Tang Yuan, Zhao Xuelian, Ding Zetao, Wang Junyong, Zhang Jing, Zhou Yichen, Ahmat Marhaba, Wang Hao, Zhu Yang, Ahmad Baseer, Abbas Zaheer, Si Dayong, Zhang Rijun, Wei Xubiao
Laboratory of Feed Biotechnology, State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
Institute of Microbiology, Xinjiang Academy of Agricultural Sciences, Urumqi 830091, China.
Antioxidants (Basel). 2025 Sep 14;14(9):1117. doi: 10.3390/antiox14091117.
Lipopolysaccharide (LPS), an essential structural molecule in the outer membrane of Gram-negative bacteria, is recognized as a principal trigger of inflammatory responses and oxidative stress. Thus, the control and clearance of LPS is essential to inhibit LPS-induced excessive inflammation, oxidative stress, and liver injury. In recent years, some native bioactive peptides, such as human β-defensin 126 (DEFB126) and thymopentin (TP5), have been reported to have inhibitory effects against LPS-induced inflammation and oxidative stress. However, the cytotoxicity, weak stability, and poor biological activity have hindered their practical application and clinical development. The development of novel hybrid peptides is a promising approach for overcoming these problems. In this study, we designed a novel hybrid peptide [DTP, DEFB126 (1-39)-TP5] that combines the active center of DEFB126 and full-length thymopentin (TP5). Compared to the parental peptides, DTP has a longer half-life, lower cytotoxicity, and greater anti-inflammatory and antioxidant activity. The anti-inflammatory and antioxidant effects of DTP were demonstrated in a murine LPS-induced sepsis model, which showed that DTP successfully inhibited the indicators associated with LPS-induced liver injury; decreased the contents of TNF-α, IL-6, and IL-1β; increased the level of glutathione (GSH); and improved the activities of catalase (CAT) and superoxide dismutase (SOD). Furthermore, our study revealed that the anti-inflammatory and antioxidant activities of DTP were associated with LPS neutralization, blockade of LPS binding to the Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex, reduction in reactive oxygen species content, and inhibition of the activation of the nuclear factor kappa-B (NF-кB) signaling pathway. These results elucidate the structural and functional properties of the peptide DTP, reveal its underlying molecular mechanisms, and shed light on its potential as a multifunctional agent for applications in agriculture, food technology, and clinical therapeutics.
脂多糖（LPS）是革兰氏阴性菌外膜中的一种重要结构分子，被认为是炎症反应和氧化应激的主要触发因素。因此，控制和清除LPS对于抑制LPS诱导的过度炎症、氧化应激和肝损伤至关重要。近年来，一些天然生物活性肽，如人β-防御素126（DEFB126）和胸腺五肽（TP5），已被报道对LPS诱导的炎症和氧化应激具有抑制作用。然而，细胞毒性、稳定性差和生物活性低阻碍了它们的实际应用和临床开发。开发新型杂合肽是克服这些问题的一种有前途的方法。在本研究中，我们设计了一种新型杂合肽[DTP，DEFB126（1-39）-TP5]，它结合了DEFB126的活性中心和全长胸腺五肽（TP5）。与亲本肽相比，DTP具有更长的半衰期、更低的细胞毒性以及更强的抗炎和抗氧化活性。DTP的抗炎和抗氧化作用在小鼠LPS诱导的脓毒症模型中得到证实，该模型表明DTP成功抑制了与LPS诱导的肝损伤相关的指标；降低了TNF-α、IL-6和IL-1β的含量；提高了谷胱甘肽（GSH）水平；并改善了过氧化氢酶（CAT）和超氧化物歧化酶（SOD）的活性。此外，我们的研究表明，DTP的抗炎和抗氧化活性与LPS中和、LPS与Toll样受体4/髓样分化因子2（TLR4/MD-2）复合物结合的阻断、活性氧含量的降低以及核因子κB（NF-κB）信号通路激活的抑制有关。这些结果阐明了肽DTP的结构和功能特性，揭示了其潜在的分子机制，并为其作为多功能剂在农业、食品技术和临床治疗中的应用潜力提供了线索。
