Dataset Information

Human ?-defensin-3 reduces excessive autophagy in intestinal epithelial cells and in experimental necrotizing enterocolitis.

ABSTRACT: Necrotizing enterocolitis (NEC) is a leading cause of mortality in preterm newborns. Intestinal barrier dysfunction is one key event in NEC pathogenesis. Human ?-defensin-3 (hBD3), one member of cationic host defence peptides, was reported to reduce the development of necrotizing enterocolitis in a neonatal rat model. And autophagy was induced in the intestine of human and animals with NEC. We hypothesized that regulation of autophagy might play a critical role in hBD3-mediated protection against NEC injury. Autophagy activity was evaluated both in intestinal epithelial cells and in NEC models. Newborn Sprague-Dawley rats were divided randomly into four groups: Control?+?NS, Control?+?rapamycin, NEC?+?NS, and NEC?+?hBD3. Body weight, histological score, survival time, enterocyte migration and mucosal barrier were recorded. Our results showed that hBD3 pretreatment could effectively inhibit autophagy activity in cultured IEC-6 and Caco2 enterocytes, and CXCR4 might be involved in hBD3-mediated autophagy suppression. Moreover, hBD3-induced inhibition of autophagy significantly promoted the intestinal epithelial cell migration by wound healing assay and transwell migration assay. In the rat model of NEC, hBD3 could noticeably reduce the expression of autophagy-activated proteins, down-regulate the expression of inflammatory mediators, and promote the mucosal integrity. Our data suggest an additional role of hBD3-mediated protection against intestinal mucosal injury: inhibition of over-activated autophagy in enterocytes.

SUBMITTER: Chen L

PROVIDER: S-EPMC6934505 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human β-defensin-3 reduces excessive autophagy in intestinal epithelial cells and in experimental necrotizing enterocolitis.

Chen Liping L Lv Zhibao Z Gao Zhimei Z Ge Guijie G Wang Xueli X Zhou Junmei J Sheng Qingfeng Q

Scientific reports 20191227 1

Necrotizing enterocolitis (NEC) is a leading cause of mortality in preterm newborns. Intestinal barrier dysfunction is one key event in NEC pathogenesis. Human β-defensin-3 (hBD3), one member of cationic host defence peptides, was reported to reduce the development of necrotizing enterocolitis in a neonatal rat model. And autophagy was induced in the intestine of human and animals with NEC. We hypothesized that regulation of autophagy might play a critical role in hBD3-mediated protection agains ...[more]

PMID: 31882811

Similar Datasets

Project description:BackgroundNecrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis.MethodsFecal samples from human neonates and mouse pups were analyzed by HPLC - MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting.ResultsThe levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (P <0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (P <0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of Enterobacteriaceae and a lower abundance of Lactobacillaceae and Lactobacillus (P <0.05). In the murine models, relative to the control group, increased abundance was observed for Clostridiaceae, Enterococcaceae, Clostridium_sensu_stricto_1, and Enterococcus, whereas decreased abundance was observed for Lactobacillaceae and Lactobacillus (P <0.05). Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a.ConclusionSuccinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.

Project description:BackgroundNecrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease primarily affecting preterm neonates. Neonates with NEC suffer from a degree of neurodevelopmental delay that is not explained by prematurity alone. There is a need to understand the pathogenesis of neurodevelopmental delay in NEC. In this study, we assessed the macroscopic and microscopic changes that occur to brain cell populations in specific brain regions in a neonatal mouse model of NEC. Moreover, we investigated the role of intestinal inflammation as part of the mechanism responsible for the changes observed in the brain of pups with NEC.MethodsBrains of mice were assessed for gross morphology and cerebral cortex thickness (using histology). Markers for mature neurons, oligodendrocytes, neural progenitor cells, microglia, and astrocytes were used to quantify their cell populations in different regions of the brain. Levels of cell apoptosis in the brain were measured by Western blotting and immunohistochemistry. Endoplasmic reticulum (ER) stress markers and levels of pro-inflammatory cytokines (in the ileum and brain) were measured by RT-qPCR and Western blotting. A Pearson test was used to correlate the levels of cytokines (ELISA) in the brain and ileum and to correlate activated microglia and astrocyte populations to the severity of NEC.ResultsNEC pups had smaller brain weights, higher brain-to-body weight ratios, and thinner cortices compared to control pups. NEC pups had increased levels of apoptosis and ER stress. In addition, NEC was associated with a reduction in the number of neurons, oligodendrocytes, and neural progenitors in specific regions of the brain. Levels of pro-inflammatory cytokines and the density of activated microglia and astrocytes were increased in the brain and positively correlated with the increase in the levels pro-inflammatory cytokines in the gut and the severity of NEC damage respectively.ConclusionsNEC is associated with severe changes in brain morphology, a pro-inflammatory response in the brain that alters cell homeostasis and density of brain cell populations in specific cerebral regions. We show that the severity of neuroinflammation is associated with the severity of NEC. Our findings suggest that early intervention during NEC may reduce the chance of acute neuroinflammation and cerebral damage.

Dataset Information

Human ?-defensin-3 reduces excessive autophagy in intestinal epithelial cells and in experimental necrotizing enterocolitis.

Publications

Human β-defensin-3 reduces excessive autophagy in intestinal epithelial cells and in experimental necrotizing enterocolitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets