肠道炎症是由肠道中的免疫失调引起的炎性疾病。它可以增加患肠癌的风险,这是全球常见的恶性肿瘤。作为一类新型的抗炎药,天然肽有可能用于治疗几种肠道炎症;然而,它们潜在的细胞毒性和较差的抗炎活性和稳定性阻止了它们的发展。已经提出杂交来克服这个问题。因此,在这项研究中,我们通过将LL-37(13-36)的活性中心与TP5结合,设计了一种杂合肽(LL-37-TP5,LTP)。半衰期和细胞毒性在体外测试,杂合肽显示比其亲本肽更长的半衰期和更低的细胞毒性。我们还在小鼠模型中检测了LTP对脂多糖(LPS)诱导的肠道炎症的抗炎作用和机制。结果表明,LTP可有效预防LPS诱导的体重下降,肠组织受损,白细胞浸润,和炎症的组织学证据。此外,LTP降低了肿瘤坏死因子-α的水平,干扰素-γ,和白细胞介素6;增加了小带闭塞蛋白1和闭塞蛋白的表达;并降低了LPS处理的小鼠空肠的通透性。值得注意的是,LTP似乎比亲本肽LL-37和TP5更有效。LTP的抗炎作用可能与中和LPS有关。抑制氧化应激,和抑制NF-κB信号通路。这项研究的结果表明,LTP可能是治疗肠道炎症的有效治疗剂。
Intestinal inflammation is an inflammatory disease resulting from immune dysregulation in the gut. It can increase the risk of enteric cancer, which is a common malignancy globally. As a new class of anti-inflammatory agents, native peptides have potential for use in the treatment of several intestinal inflammation conditions; however, their potential cytotoxicity and poor anti-inflammatory activity and stability have prevented their development. Hybridization has been proposed to overcome this problem. Thus, in this study, we designed a hybrid peptide (LL-37-TP5, LTP) by combing the active centre of LL-37 (13-36) with TP5. The half-life and cytotoxicity were tested in vitro, and the hybrid peptide showed a longer half-life and lower cytotoxicity than its parental peptides. We also detected the anti-inflammatory effects and mechanisms of LTP on Lipopolysaccharide (LPS)-induced intestinal inflammation in murine model. The results showed that LTP effectively prevented LPS-induced weight loss, impairment of intestinal tissues, leukocyte infiltration, and histological evidence of inflammation. Additionally, LTP decreased the levels of tumour necrosis factor-alpha, interferon-gamma, and interleukin-6; increased the expression of zonula occludens-1 and occludin; and reduced permeability in the jejunum of LPS-treated mice. Notably, LTP appeared to be more potent than the parental peptides LL-37 and TP5. The anti-inflammatory effects of LTP may be associated with the neutralization of LPS, inhibition of oxidative stress, and inhibition of the NF-κB signalling pathway. The findings of this study suggest that LTP might be an effective therapeutic agent for treating intestinal inflammation.