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.

中文翻译：

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一种高效的杂化肽通过中和脂多糖和拮抗脂多糖-受体相互作用来改善肠道炎症和粘膜屏障损伤

肠道炎症性疾病，例如炎症性肠病，是世界范围内人类和动物死亡率和发病率的主要原因。虽然一些天然肽具有作为肠道炎症治疗剂的巨大潜力，但潜在的细胞毒性、抗刺激作用和抗炎活性的抑制可能会限制它们作为抗炎剂的发展。肽杂交是设计和改造新型功能肽的有效方法，因为杂交肽结合了各种天然肽的优点和优点。在本研究中，设计了一种新型混合抗炎肽，它结合了天蚕素 A (C) 的活性中心和 LL-37 (L) 的核心功能区 [C-L 肽；C (1-8)-L (17-30)] 通过计算机分析降低细胞毒性并提高亲本肽的抗炎活性。由此产生的 C-L 肽表现出比单独的 C 或 L 肽更低的细胞毒性。C-L 还在 RAW264.7 巨噬细胞和小鼠模型的肠道中对脂多糖 (LPS) 诱导的炎症反应发挥保护作用。与亲本肽相比，杂合肽表现出更高的抗炎活性。C-L 在保护肠道组织免受损伤、LPS 诱导的体重减轻和白细胞浸润方面发挥作用。此外，C-L 降低肿瘤坏死因子-α (TNF-α)、白细胞介素-6 (IL-6)、IL-1β 和干扰素-γ (IFN-γ) 的表达水平，并减少细胞细胞凋亡。它还减少了由 LPS 引起的粘膜屏障损伤。杂合肽的抗炎作用主要归因于其 LPS 中和活性和拮抗 LPS 诱导的 Toll 样受体 4-骨髓分化因子 2 (TLR4/MD2) 的激活。该肽还影响 TLR4-（核因子 κB）信号通路，调节 LPS 刺激后的炎症反应。总的来说，这些发现表明，新设计的肽 C-L 可以开发成一种用于动物或人类的新型抗炎剂。