Laboratory of Feed Biotechnology, State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA.
Int J Mol Sci. 2019 Aug 15;20(16):3974. doi: 10.3390/ijms20163974.
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.
肠道炎症是一种由肠道免疫失调引起的炎症性疾病。它会增加患肠道癌症的风险，而肠道癌症是全球常见的恶性肿瘤。作为一类新型的抗炎药物，天然肽类药物具有治疗多种肠道炎症疾病的潜力；然而，它们的潜在细胞毒性和较差的抗炎活性和稳定性阻碍了它们的发展。杂交已被提议用于解决这个问题。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）。我们在体外测试了其半衰期和细胞毒性，结果表明，与亲本肽相比，杂合肽具有更长的半衰期和更低的细胞毒性。我们还检测了 LTP 对脂多糖（LPS）诱导的肠道炎症的抗炎作用及其机制。结果表明，LTP 可有效预防 LPS 诱导的体重减轻、肠道组织损伤、白细胞浸润和炎症组织学证据。此外，LTP 降低了肿瘤坏死因子-α、干扰素-γ和白细胞介素-6 的水平；增加了紧密连接蛋白-1 和紧密连接蛋白的表达；并降低了 LPS 处理的小鼠空肠的通透性。值得注意的是，LTP 的作用似乎比亲本肽 LL-37 和 TP5 更强。LTP 的抗炎作用可能与中和 LPS、抑制氧化应激和抑制 NF-κB 信号通路有关。本研究结果表明，LTP 可能是一种治疗肠道炎症的有效治疗药物。
