Dimethyl fumarate protects against intestine damage in necrotizing enterocolitis by inhibiting the Toll-like receptor (TLR) inflammatory signaling pathway

Yanhong Mi; Xiaoxiao Xie; Zhongkun Bao; Xiaoyu Xiong; Xinhong Wang; Hongxi Zhang

doi:10.1016/j.tice.2022.102003

Dimethyl fumarate protects against intestine damage in necrotizing enterocolitis by inhibiting the Toll-like receptor (TLR) inflammatory signaling pathway

Tissue Cell. 2023 Apr:81:102003. doi: 10.1016/j.tice.2022.102003. Epub 2022 Dec 16.

Authors

Yanhong Mi¹, Xiaoxiao Xie², Zhongkun Bao³, Xiaoyu Xiong⁴, Xinhong Wang⁵, Hongxi Zhang⁶

Affiliations

¹ Department of Radiology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, Zhejiang Province, China.
² Department of Radiology, Wu YunShan Hospital of Hangzhou, Hangzhou, Zhejiang Province, China.
³ Department of Radiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
⁴ Department of Neonatology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
⁵ Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
⁶ Department of Radiology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, Zhejiang Province, China. Electronic address: hongxizhang11@zju.edu.cn.

PMID: 36682224
DOI: 10.1016/j.tice.2022.102003

Abstract

Objective: Necrotizing enterocolitis (NEC) is a severe disease in newborns, this study aimed to investigate the protective effect of dimethyl fumarate (DMF) on NEC and its possible mechanism.

Methods: In vivo, the mice were divided into the control, NEC, and NEC+DMF group. The NEC model was established by artificial feeding, hypoxic for 4 days, and lipopolysaccharide (LPS) stimulation on day 2 and day 3. DMF (25 mg/kg/d) was administered to NEC mice on day 1 and day 3. On the 11th day, the blood and intestinal tissues of mice were taken for enzyme-linked immunosorbent assay (ELISA), pathological examination, quantitative real-time PCR (RT-qPCR), Western blot, and immunohistochemical (IHC) detection. In vitro, human colorectal cells (FHC) were induced by LPS (100 ng/mL) and was divided into the control, LPS, and LPS+DMF group. The effect of DMF (20 μM) on cell viability and TLR4 signal transduction was detected by MTT and RT-qPCR, respectively.

Results: Compared to the NEC mice, DMF attenuated NEC-induced weight loss and abdominal distension diarrhea in mice, and alleviated NEC-induced intestinal pathological injuries. In addition, DMF reduced the expression of IL-6, IL-1β, TNF-α, NF-κB, and TLR4 in NEC mice intestinal tissues. Furthermore, DMF inhibited NEC-induced intestinal cell apoptosis as well as the protein expression of BCL2-Associated X (BAX), caspase-3, caspase-9, and increased Bcl-2 (B-cell lymphoma-2) expression. In vitro, DMF improved cell viability, and restrained NF-κB and TLR4 expression in LPS-induced NEC cells.

Conclusion: DMF has a protective effect against intestine damage of NEC, which is related to the inhibition of the TLR signaling pathway, alleviating the inflammatory response.

Keywords: Dimethyl fumarate; Inflammatory reaction; Necrotizing enterocolitis; Toll-Like Receptors.

MeSH terms

Animals
Dimethyl Fumarate / pharmacology
Disease Models, Animal
Enterocolitis, Necrotizing* / drug therapy
Enterocolitis, Necrotizing* / metabolism
Enterocolitis, Necrotizing* / prevention & control
Humans
Infant, Newborn
Intestines / pathology
Lipopolysaccharides / toxicity
Mice
NF-kappa B* / metabolism
Signal Transduction
Toll-Like Receptor 4 / metabolism

Substances

NF-kappa B
Dimethyl Fumarate
Toll-Like Receptor 4
Lipopolysaccharides