Abstract
Intestinal inflammatory disorders, such as inflammatory bowel disease (IBD), are associated with increased pro-inflammatory cytokine secretion in the intestines. Furthermore, intestinal inflammation increases the risk of enteric cancer, which is a common malignancy globally. Native anti-inflammatory peptides are a class of anti-inflammatory agents that could be used in the treatment of several intestinal inflammation conditions. However, potential cytotoxicity, and poor anti-inflammatory activity have prevented their development as anti-inflammatory agents. Therefore, in this study, we designed and developed a novel hybrid peptide for the treatment of intestinal inflammation. Eight hybrid peptides were designed by combining the active centers of antimicrobial peptides, including LL-37 (13-36), YW12D, innate defense regulator 1, and cathelicidin 2 (1-13) with thymopentin or the active center of thymosin alpha 1 (Tα1) (17-24). The hybrid peptide, LL-37-Tα1 (LTA), had improved anti-inflammatory activity with minimal cytotoxicity. LTA was screened by molecule docking and in vitro experiments. Likewise, its anti-inflammatory effects and mechanisms were also evaluated using a lipopolysaccharide (LPS)-induced intestinal inflammation murine model. The results showed that LTA prevented LPS-induced impairment in the jejunum epithelium tissues and infiltration of leukocytes, which are both histological markers of inflammation. Additionally, LTA decreased the levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-6, and interleukin-1β. LTA increased the expression of zonula occludens-1 and occludin, and reduced permeability and apoptosis in the jejunum of LPS-treated mice. Additionally, its anti-inflammatory effect is associated with neutralizing LPS, binding to the Toll-like receptor 4-myeloid differentiation factor 2 (TLR4/MD-2) complex, and modulating the nuclear factor-kappa B signal transduction pathway. The findings of this study suggest that LTA may be an effective therapeutic agent in the treatment of intestinal inflammation.
Highlights
Intestinal inflammation is a defensive response against infections and damage caused by microbiological toxins or noxious substances [1]
The hybrid peptides were constructed by combining the active center of LL-37, YW12D, Innate defense regulator (IDR)-1, and cathelicidin 2 (CATH2) with the TP5 or the active center of Thymosin alpha 1 (Tα1).The amino acid sequences of the parental and hybrid peptides are listed in the Table 1
As an initial screen of the anti-inflammatory peptides, the binding modes of the eight hybrid peptides to molecular dynamics (MD)-2 were analyzed by molecular docking
Summary
Intestinal inflammation is a defensive response against infections and damage caused by microbiological toxins or noxious substances [1]. Clinical symptoms of intestinal inflammation include abdominal pain, diarrhea, rectal bleeding, weight loss, malnutrition, and fever [2]. Intestinal patients, such as those with inflammatory bowel disease (IBD), have an increased risk of developing colorectal and small intestinal cancers [3–5]. Intestinal inflammation is treated with corticosteroids, glucocorticoids [7, 8]. This treatment can successfully decrease the production of pro-inflammatory cytokines and chemokines, cell adhesion molecules, and other key mediators of inflammation [9]; prolonged use of corticosteroids is related to side effects, including impaired wound healing, mild hirsutism, linear growth inhibition, myopathy, osteoporosis, osteonecrosis, peptic ulcers, pancreatitis, and candidiasis [10, 11]. There is a need to identify and develop new drugs that have both the desired efficiency and improved safety
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
