonizing the activation of LPS-induced Toll-like receptor 4-myeloid differentiation factor 2 (TLR4/MD2). The peptide also affected the TLR4-(nuclear factor κB) signaling pathway, modulating the inflammatory response upon LPS stimulation. Collectively, these findings suggest that the newly designed peptide, C-L, could be developed into a novel anti-inflammatory agent for animals or humans. |
| Databáze: | OpenAIRE |
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